USPatent applicationPatented

Gene products related to werner's syndrome

Granted 24 Jun 2003 · 3 office actions

Current assignee: National Institutes of Health · originally Ying-Hui Fu

Law firm: Law firm · Log in to unlock

Attorney: Attorney · Log in to unlock

Inventors: Ying-Hui Fu, Chang-En Yu, Junko Oshima, John T. Mulligan +1 · Examiner: Karen Cochrane Carlson · AU 1653 · TC 1600

Application· this page
9618166
filed 17 Jul 2000
Publication
Not published
not published
Patent
US 6,583,112
granted 24 Jun 2003

Life of the application

11 dated events
⤢ drag to zoom199520002005201020152020ProsecutionOwnershipTerm & fees
ProsecutionOwnershipTerm & feeshover for detail · click to open

Abstract

The present invention discloses nucleic acid molecules encoding WRN gene products, expression vectors and host cells suitable for expressing such products.

Description

78 parts
›This application is a continuation of U.S. patent…

This application is a continuation of U.S. patent application Ser. No. 08/781,891, filed Dec. 27, 1996, now U.S. Pat. No. 6,090,620, which application is a continuation-in-part of U.S. application Ser. No. 08/632,175, filed Apr. 12, 1996, now abandoned; which is a continuation-in-part of U.S. patent application Ser. No. 08/594,242, filed Jan. 30, 1996, now abandoned; which is a continuation-in-part of U.S. patent application Ser. No. 08/580,539, filed Dec. 29, 1995, now abandoned. This application also claims priority to U.S. patent application Ser. No. 60/009,409 filed Dec. 29, 1995, and U.S. patent application Ser. No. 60/010,835 filed Jan. 30, 1996.

›TECHNICAL FIELD

The present invention relates generally to Werner's Syndrome and more specifically to methods and compositions suitable for use in diagnosis and treatment of Werner's Syndrome.

›BACKGROUND OF THE INVENTION

Werner Syndrome (WS) is an autosomal recessive disorder with a complex phenotype. The disorder manifests itself in premature occurrence of age-related diseases and premature appearance of some of the physical features of normal aging. The onset of symptoms usually occurs after adolescence. The disorder progresses throughout life and typically patients have a shortened life expectancy with a modal age of death at 47. The prevalence of Werner Syndrome is estimated for heterozygotes to be 1-5 per 1,000 individuals, and for homozygotes to be 1-22 per 1,000,000 individuals.

Clinical symptoms of Werner Syndrome include both a prevalence of age-related diseases and physical features of aging. Such diseases include arteriosclerosis and heart disease, both benign and malignant neoplasms (usually sarcomas), diabetes mellitus, osteoporosis, and ocular cataracts. The physical appearance of WS patients is often manifest as a short stature, premature graying or loss sarcomas), diabetes mellitus, osteoporosis, and ocular cataracts. The physical appearance of WS patients is often manifest as a short stature, premature graying or loss of hair, hypogonadism, altered skin pigmentation, hyperkeratosis, tight skin, bird-like facies, cutaneous atrophy, cutaneous leg ulcers, and telangiectasia. Most of these diseases and features are present in from 40-90% of WS patients. Diagnosis of WS relies mainly upon the appearance of a certain number of these diseases and features. One biochemical test, excessive excretion of hyaluronic acid in urine, may also be used to assist diagnosis.

In addition to the noted signs and symptoms of aging, Werner Syndrome mimics normal aging as evidenced by the replicative potential of fibroblasts isolated from WS subjects. Replication potential of fibroblasts is reduced in these patients compared to fibroblasts isolated from age-matched controls, and is comparable to the replicative potential of fibroblasts taken from elderly subjects. Moreover, an increased mutation rate has been described in WS patients. Such abnormality is manifest as chromosomal instability, such as inversions, reciprocal translocations, deletions, and pseudodiploidy, and as increased mutation rate at the hypoxanthine phosphoribosyl transferase (HPRT) gene.

Werner Syndrome has been recognized as an autosomal recessive disorder. Goto et al. (Goto et al., Nature 355:735-738, 1992) mapped the WS gene onto the short arm of chromosome 8, using 21 affected Japanese families. The gene is located between marker D8S87 and ankyrin (ANK1). More recently, more refined mapping has pinpointed the WS gene to a region between marker D8S131 and D8S87, an 8.3 cM interval. Identification of the gene and gene product should add considerably to understanding the basis of Werner Syndrome and enable biochemical and genetic approaches to diagnosis and treatment.

The present invention provides a novel, previously unidentified gene for Werner Syndrome and compositions for diagnosis and treatment of WS, and further provides other related advantages.

›SUMMARY OF THE INVENTION · 1 of 2

Briefly stated, the present invention provides isolated nucleic acid molecules encoding the WRN gene, as well as portions thereof, representative of which are provided in the Figures. The protein which is encoded by the WRN gene is referred to hereinafter as the “WRN protein”. Within other embodiments, nucleic acid molecules are provided which encode a mutant WRN gene product that increases the probability of Werner's Syndrome (in a statistically significant manner). Representative illustrations of such mutants are provided in Example 3.

Within other aspects of the present invention, isolated nucleic acid molecules are provided, selected from the group consisting of (a) an isolated nucleic acid molecule as set forth in the Figures, or complementary sequence thereof, (b) an isolated nucleic acid molecule that specifically hybridizes to the nucleic acid molecule of (a) under conditions of high stringency, and (c) an isolated nucleic acid that encodes a WRN gene product (WRN protein). As utilized herein, it should be understood that a nucleic acid molecule hybridizes “specifically” to an WRN gene (or related sequence) if it hybridizes detectably to such a sequence, but does not significantly or detectably hybridize to the Bloom's Syndrome gene (Ellis et al., Cell 83:655-666, 1995).

Within other aspects, expression vectors are provided comprising a promoter operably linked to one of the nucleic acid molecule described above. Representative examples of suitable promoters include tissue-specific promoters, as well as promoters such as the CMV I-E promoter, SV40 early promoter and MuLV LTR. Within related aspects, viral vectors are provided that are capable of directing the expression of a nucleic acid molecule as described above. Representative examples of such viral vectors include herpes simplex viral vectors, adenoviral vectors, adenovirus-associated viral vectors and retroviral vectors. Also provided are host cells (e.g., human, dog, monkey, rat or mouse cells) which carry the above-described vectors.

Within other aspects of the present invention, isolated proteins or polypeptides are provided comprising a WRN gene product, as well as peptides of greater than 12, 13 or 20 amino acids. Within another embodiment, the protein is a mutant WRN gene product that increases the probability of Werner's Syndrome.

Within yet another aspect of the present invention, methods of treating or preventing Werner's Syndrome are provided (as well as for related diseases which are discussed in more detail below), comprising the step of administering to a patient a vector containing or expressing a nucleic acid molecule as described above, thereby reducing the likelihood or delaying the onset of Werner's Syndrome (or the related disease) in the patient. Within a related aspect, methods of treating or preventing Werner's Syndrome (and related diseases) are provided, comprising the step of administering to a patient a protein as described above, thereby reducing the likelihood or delaying the onset of Werner's Syndrome (or a related disease) in the patient. Within certain embodiments, the above methods may be accomplished by in vivo administration.

Also provided by the present invention are pharmaceutical compositions comprising a nucleic acid molecule, vector, host cell, protein, or antibody as described above, along with a pharmaceutically acceptable carrier or diluent.

Within other aspects of the present invention, antibodies are provided which specifically bind to an WRN protein or to unique peptides derived therefrom. As utilized herein, it should be understood that an antibody is specific for an WRN protein (or peptide) if it binds detectably, and with a K d of 10 −7 M or less (e.g., 10 −8 M, 10 −9 M, etc.), but does not bind detectably (or with an affinity of greater than 10 −7 M, (e.g., 10 −6 M, 10 −5 M, etc.) to an unrelated helicase (e.g., the Bloom's Syndrome gene, supra). Also provided are hybridomas which are capable of producing such antibodies.

Within other aspects of the present invention, nucleic acid probes are provided which are capable of specifically hybridizing (as defined below) to an WRN gene under conditions of high stringency. Within one related aspect, such probes comprise at least a portion of the nucleotide sequence shown in the Figures, or its complementary sequence, the probe being capable of specifically hybridizing to a mutant WRN gene under conditions of high stringency. Representative probes of the present invention are generally at least 12 nucleotide bases in length, although they may be 14, 16, 18 bases or longer. Also provided are primer pairs capable of specifically amplifying all or a portion of any of the nucleic acid molecules disclosed herein.

Within other aspects of the invention, methods are provided for diagnosing a patient having an increased likelihood of contracting Werner's Syndrome (or a related disease), comprising the steps of (a) obtaining from a patient a biological sample containing nucleic acid, (b) incubating the nucleic acid with a probe which is capable of specifically hybridizing to a mutant WRN gene under conditions and for time sufficient to allow hybridization to occur, and (c) detecting the presence of hybridized probe, and thereby determining that said patient has an increased likelihood of contracting Werner's Syndrome (or a related disease). Within another aspect, methods are provided comprising the steps of (a) obtaining from a patient a biological sample containing nucleic acid, (b) amplifying a selected nucleic acid sequence associated with a mutant WRN gene, and (c) detecting the presence of an amplified nucleic acid sequence, and thereby determining that the patient has an increased likelihood of contracting Werner's Syndrome (or a related disease). Suitable biological samples include nucleated cells obtained from the peripheral blood, from buccal swabs, or brain tissue.

Within another aspect, peptide vaccines are provided which comprise a portion of a mutant WRN gene product containing a mutation, in combination with a pharmaceutically acceptable carrier or diluent.

›SUMMARY OF THE INVENTION · 2 of 2

Within yet another aspect, transgenic animals are provided whose germ cells and somatic cells contain a WRN gene (or lack thereof, i.e., a “knockout”) which is operably linked to a promoter effective for the expression of the gene, the gene being introduced into the animal, or an ancestor of the animal, at an embryonic stage. Within one embodiment, the animal is a mouse, rat or dog. Within other embodiments, the WRN gene is expressed from a vector as described above. Within yet another embodiment, the WRN gene encodes a mutant WRN gene product.

These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain procedures or compositions (e.g., plasmids, etc.), and are therefore incorporated by reference in their entirety.

›BRIEF DESCRIPTION OF THE DRAWINGS AND SEQUENCE LISTING

FIG. 1 is a genetic and physical map of the WRN region. The genetic map (A) of the region is sex-equal with distances given in cM. The polymorphic loci used (B) are di-nucleotide and tri-nucleotide repeat STRP loci. The physical map presented (C) has approximate distances determined from sizes of over-lapping non-chimeric YACs, and from genomic DNA sequence from overlapping P1 clones 2233, 2253, 3833, 2236, and 3101. Marker order was determined from the sequence-tagged site (STS) content of YACs, P1 clones, and cosmid clones and from genomic DNA sequence from P1 clones. The YACs presented (D) represent the minimal tiling and are the YACs used for cDNA selection experiments. The P1 and cosmid clones needed for the minimum tiling path are shown (E). Clones shown are P1 clones except for 8C11, which is a cosmid clone. Clone order was established by STS content.

FIGS. 2A and 2B are the DNA (SEQ ID No. 70) and predicted amino acid (SEQ ID No. 71) sequences of the WRN gene transcript. The one-letter amino acid code is used in FIG. 2 B.

FIGS. 3A-3C are the DNA and predicted amino acid sequence of an alternate WRN gene transcript (SEQ ID Nos. 72 and 73).

FIGS. 4A-4G are an alignment of the WRN gene product (SEQ ID No. 74) with known helicases from S. pombe (SEQ ID No. 76), E. coli (SEQ ID No. 75), human (SEQ ID No. 77) and the Bloom's Syndrome gene “BLM” (SEQ ID No. 78).

FIGS. 5A-5U are the genomic DNA sequence of the region containing a WRN gene (SEQ ID No. 79).

FIG. 6 presents a cDNA sequence of the mouse WRN gene (SEQ ID Nos. 205 and 206).

FIG. 7 is a genomic DNA sequence of the mouse WRN gene (SEQ ID Nos. 207-209).

FIGS. 8A-8D depicts a diagram of the WRN gene product with location of mutations. A, WRN cDNA. Numbering across the top refers to the cDNA sequence as numbered in GenBank L76937. B, Predicted WRN gene product. The helicase domain is designated as “HD”, motifs from I to VI are indicated. C, Location of mutations. Numbering across the bottom refer to the mutations. *: nonsense mutation. {circumflex over ( )}: frame shift mutation caused by a single base deletion. Gray lines: frame shift mutations causing deletion of exon(s). D, Predicted proteins. Lines represent the different predicted truncated proteins produced from mutations in the WRN gene.

FIGS. 9A, 9 B, and 9 C are photomeceographs showing localization of the WRN gene product by fluorescent antibody staining (panel A), nuclei (panel B), and the size of cells (panel C) expressing the WRN gene.

FIG. 10 shows the alignment of the mouse and human WRN gene products.

DETAILED DESCRIPTION OF THE INVENTION
›Definitions · 1 of 11

Prior to setting forth the invention in detail, it may be helpful to an understanding thereof to set forth definitions of certain terms and to list and to define the abbreviations that will be used hereinafter.

“Genetic marker” is any segment of a chromosome that is distinguishably unique in the genome, and polymorphic in the population so as to provide information about the inheritance of linked DNA sequences, genes and/or other markers.

“Vector” refers to an assembly which is capable of directing the expression of a WRN gene, as well as any additional sequence(s) or gene(s) of interest. The vector must include transcriptional promoter elements which are operably linked to the genes of interest. The vector may be composed of either deoxyribonucleic acids (“DNA”), ribonucleic acids (“RNA”), or a combination of the two (e.g., a DNA-RNA chimeric). Optionally, the vector may include a polyadenylation sequence, one or more restriction sites, as well as one or more selectable markers such as neomycin phosphotransferase or hygromycin phosphotransferase. Additionally, .depending on the host cell chosen and the vector employed, other genetic elements such as an origin of replication, additional nucleic acid restriction sites, enhancers, sequences conferring inducibility of transcription, and selectable markers, may also be incorporated into the vectors described herein.

Abbreviations: YAC, yeast artificial chromosome; EST, expressed sequence tag; PCR, polymerase chain reaction; RT-PCR, PCR process in which RNA is first transcribed into DNA at the first step using reverse transcriptase (RT); cDNA, any DNA made by copying an RNA sequence into DNA form.

As noted above, the present invention provides methods and compositions for the detection and treatment of Werner's Syndrome, as well as related diseases. These methods and compositions include a family of Werner's Syndrome-related genes, and the proteins encoded thereby, that have been implicated in the onset of Werner's Syndrome. These genes and proteins, including genetic markers, nucleic acid sequences and clones, are also useful in the creation of in vitro and animal models and screening tests useful for the study of Werner's Syndrome, including the possible identification of other genes implicated in Werner's Syndrome. The present invention also provides vector constructs, genetic markers, nucleic acid sequences, clones, diagnostic tests and compositions and methods for the identification of individuals likely to suffer from Werner's Syndrome.

Genes and Gene Products Related to Werner's Syndrome

The present invention provides isolated nucleic acid molecules comprising a portion of the gene which is implicated in the onset of WS. Briefly, as can be seen from FIG. 4, this gene encodes a protein that is similar in amino acid sequence to several known ATP-dependent DNA helicases (enzymes that unwind the DNA duplex). It is less similar to known RNA-DNA helicases. Helicases are involved in the replication of DNA, often binding the replication origin, and/or the replication complex. In addition, the single stranded DNA that is involved in recombination can be generated by DNA helicases.

Although various aspects of the WRN gene (or portions thereof) are shown in the Figures, it should be understood that within the context of the present invention, reference to one or more of these genes includes derivatives of the genes that are substantially similar to the genes (and, where appropriate, the proteins (including peptides and polypeptides) that are encoded by the genes and their derivatives). As used herein, a nucleotide sequence is deemed to be “substantially similar” if: (a) the nucleotide sequence is derived from the coding region of the described genes and includes, for example, portions of the sequence or allelic variations of the sequences discussed above, or alternatively, encodes a helicase-like activity (Bjornson et al., Biochem . 3307:14306-14316, 1994); (b) the nucleotide sequence is capable of hybridization to nucleotide sequences of the present invention under high or very high stringency (see Sambrook et al., Molecular Cloning: A Laboratory Manual , 2nd ed., Cold Spring Harbor Laboratory Press, NY, 1989); or (c) the DNA sequences are degenerate as a result of the genetic code to the DNA sequences defined in (a) or (b). Further, the nucleic acid molecule disclosed herein includes both complementary and non-complementary sequences, provided the sequences otherwise meet the criteria set forth herein. Within the context of the present invention, high stringency means standard hybridization conditions (e.g., 5×SSPE, 0.5% SDS at 65° C., or the equivalent) while very high stringency means conditions of hybridization such that the nucleotide sequence is able to selectively hybridize to a single allele of the WS-related gene.

The WRN gene may be isolated from genomic DNA or cDNA. Genomic DNA libraries constructed in chromosomal vectors, such as YACs (yeast artificial chromosomes), bacteriophage vectors, such as λEMBL3, λgt10, cosmids, or plasmids are suitable for use. cDNA libraries constructed in bacteriophage vectors, plasmids, or others, are suitable for screening. Such libraries may be constructed using methods and techniques known in the art (see Sambrook et al., Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Press, 1989) or purchased from commercial sources (e.g., Clontech, Palo Alto, Calif.). Within one embodiment, the WRN gene is isolated by PCR performed on genomic DNA, cDNA or DNA from libraries, or is isolated by probe hybridization of genomic DNA or cDNA libraries. Primers for PCR and probes for hybridization screening may be designed based on the DNA sequence of WRN presented herein. The DNA sequence of a portion of the WRN gene and the entire coding sequence is presented in the Figures. Primers for PCR should be derived from sequences in the 5′ and 3′ untranslated region in order to isolate a full-length cDNA. The primers should not have self-complementary sequences nor have complementary sequences at their 3′ end (to prevent primer-dimer formation). Preferably, the primers have a GC content of about 50% and contain restriction sites. The primers are annealed to cDNA and sufficient cycles of PCR are performed to yield a product readily visualized by gel electrophoresis and staining. The amplified fragment is purified and inserted into a vector, such as λgt10 or pBS(M13+), and propagated. An oligonucleotide hybridization probe suitable for screening genomic or cDNA libraries may be designed based on the sequence provided herein. Preferably, the oligonucleotide is 20-30 bases long. Such an oligonucleotide may be synthesized by automated synthesis. The oligonucleotide may be conveniently labeled at the 5′ end with a reporter molecule, such as a radionuclide, (e.g., 32 P) or biotin. The library is plated as colonies or phage, depending upon the vector, and the recombinant DNA is transferred to nylon or nitrocellulose membranes. Following denaturation, neutralization, and fixation of the DNA to the membrane, the membranes are hybridized with the labeled probe. The membranes are washed and the reporter molecule detected. The hybridizing colonies or phage are isolated and propagated. Candidate clones or PCR amplified fragments may be verified as containing WRN DNA by any of various means. For example, the candidate clones may be hybridized with a second, nonoverlapping probe or subjected to DNA sequence analysis. In these ways, clones containing WRN gene, which are suitable for use in the present invention are isolated.

›Definitions · 2 of 11

The structure of the proteins encoded by the nucleic acid molecules described herein may be predicted from the primary translation products using the hydrophobicity plot function of, for example, P/C Gene, Lasergen System, DNA STAR, Madison, Wisconsin, or according to the methods described by Kyte and Doolittle ( J. Mol. Biol . 157:105-132, 1982).

WRN proteins of the present invention may be prepared in the form of acidic or basic salts, or in neutral form. In addition, individual amino acid residues may be modified by oxidation or reduction. Furthermore, various substitutions, deletions, or additions may be made to the amino acid or nucleic acid sequences, the net effect of which is to retain or further enhance or decrease the biological activity of the mutant or wild-type protein. Moreover, due to degeneracy in the genetic code, for example, there may be considerable variation in nucleotide sequences encoding the same amino acid sequence.

Other derivatives of the WRN proteins disclosed herein include conjugates of the proteins along with other proteins or polypeptides. This may be accomplished, for example, by the synthesis of N-terminal or C-terminal fusion proteins which may be added to facilitate purification or identification of WRN proteins (see U.S. Pat. No. 4,851,341; see also, Hopp et al., Bio/Technology 6:1204, 1988.) Alternatively, fusion proteins such as WRN protein-β-galactosidase or WRN protein-luciferase may be constructed in order to assist in the identification, expression, and analysis of WRN proteins.

WRN proteins of the present invention may be constructed using a wide variety of techniques described herein. Further, mutations may be introduced at particular loci by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites enabling ligation to fragments of the native sequence. Following ligation, the resulting reconstructed sequence encodes a derivative having the desired amino acid insertion, substitution, or deletion.

Alternatively, oligonucleotide-directed site-specific (or segment specific) mutagenesis procedures may be employed to provide an altered gene having particular codons altered according to the substitution, deletion, or insertion required. Exemplary methods of making the alterations set forth above are disclosed by Walder et al. ( Gene 42:133, 1986); Bauer et al. ( Gene 37:73, 1985); Craik ( BioTechniques , January 1985, 12-19); Smith et al. ( Genetic Engineering: Principles and Methods , Plenum Press, 1981); and Sambrook et al. (supra). Deletion or truncation derivatives of WRN proteins (e.g., a soluble extracellular portion) may also be constructed by utilizing convenient restriction endonuclease sites adjacent to the desired deletion. Subsequent to restriction, overhangs may be filled in, and the DNA religated. Exemplary methods of making the alterations set forth above are disclosed by Sambrook et al. ( Molecular Cloning: A Laboratory Manual , 2d Ed., Cold Spring Harbor Laboratory Press, 1989).

Mutations of the present invention preferably preserve the reading frame of the coding sequences. Furthermore, the mutations will preferably not create complementary regions that could hybridize to produce secondary mRNA structures, such as loops or hairpins, that would adversely affect translation of the mRNA. Although a mutation site may be predetermined, it is not necessary that the nature of the mutation per se be predetermined. For example, in order to select for optimum characteristics of mutants at a given site, random mutagenesis may be conducted at the target codon and the expressed mutants screened for indicative biological activity. Alternatively, mutations may be introduced at particular loci by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites enabling ligation to fragments of the native sequence. Following ligation, the resulting reconstructed sequence encodes a derivative having the desired amino acid insertion, substitution, or deletion.

WRN proteins may also be constructed utilizing techniques of PCR mutagenesis, chemical mutagenesis (Drinlkwater and Klinedinst, PNAS 83:3402-3406, 1986), by forced nucleotide misincorporation (e.g, Liao and Wise Gene 88:107-111, 1990), or by use of randomly mutagenized oligonucleotides (Horwitz et al., Genome 3:112-117, 1989).

Proteins can be isolated by, among other methods, culturing suitable host and vector systems to produce the recombinant translation products of the present invention. Supernates from such cell lines, or protein inclusions or whole cells where the protein is not excreted into the supemate, can then be treated by a variety of purification procedures in order to isolate the desired proteins. For example, the supernate may be first concentrated using commercially available protein concentration filters, such as an Amicon or Millipore Pellicon ultrafiltration unit. Following concentration, the concentrate may be applied to a suitable purification matrix such as, for example, an anti-protein antibody bound to a suitable support. Alternatively, anion or cation exchange resins may be employed in order to purify the protein. As a further alternative, one or more reverse-phase high performance liquid chromatography (RP- HPLC) steps may be employed to further purify the protein. Other methods of isolating the proteins of the present invention are well known in the skill of the art.

A protein is deemed to be “isolated” within the context of the present invention if no other (undesired) protein is detected pursuant to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis followed by Coomassie blue staining. Within other embodiments, the desired protein can be isolated such that no other (undesired) protein is detected pursuant to SDS-PAGE analysis followed by silver staining.

Expression of a WRN Gene

The present invention also provides for the manipulation and expression of the above described genes by culturing host cells containing a vector capable of expressing the above-described genes. Such vectors or vector constructs include either synthetic or cDNA-derived nucleic acid molecules encoding WRN proteins, which are operably linked to suitable transcriptional or translational regulatory elements. Suitable regulatory elements may be derived from a variety of sources, including bacterial, fungal, viral, mammalian, insect, or plant genes. Selection of appropriate regulatory elements is dependent on the host cell chosen, and may be readily accomplished by one of ordinary skill in the art. Examples of regulatory elements include: a transcriptional promoter and enhancer or RNA polymerase binding sequence, a transcriptional termninator, and a ribosomal binding sequence, including a translation initiation signal.

›Definitions · 3 of 11

Nucleic acid molecules that encode any of the WRN proteins described above may be readily expressed by a wide variety of prokaryotic and eukaryotic host cells, including bacterial, mammalian, yeast or other fungi, viral, insect, or plant cells. Methods for transforming or transfecting such cells to express foreign DNA are well known in the art (see, e.g., Itakura et al., U.S. Pat. No. 4,704,362; Hinnen et al., Proc. Natl. Acad Sci. USA 75:1929-1933, 1978; Murray et al., U.S. Pat. No. 4,801,542; Upshall et al., U.S. Pat. No. 4,935,349; Hagen et al., U.S. Pat. No. 4,784,950; Axel et al. U.S. Pat. No. 4,399,216; Goeddel et al., U.S. Pat. No. 4,766,075; and Sambrook et al. Molecular Cloning: A Laboratory Manual 2nd edition, Cold Spring Harbor Laboratory Press, 1989; for plant cells see Czako and Marton, Plant Physiol . 104:1067-1071, 1994; and Paszkowski et al., Biotech . 24:387-392, 1992).

Bacterial host cells suitable for carrying out the present invention include E. coli, B. subtilis, Salmonella typhimurium , and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, as well as many other bacterial species well known to one of ordinary skill in the art. Representative examples of bacterial host cells include DH5α (Stratagene, LaJolla, Calif.).

Bacterial expression vectors preferably comprise a promoter which functions in the host cell, one or more selectable phenotypic markers, and a bacterial origin of replication. Representative promoters include the β-lactamase (penicillinase) and lactose promoter system (see Chang et al., Nature 275:615, 1978), the T7 RNA polymerase promoter (Studier et al., Meth. Enzymol . 185:60-89, 1990), the lambda promoter (Elvin et al., Gene 87:123-126, 1990), the trp promoter (Nichols and Yanofsky, Meth. in Enzymology 101:155, 1983) and the tac promoter (Russell et al., Gene 20: 231, 1982). Representative selectable markers include various antibiotic resistance markers such as the kanamycin or ampicillin resistance genes. Many plasmids suitable for transforming host cells are well known in the art. including among others, pBR322 (see Bolivar et al., Gene 2:95, 1977), the pUC plasmids pUC18, pUC19, pUC118, pUC119 (see Messing, Meth. in Enzymology 101:20-77, 1983 and Vieira and Messing, Gene 19:259-268, 1982), and pNH8A, pNH16a, pNH18a, and Bluescript M13 (Stratagene, La Jolla, Calif.).

Yeast and fungi host cells suitable for carrying out the present invention include, among others, Saccharomyces pombe, Saccharomyces cerevisiae , the genera Pichia or Kluyveromyces and various species of the genus Aspergillus (McKnight et al., U.S. Pat. No. 4,935,349). Suitable expression vectors for yeast and fungi include, among others, YCp50 (ATCC No. 37419) for yeast, and the amdS cloning vector pV3 (Turnbull, Bio/Technology 7:169, 1989), YRp7 (Struhl et al., Proc. Natl. Acad. Sci. USA 76:1035-1039, 1978), YEp13 (Broach et al., Gene 8:121-133, 1979), pJDB249 and pJDB219 (Beggs, Nature 275:104-108, 1978) and derivatives thereof.

Preferred promoters for use in yeast include promoters from yeast glycolytic genes (Hitzeman et al., J. Biol. Chem . 255:12073-12080, 1980; Alber and Kawasaki, J. Mol. Appl. Genet . 1:419-434, 1982) or alcohol dehydrogenase genes (Young et al., in Genetic Engineering of Microorganisms for Chemicals , Hollaender et al. (eds.), p. 355, Plenum, New York, 1982; Ammerer, Meth. Enzymol . 101:192-201, 1983). Examples of useful promoters for fungi vectors include those derived from Aspergillus nidulans glycolytic genes, such as the adh3 promoter (McKnight et al., EMBO J . 4:2093-2099, 1985). The expression units may also include a transcriptional terminator. An example of a suitable terminator is the adh3 terminator (McKnight et al., ibid., 1985).

As with bacterial vectors, the yeast vectors will generally include a selectable marker, which may be one of any number of genes that exhibit a dominant phenotype for which a phenotypic assay exists to enable transformants to be selected. Preferred selectable markers are those that complement host cell auxotrophy, provide antibiotic resistance or enable a cell to utilize specific carbon sources, and include leu2 (Broach et al., ibid.), ura3 (Botstein et al., Gene 8:17, 1979), or his3 (Struhl et al., ibid.). Another suitable selectable marker is the cat gene, which confers chloramphenicol resistance on yeast cells.

Techniques for transforming fungi are well known in the literature, and have been described, for instance, by Beggs (ibid.), Hinnen et al. ( Proc. Natl. Acad. Sci. USA 75:1929-1933, 1978), Yelton et al. ( Proc. Natl. Acad. Sci. USA 81:1740-1747, 1984), and Russell ( Nature 301:167-169, 1983). The genotype of the host cell may contain a genetic defect that is complemented by the selectable marker present on the expression vector. Choice of a particular host and selectable marker is well within the level of ordinary skill in the art.

Protocols for the transformation of yeast are also well known to those of ordinary skill in the art. For example, transformation may be readily accomplished either by preparation of spheroplasts of yeast with DNA (see Hinnen et al., PNAS USA 75:1929, 1978) or by treatment with alkaline salts such as LiCl (see Itoh et al., J. Bacteriology 153:163, 1983). Transformation of fungi may also be carried out using polyethylene glycol as described by Cullen et al. ( Bio/Technology 5:369, 1987).

Viral vectors include those which comprise a promoter that directs the expression of an isolated nucleic acid molecule that encodes an WRN protein as described above. A wide variety of promoters may be utilized within the context of the present invention; including for example, promoters such as MoMLV LTR, RSV LTR, Friend MuLV LTR, adenoviral promoter (Ohno et al., Science 265: 781-784, 1994), neomycin phosphotransferase promoter/enhancer, late parvovirus promoter (Koering et al., Hum. Gene Therap . 5:457-463, 1994), Herpes TK promoter, SV40 promoter, metallothionein IIa gene enhancer/promoter, cytomegalovirus immediate early promoter, and the cytomegalovirus immediate late promoter. Within particularly preferred embodiments of the invention, the promoter is a tissue-specific promoter (see e.g., WO 91/02805; EP 0,415,731; and WO 90/07936). Representative examples of suitable tissue specific promoters include neural specific enolase promoter, platelet derived growth factor beta promoter, bone morpho-genetic protein promoter, human alphal-chimaerin promoter, synapsin I promoter and synapsin II promoter. In addition to the above-noted promoters, other viral-specific promoters (e.g., retroviral promoters (including those noted above, as well as others such as HIV promoters), hepatitis, herpes (e.g., EBV), and bacterial, fungal or parasitic (e.g., malarial) -specific promoters may be utilized in order to target a specific cell or tissue which is infected with a virus, bacteria, fungus or parasite.

›Definitions · 4 of 11

Thus, WRN proteins of the present invention may be expressed from a variety of viral vectors, including for example, herpes viral vectors (e.g., U.S. Pat. No. 5,288,641), adenoviral vectors (e.g., WO 94/26914, WO 93/9191; Kolls et al., PNAS 91(1):215-219, 1994; Kass-Eisler et al., PNAS 90(24):11498-502, 1993; Guzman et al., Circulation 88(6):2838-48, 1993; Guzman et al., Cir. Res . 73(6):1202-1207, 1993; Zabner et al., Cell 75(2):207-216, 1993; Li et al., Hum Gene Ther . 4(4):403-409, 1993; Caillaud et al., Eur. J. Neurosci . 5(10:1287-1291, 1993; Vincent et al., Nat. Genet . 5(2):130-134, 1993; Jaffe et al., Nat. Genet . 1(5):372-378, 1992; and Levrero et al, Gene 101(2):195-202, 1991), adeno-associated viral vectors (WO 95/13365; Flotte et al., PNAS 90(22):10613-10617, 1993), baculovirus vectors, parvovirus vectors (Koering et al., Hum. Gene Therap . 5:457-463, 1994), pox virus vectors (Panicali and Paoletti, PNAS 79:4927-4931, 1982; and Ozaki et al., Biochem. Biophys. Res. Comm . 193(2):653-660, 1993), and retroviruses (e.g., EP 0,415,731; WO 90/07936; WO 91/0285, WO 94/03622; WO 93/25698; WO 93/25234; U.S. Pat. No. 5,219,740; WO 93/11230; WO 93/10218. Viral vectors may likewise be constructed which contain a mixture of different elements (e.g., promoters, envelope sequences and the like) from different viruses, or non-viral sources. Within various embodiments, either the viral vector itself, or a viral particle which contains the viral vector may be utilized in the methods and compositions described below.

Mammalian cells suitable for carrying out the present invention include, among others: PC12 (ATCC No. CRL1721), N1E-115 neuroblastoma, SK-N-BE(2)C neuroblastoma, SHSY5 adrenergic neuroblastoma, NS20Y and NG108-15 murine cholinergic cell lines, or rat F2 dorsal root ganglion line, COS (e.g., ATCC No. CRL 1650 or 1651), BHK (e.g., ATCC No. CRL 6281; BHK 570 cell line (deposited with the American Type Culture Collection under accession number CRL 10314), CHO (ATCC No. CCL 61), HeLa (e.g., ATCC No. CCL 2), 293 (ATCC No. 1573; Graham et al., J. Gen. Virol . 36:59-72, 1977) and NS-1 cells. Other mammalian cell lines may be used within the present invention, including Rat Hep I (ATCC No. CRL 1600), Rat Hep II (ATCC No. CRL 1548), TCMK (ATCC No. CCL 139), Human lung (ATCC No. CCL 75.1), Human hepatoma (ATCC No. HTB-52), Hep G2 (ATCC No. HB 8065), Mouse liver (ATCC No. CCL 29.1), NCTC 1469 (ATCC No. CCL 9.1), SP2/0-Ag14 (ATCC No. 1581), HIT-T15 (ATCC No. CRL 1777), and RINm 5AHT 2 B (Orskov and Nielson, FEBS 229(1):175-178, 1988).

Mammalian expression vectors for use in carrying out the present invention will include a promoter capable of directing the transcription of a cloned gene or cDNA. Preferred promoters include viral promoters and cellular promoters. Viral promoters include the cytomegalovirus immediate early promoter (Boshart et al., Cell 41:521-530, 1985), cytomegalovirus immediate late promoter, SV40 promoter (Subramani et al., Mol. Cell. Biol . 1:854-864, 1981), MMTV LTR, RSV LTR, metallothionein-1, adenovirus E1a. Cellular promoters include the mouse metallothionein-1 promoter (Palmiter et al., U.S. Pat. No. 4,579,821), a mouse V κ promoter (Bergman et al., Proc. Natl. Acad. Sci. USA 81:7041-7045, 1983; Grant et al., Nucl. Acids Res . 15:5496, 1987) and a mouse V H promoter (Loh et al., Cell 33:85-93, 1983). The choice of promoter will depend, at least in part, upon the level of expression desired or the recipient cell line to be transfected.

Such expression vectors may also contain a set of RNA splice sites located downstream from the promoter and upstream from the DNA sequence encoding the peptide or protein of interest. Preferred RNA splice sites may be obtained from adenovirus and/or immunoglobulin genes. Also contained in the expression vectors is a polyadenylation signal located downstream of the coding sequence of interest. Suitable polyadenylation signals include the early or late polyadenylation signals from SV40 (Kaufman and Sharp, ibid), the polyadenylation signal from the Adenovirus 5 E1B region and the human growth hormone gene terminator (DeNoto et al., Nuc. Acids Res . 9:3719-3730, 1981). The expression vectors may include a noncoding viral leader sequence, such as the Adenovirus 2 tripartite leader, located between the promoter and the RNA splice sites. Preferred vectors may also include enhancer sequences, such as the SV40 enhancer. Expression vectors may also include sequences encoding the adenovirus VA RNAs. Suitable expression vectors can be obtained from commercial sources (e.g., Stratagene, La Jolla, Calif.).

Vector constructs comprising cloned DNA sequences can be introduced into cultured mammalian cells by, for example, calcium phosphate-mediated transfection (Wigler et al., Cell 14:725, 1978; Corsaro and Pearson, Somatic Cell Genetics 7:603, 1981; Graham and Van der Eb, Virology 52:456, 1973), electroporation (Neumann et al., EMBO J. 1:841-845, 1982), or DEAE-dextran mediated transfection (Ausubel et al. (eds.), Current Protocols in Molecular Biology , John Wiley and Sons, Inc., NY, 1987). To identify cells that have stably integrated the cloned DNA, a selectable marker is generally introduced into the cells along with the gene or cDNA of interest. Preferred selectable markers for use in cultured mammalian cells include genes that confer resistance to drugs. such as neomycin, hygromycin, and methotrexate. The selectable marker may be an amplifiable selectable marker. Preferred amplifiable selectable markers are the DHFR gene and the neomycin resistance gene. Selectable markers are reviewed by Thilly ( Mammalian Cell Technology , Butterworth Publishers, Stoneham, Mass., which is incorporated herein by reference).

Mammalian cells containing a suitable vector are allowed to grow for a period of time, typically 1-2 days, to begin expressing the DNA sequence(s) of interest. Drug selection is then applied to select for growth of cells that are expressing the selectable marker in a stable fashion. For cells that have been transfected with an amplifiable, selectable marker the drug concentration may be increased in a stepwise manner to select for increased copy number of the cloned sequences, thereby increasing expression levels. Cells expressing the introduced sequences are selected and screened for production of the protein of interest in the desired form or at the desired level. Cells that satisfy these criteria can then be cloned and scaled up for production.

›Definitions · 5 of 11

Protocols for the transfection of mammalian cells are well known to those of ordinary skill in the art. Representative methods include calcium phosphate mediated transfection, electroporation, lipofection, retroviral, adenoviral and protoplast fusion-mediated transfection (see Sambrook et al., supra). Naked vector constructs can also be taken up by muscular cells or other suitable cells subsequent to injection into the muscle of a mammal (or other animals).

Numerous insect host cells known in the art can also be useful within the present invention, in light of the subject specification. For example, the use of baculoviruses as vectors for expressing heterologous DNA sequences in insect cells has been reviewed by Atkinson et al. ( Pestic. Sci . 28:215-224,1990).

Numerous plant host cells known in the art can also be useful within the present invention, in light of the subject specification. For example, the use of Agrobacterium rhizogenes as vectors for expressing genes in plant cells has been reviewed by Sinkar et al., ( J. Biosci . ( Bangalore ) 11:47-58, 1987).

WRN proteins may be prepared by growing (typically by culturing) the host/vector systems described above, in order to express the recombinant WRN proteins. Recombinantly produced WRN proteins may be further purified as described in more detail below.

Within related aspects of the present invention, WRN proteins may be expressed in a transgenic animal whose germ cells and somatic cells contain a WRN gene which is operably linked to a promoter effective for the expression of the gene. Alternatively, in a similar manner transgenic animals may be prepared that lack the WRN gene (e.g., “knockout” mice). Such transgenics may be prepared in a variety non-human animals, including mice, rats, rabbits, sheep, dogs, goats and pigs (see Hammer et al. Nature 315:680-683, 1985, Palmiter et al. Science 222:809-814, 1983, Brinster et al. Proc. Natl. Acad. Sci. USA 82:4438-4442, 1985, Palmiter and Brinster Cell 41:343-345, 1985 and U.S. Pat. Nos. 5,175,383, 5,087,571, 4,736,866, 5,387,742, 5,347,075, 5,221,778, and 5,175,384).

Briefly, an expression vector, including a nucleic acid molecule to be expressed together with appropriately positioned expression control sequences, is introduced into pronuclei of fertilized eggs, for example, by microinjection. Integration of the injected DNA is detected by blot analysis of DNA from tissue samples. It is preferred that the introduced DNA be incorporated into the germ line of the animal so that it is passed on to the animal's progeny. Tissue-specific expression may be achieved through the use of a tissue-specific promoter, or through the use of an inducible promoter, such as the metallothionein gene promoter (Palmiter et al., 1983, ibid), which allows regulated expression of the transgene.

Vectors of the present invention may contain or express a wide variety of additional nucleic acid molecules in place of or in addition to an WRN protein as described above, either from one or several separate promoters. For example, the viral vector may express a lymphokine or lymphokine receptor, antisense or ribozyme sequence or toxins. Representative examples of lymphokines include IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, G-CSF, M-CSF, alpha-interferon, beta-interferon, gamma-interferon, and tumor necrosis factors, as well as their respective receptors. Representative examples of antisense sequences include antisense sequences which block the expression of WRN protein mutants. Representative examples of toxins include: ricin, abrin, diphtheria toxin, cholera toxin, saporin, gelonin, pokeweed antiviral protein, tritin, Shigella toxin, and Pseudomonas exotoxin A.

Within other aspects of the invention, antisense oligonucleotide molecules are provided which specifically inhibit expression of mutant WRN nucleic acid sequences (see generally, Hirashima et al. in Molecular Biology of RNA: New Perspectives (M. Inouye and B. S. Dudock, eds., 1987 Academic Press, San Diego, p. 401); Oligonucleotides: Antisense Inhibitors of Gene Expression (J. S. Cohen, ed., 1989 MacMillan Press, London); Stein and Cheng, Science 261:1004-1012 (1993); WO 95/10607; U.S. Pat. No. 5,359,051; WO 92/06693; and EP-A 2-612844 ). Briefly, such molecules are constructed such that they are complementary to, and able to form Watson-Crick base pairs with, a region of transcribed WRN mutant mRNA sequence containing an WRN mutation. The resultant double-stranded nucleic acid interferes with subsequent processing of the mRNA, thereby preventing protein synthesis.

Within other related aspects of the invention, ribozyme molecules are provided wherein an antisense oligonucleotide sequence is incorporated into a ribozyme which can specifically cleave mRNA molecules transcribed from a mutant WRN gene (see generally, Kim et al. Proc. Nat. Acad Sci. USA 84:8788 (1987); Haseloff, et al. Nature 234:585 (1988), Cech, JAMA 260:3030 (1988); Jeffries, et al. Nucleic Acids Res . 17:1371 (1989); U.S. Pat. No. 5,093,246; U.S. Pat. No. 5,354,855; U.S. Pat. No. 5,144,019; U.S. Pat. No. 5,272,262; U.S. Pat. No. 5,254,678; and U.S. Pat. No. 4,987,071). According to this aspect of the invention, the antisense sequence which is incorporated into a ribozyme includes a sequence complementary to, and able to form Watson-Crick base pairs with, a region of the transcribed mutant WRN mRNA containing an WRN mutation. The antisense sequence thus becomes a targeting agent for delivery of catalytic ribozyme activity specifically to mutant WRN mRNA, where such catalytic activity cleaves the mRNA to render it incapable of being subsequently processed for WRN protein translation.

Host Cells

As discussed above, nucleic acid molecules which encode the WRN proteins of the present invention (or the vectors which contain and/or express related mutants) may readily be introduced into a wide variety of host cells. Representative examples of such host cells include plant cells, eukaryotic cells, and prokaryotic cells. Within preferred embodiments, the nucleic acid molecules are introduced into cells from a vertebrate or warrn-blooded animal, such as a human, macaque, dog, cow, horse, pig, sheep, rat, hamster, mouse or fish cell, or any hybrid thereof.

›Definitions · 6 of 11

Preferred prokaryotic host cells for use within the present invention include E. coli , Salmonella, Bacillus, Shigella, Pseudomonas, Streptomyces and other genera. Techniques for transforming these hosts and expressing foreign DNA sequences cloned therein are well known in the art (see, e.g., Maniatis et al., Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Laboratory, 1982, which is incorporated herein by reference; or Sambrook et al., supra). Vectors used for expressing cloned DNA sequences in bacterial hosts will generally contain a selectable marker, such as a gene for antibiotic resistance, and a promoter that functions in the host cell. Appropriate promoters include the trp (Nichols and Yanofsky, Meth. Enzymol . 101:155-164, 1983), lac (Casadaban et al., J. Bacteriol . 143:971-980, 1980), and phage λ (Queen, J. Mol. Appl. Genet . 2:1-10, 1983) promoter systems. Plasmids useful for transforming bacteria include the pUC plasmids (Messing, Meth. Enzymol . 101:20-78, 1983; Vieira and Messing, Gene 19:259-268, 1982), pBR322 (Bolivar et al., Gene 2:95-113, 1977), pCQV2 (Queen, ibid.), and derivatives thereof. Plasmids may contain both viral and bacterial elements.

Preferred eukaryotic cells include cultured mammalian cell lines (e.g., rodent or human cell lines) and fungal cells, including species of yeast (e.g., Saccharomyces spp., particularly S. cerevisiae , Schizosaccharomyces spp., or Kluyveromyces spp.) or filamentous fungi (e.g., Aspergillus spp., Neurospora spp.). Strains of the yeast Saccharomyces cerevisiae are particularly preferred. Methods for producing recombinant proteins in a variety of prokaryotic and eukaryotic host cells are generally known in the art (see, “Gene Expression Technology,” Methods in Enzymology , Vol. 185, Goeddel (ed.), Academic Press, San Diego, Calif., 1990; see also, “Guide to Yeast Genetics and Molecular Biology,” Methods in Enzymology , Guthrie and Fink (eds.), Academic Press, San Diego, Calif., 1991). In general, a host cell will be selected on the basis of its ability to produce the protein of interest at a high level or its ability to carry out at least some of the processing steps necessary for the biological activity of the protein. In this way, the number of cloned DNA sequences that must be introduced into the host cell can be minimized and overall yield of biologically active protein can be maximized.

The nucleic acid molecules (or vectors) may be introduced into host cells by a wide variety of mechanisms, including for example calcium phosphate-mediated transfection (Wigler et al., Cell 14:725, 1978), lipofection; gene gun (Corsaro and Pearson, Somatic Cell Gen . 7:603, 1981; Graham and Van der Eb, Virology 52:456, 1973), electroporation (Neumann et al., EMBO J . 1:841-845, 1982), retroviral, adenoviral, protoplast fusion-mediated transfection or DEAE-dextran mediated transfection (Ausubel et al., (eds.), Current Protocols in Molecular Biology , John Wiley and Sons, Inc., New York, N.Y., 1987).

Host cells containing vector constructs of the present invention are then cultured to express a DNA molecule as described above. The cells are cultured according to standard methods in a culture medium containing nutrients required for growth of the chosen host cells. A variety of suitable media are known in the art and generally include a carbon source, a nitrogen source, essential amino acids, vitamins and minerals, as well as other components, e.g., growth factors or serum, that may be required by the particular host cells. The growth medium will generally select for cells containing the DNA construct(s) by, for example, drug selection or deficiency in an essential nutrient which is complemented by the selectable marker on the DNA construct or co-transfected with the DNA construct.

Suitable growth conditions for yeast cells, for example, include culturing in a chemically defined medium, comprising a nitrogen source, which may be a non-amino acid nitrogen source or a yeast extract, inorganic salts, vitamins and essential amino acid supplements at a temperature between 4° C. and 37° C., with 30° C. being particularly preferred. The pH of the medium is preferably maintained at a pH greater than 2 and less than 8, more preferably pH 5-6. Methods for maintaining a stable pH include buffering and constant pH control. Preferred agents for pH control include sodium hydroxide. Preferred buffering agents include succinic acid and Bis-Tris (Sigma Chemical Co., St. Louis, Mo.). Due to the tendency of yeast host cells to hyperglycosylate heterologous proteins, it may be preferable to express the nucleic acid molecules of the present invention in yeast cells having a defect in a gene required for asparagine-linked glycosylation. Such cells are preferably grown in a medium containing an osmotic stabilizer. A preferred osmotic stabilizer is sorbitol supplemented into the medium at a concentration between 0.1 M and 1.5 M, preferably at 0.5 M or 1.0 M.

Cultured mammalian cells are generally cultured in commercially available serum-containing or serum-free media. Selection of a medium and growth conditions appropriate for the particular cell line used is well within the level of ordinary skill in the art.

Antibodies

Antibodies to the WRN proteins discussed above may readily be prepared given the disclosure provided herein. Such antibodies may, within certain embodiments, specifically recognize wild type WRN protein rather than a mutant WRN protein, mutant WRN protein rather than wild type WRN protein, or equally recognize both the mutant and wild-type forms of WRN protein. Antibodies may be used for isolation of the protein, establishing intracellular localization of the WRN protein, inhibiting activity of the protein (antagonist), or enhancing activity of the protein (agonist). Knowledge of the intracellular location of the WRN gene product may be abnormal in patients with WRN mutations, thus allowing the development of a rapid screening assay. As well, assays for small molecules that interact with the WRN gene product will be facilitated by the development of antibodies and localization studies.

›Definitions · 7 of 11

Within the context of the present invention, antibodies are understood to include monoclonal antibodies, polyclonal antibodies, anti-idiotypic antibodies, antibody fragments (e.g., Fab, and F(ab′) 2 , F v variable regions, or complementarity determining regions). As discussed above, antibodies are understood to be specific against an WRN protein if it binds with a K d of greater than or equal to 10 −7 M, preferably greater than of equal to 10 −8 M. The affinity of a monoclonal antibody or binding partner can be readily determined by one of ordinary skill in the art (see Scatchard, Ann. N.Y. Acad. Sci . 51:660-672, 1949).

Briefly, polyclonal antibodies may be readily generated by one of ordinary skill in the art from a variety of warm-blooded animals such as horses, cows, various fowl, rabbits, mice, or rats. Typically, an WRN protein or unique peptide thereof of 13-20 amino acids (preferably conjugated to keyhole limpet hemocyanin by cross-linking with glutaraldehyde) is utilized to immunize the animal through intraperitoneal, intramuscular, intraocular, or subcutaneous injections, an adjuvant such as Freund's complete or incomplete adjuvant. Merely as an example, a peptide corresponding to residues 1375 through 1387 of the WRN polypeptide sequence is used to raise a rabbit polyclonal antiserum. Following several booster immunizations. samples of serum are collected and tested for reactivity to the WRN protein or peptide. Particularly preferred polyclonal antisera will give a signal on one of these assays that is at least three times greater than background. Once the titer of the animal has reached a plateau in terms of its reactivity to the protein, larger quantities of antisera may be readily obtained either by weekly bleedings, or by exsanguinating the animal.

Monoclonal antibodies may also be readily generated using conventional techniques (see U.S. Pat. Nos. RE 32,011, 4,902,614, 4,543,439, and 4,411,993 which are incorporated herein by reference; see also Monoclonal Antibodies, Hybridomas: A New Dimension in Biological Analyses , Plenum Press, Kennett. McKearn. and Bechtol (eds.), 1980, and Antibodies: A Laboratory Manual , Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, 1988, which are also incorporated herein by reference).

Briefly, within one embodiment a subject animal such as a rat or mouse is injected with an WRN protein or portion thereof as described above. The protein may be admixed with an adjuvant such as Freund's complete or incomplete adjuvant in order to increase the resultant immune response. Between one and three weeks after the initial immunization the animal may be reimmunized with another booster immunization, and tested for reactivity to the protein utilizing assays described above. Once the animal has reached a plateau in its reactivity to the injected protein, it is sacrificed, and organs which contain large numbers of B cells such as the spleen and lymph nodes are harvested.

Cells which are obtained from the immunized animal may be immortalized by transfection with a virus such as the Epstein-Barr virus (EBV) (see Glasky and Reading, Hybridoma 8(4):377-389, 1989). Alternatively, within a preferred embodiment, the harvested spleen and/or lymph node cell suspensions are fused with a suitable myeloma cell in order to create a “hybridoma” which secretes monoclonal antibody. Suitable myeloma lines include, for example, NS-1 (ATCC No. TIB 18), and P3X63- Ag8.653 (ATCC No. CRL 1580).

Following the fusion, the cells may be placed into culture plates containing a suitable medium, such as RPMI 1640, or DMEM (Dulbecco's Modified Eagles Medium) (JRH Biosciences, Lenexa, Kans.), as well as additional ingredients, such as fetal bovine serum (FBS, i.e., from Hyclone, Logan, Utah, or JRH Biosciences). Additionally, the medium should contain a reagent which selectively allows for the growth of fused spleen and myeloma cells such as HAT (hypoxanthine, aminopterin, and thymidine) (Sigma Chemical Co., St. Louis, Mo.). After about seven days, the resulting fused cells or hybridomas may be screened in order to determine the presence of antibodies which are reactive against an WRN protein. A wide variety of assays may be utilized to determine the presence of antibodies which are reactive against the proteins of the present invention, including for example countercurrent immuno-electrophoresis, radioimmunoassays, radioimmunoprecipitations, enzyme-linked immuno-sorbent assays (ELISA), dot blot assays, western blots, immunoprecipitation, Inhibition or Competition Assays, and sandwich assays (see U.S. Pat. Nos. 4,376,110 and 4,486,530; see also Antibodies: A Laboratory Manual , Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, 1988). Following several clonal dilutions and reassays, a hybridoma producing antibodies reactive against the WRN protein may be isolated.

Other techniques may also be utilized to construct monoclonal antibodies (see William D. Huse et al., “Generation of a Large Combinational Library of the Immunoglobulin Repertoire in Phage Lambda,” Science 246:1275-1281, December 1989; see also L. Sastry et al., “Cloning of the Immunological Repertoire in Escherichia coli for Generation of Monoclonal Catalytic Antibodies: Construction of a Heavy Chain Variable Region-Specific cDNA Library,” Proc. Natl. Acad. Sci. USA 86:5728-5732, August 1989; see also Michelle Alting-Mees et al., “Monoclonal Antibody Expression Libraries: A Rapid Alternative to Hybridomas,” Strategies in Molecular Biology 3:1-9, January 1990; these references describe a commercial system available from Stratacyte, La Jolla, Calif., which enables the production of antibodies through recombinant techniques). Briefly, mRNA is isolated from a B cell population, and utilized to create heavy and light chain immunoglobulin cDNA expression libraries in the λImmunoZap(H) and λImmunoZap(L) vectors. These vectors may be screened individually or co-expressed to form Fab fragments or antibodies (see Huse et al., supra; see also Sastry et al., supra). Positive plaques may subsequently be converted to a non-lytic plasmid which allows high level expression of monoclonal antibody fragments from E. coli.

›Definitions · 8 of 11

Similarly, portions or fragments, such as Fab and Fv fragments, of antibodies may also be constructed utilizing conventional enzymatic digestion or recombinant DNA techniques to incorporate the variable regions of a gene which encodes a specifically binding antibody. Within one embodiment, the genes which encode the variable region from a hybridoma producing a monoclonal antibody of interest are amplified using nucleotide primers for the variable region. These primers may be synthesized by one of ordinary skill in the art, or may be purchased from commercially available sources. Stratacyte (La Jolla, Calif.) sells primers for mouse and human variable regions including, among others, primers for V Ha , V Hb , V Hc , V Hd , C Hl , V L and C L regions. These primers may be utilized to amplify heavy or light chain variable regions, which may then be inserted into vectors such as ImmunoZAP™ H or ImmunoZAP™ L (Stratacyte), respectively. These vectors may then be introduced into E. coli , yeast, or mammalian-based systems for expression. Utilizing these techniques, large amounts of a single-chain protein containing a fusion of the V H and V L domains may be produced (see Bird et al., Science 242:423-426, 1988). In addition, such techniques may be utilized to change a “murine” antibody to a “human” antibody, without altering the binding specificity of the antibody.

Once suitable antibodies have been obtained, they may be isolated or purified by many techniques well known to those of ordinary skill in the art (see Antibodies. A Laboratory Manual , Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, 1988). Suitable techniques include peptide or protein affinity columns, HPLC or RP-HPLC, purification on protein A or protein G columns, or any combination of these techniques.

Assays

Assays useful within the context of the present invention include those assays for detecting agonists or antagonists of WRN protein activity. Other assays are useful for the screening of peptide or organic molecule libraries. Still other assays are useful for the identification and/or isolation of nucleic acid molecules and/or peptides within the present invention, the identification of proteins that interact or bind the WRN protein, for diagnosis of a patient with an increased likelihood of contracting Werner's Syndrome, or for diagnosis of a patient with susceptibility to or manifestation of a WRN-related disease.

Nucleic Acid Based Diagnostic Tests

Briefly, another aspect of the present invention provides probes and primers for detecting the WRN genes and/or mutants thereof. In one embodiment of this aspect, probes are provided that are capable of specifically hybridizing to DNA or RNA of the WRN genes. For purposes of the present invention, probes are “capable of hybridizing” to DNA or RNA of the WRN gene if they hybridize to an WRN gene under conditions of either high or moderate stringency (see Sambrook et al., supra) but not significantly or detectably to the an unrelated helicase gene such as the Bloom's Syndrome gene (Ellis et al., Cell 83:655-666, 1995). Preferably, the probe hybridizes to suitable nucleotide sequences under high stringency conditions, such as hybridization in 5×SSPE, 1×Denhardt's solution, 0.1% SDS at 65° C., and at least one wash to remove unhybridized probe in the presence of 0.2×SSC, 1×Denhardt's solution, 0.1% SDS at 65° C. Except as otherwise provided herein, probe sequences are designed to allow hybridization to WRN genes, but not to DNA or RNA sequences from other genes. The probes are used, for example, to hybridize to nucleic acid that is present in a biological sample isolated from a patient. The hybridized probe is then detected, thereby indicating the presence of the desired cellular nucleic acid. Preferably, the cellular nucleic acid is subjected to an amplification procedure, such as PCR, prior to hybridization. Alternatively, the WRN gene may be amplified and the amplified product subjected to DNA sequencing. Mutants of WRN may be detected by DNA sequence analysis or hybridization with allele-specific oligonucleotide probes under conditions and for time sufficient to allow hybridization to the specific allele. Typically, the hybridization buffer and wash will contain tetramethyl ammonium chloride or the like (see Sambrook et al., supra).

Nucleic acid probes of the present invention may be composed of either deoxyribonucleic acids (DNA), ribonucleic acids (RNA), nucleic acid analogues (e.g., peptide nucleic acids), or any combination thereof, and may be as few as about 12 nucleotides in length, usually about 14 to 18 nucleotides in length, and possibly as large as the entire sequence of a WRN gene. Selection of probe size is somewhat dependent upon the use of the probe, and is within the skill of the art.

Suitable probes can be constructed and labeled using techniques that are well known in the art. Shorter probes of, for example, 12 bases can be generated synthetically and labeled with 32 P using T 4 polynucleotide kinase. Longer probes of about 75 bases to less than 1.5 kb are preferably generated by, for example, PCR amplification in the presence of labeled precursors such as [α- 32 P]dCTP, digoxigenin-dUTP, or biotin-dATP. Probes of more than 1.5 kb are generally most easily amplified by transfecting a cell with a plasmid containing the relevant probe, growing the transfected cell into large quantities, and purifying the relevant sequence from the transfected cells. (See Sambrook et al., supra.) Probes can be labeled by a variety of markers, including for example, radioactive markers, fluorescent markers, enzymatic markers, and chromogenic markers. The use of 32 P is particularly preferred for marking or labeling a particular probe.

It is a feature of this aspect of the invention that the probes can be utilized to detect the presence of WRN mRNA or DNA within a sample. However, if the relevant sample is present in only a limited number, then it may be beneficial to amplify the relevant sequence so that it may be more readily detected or obtained.

›Definitions · 9 of 11

A variety of methods may be utilized in order to amplify a selected sequence, including, for example, RNA amplification (see Lizardi et al., Bio/Technology 6:1197-1202, 1988; Kramer et al., Nature 339:401-402, 1989; Lomeli et al., Clinical Chem . 35(9):1826-1831, 1989; U.S. Pat. No. 4,786,600), and DNA amplification utilizing LCR or polymerase chain reaction (“PCR”) (see, U.S. Pat. Nos. 4,683,195, 4,683,202, and 4,800,159) (see also U.S. Pat. Nos. 4,876.187 and 5,011,769, which describe an alternative detection/amplification system comprising the use of scissile linkages), or other nucleic acid amplification procedures that are well within the level of ordinary skill in the art. With respect to PCR, for example, the method may be modified as known in the art. Transcriptional enhancement of PCR may be accomplished by incorporation of bacteriophage T7 RNA polymerase promoter sequences in one of the primary oligonucleotides, and immunoenzymatic detection of the products from the enhanced emitter may be effected using anti-RNA:DNA antibodies (Blais, Appl. Environ. Microbiol . 60:348-352, 1994). PCR may also be used in combination with reverse dot-blot hybridization (lida et al., FEMS Microbiol. Lett . 114:167-172, 1993). PCR products may be quantitatively analyzed by incorporation of dUTP (Dupl{grave over (aa)} et al., Anal. Biochem . 212:229-236, 1993), and samples may be filter sampled for PCR-gene probe detection (Bej et al., Appl. Environ. Microbiol . 57:3529-3534, 1991).

Within a particularly preferred embodiment, PCR amplification is utilized to detect the WRN DNA. Briefly, as described in greater detail below, a DNA sample is denatured at 95° C. in order to generate single-stranded DNA. The DNA sample may be a cDNA generated from RNA. Specific primers are then annealed to the single-stranded DNA at 37° C. to 70° C., depending on the proportion of AT/GC in the primers. The primers are extended at 72° C. with Taq DNA polymerase or other thermostable DNA polymerase in order to generate the opposite strand to the template. These steps constitute one cycle, which may be repeated in order to amplify the selected sequence. For greater specificity, nested PCR may be performed. In nested PCR, a second amplification is performed using a second set of primers derived from sequences within the first amplified product. The entire coding region of WRN may be amplified from cDNA using three sets of primers to generate fragment lengths that are a convenient size for determining their sequence. In a preferred embodiment, nested PCR is performed.

Within an alternative preferred embodiment, LCR amplification is utilized for amplification. LCR primers are synthesized such that the 5′ base of the upstream primer is capable of hybridizing to a unique base pair in a desired gene to specifically detect an WRN gene.

Within another preferred embodiment, the probes are used in an automated, non-isotopic strategy wherein target nucleic acid sequences are amplified by PCR, and then desired products are determined by a colorimetric oligonucleotide ligation assay (OLA) (Nickerson et al., Proc. Natl. Acad. Sci. USA 81:8923-8927, 1990).

Primers for the amplification of a selected sequence should be selected from sequences that are highly specific to WRN (and not, e.g., the Bloom's Syndrome gene. supra) and form stable duplexes with the target sequence. The primers should also be non-complementary, especially at the 3′ end, should not form dimers with themselves or other primers, and should not form secondary structures or duplexes with other regions of DNA. In general, primers of about 18 to 20 nucleotides are preferred, and can be easily synthesized using techniques well known in the art. PCR products, and other nucleic acid amplification products, may be quantitated using techniques known in the art (Duplàa et al., Anal. Biochem . 212:229-236, 1993; Higuchi et al., Bio/Technology 11:1026-1030).

Within one embodiment of the invention, nucleic acid diagnostics may be developed which are capable of detecting the presence of Wemer's Syndrome, or of various related diseases that may be caused by Werner's Syndrome. Briefly, severe mutations in the WRN gene may lead to Werner's Syndrome, as well as a host of related diseases, including for example, increased frequency of some benign and malignant neoplasms (especially sarcomas), cataracts, cardiovascular disease, osteoporosis, type I or type II diabetes, cataracts, sclerodoma-like skin changes and hyperkeratosis. Less severe mutations of the gene may lead to the onset of the same set of diseases, but at an older age. In addition, many of the related diseases may be associated with mutations in the WRN gene. For example, diabetes and osteoporosis are often associated with aging. Aging population and individuals with these (or other) diseases are screened for mutations in WRN. Any of the assays described herein may be used. RT-PCR is especially preferred in conjunction with DNA sequence determination. To correlate a mutation or polymorphism with disease, sibling pairs in which one sibling has disease are preferred subjects. Once a mutation is identified, other convenient screening assays may be used to assay particular nucleotide changes.

Since the sequences of the two copies of the gene from non-Werner's affected individuals can be correlated with the medical histories of these patients to define these correspondences, these alleles can therefore be used as diagnostics for susceptibilities to these diseases, once the relationship is defined. Certain non-null forms of the gene, for example, in either the homozygous or heterozygous state may significantly affect the propensity for the carriers to develop, for example, cancer. These propensities can be ascertained by examining the sequences of the gene (both copies) in a statistically significant sample of cancer patients. Other diseases (see above) can be similarly examined for significant correlations with certain alleles. To detect such a causal relationship one can use a chi-squared test, or other statistical test, to examine the significance of any correlation between the appropriate genotypes and the disease state as recorded in the medical records, using standard good practices of medical epidemiology. The sequences that define each of the alleles are then valuable diagnostic indicators for an increased susceptibility to the disease. Thus, from the nucleic acid sequences provided herein, a wide variety of Werner's Syndrome-related diseases may be readily detected.

›Definitions · 10 of 11

Another cellular phenotype of the cells from Werner's patients is the increased frequency of deletion mutation in these cells. Clearly, the defective helicase in these cells leads to a specific mutator phenotype, while not rendering the cells hypersensitive to a variety of chemical or physical mutagens that damage DNA, like ionizing radiation. Disease states, or sensitivities that result from an elevated deletion frequency can therefore be controlled, in part. by alterations of the Wemer's gene, and some alleles may therefore be diagnostic of this class of medical conditions.

Assays for Agonists and Antagonists

An agonist or antagonist of the WRN gene product comprising a protein, peptide. chemical, or peptidomimetic that binds to the WRN gene product or interacts with a protein that binds to the WRN gene product such that the binding of the agonist or antagonist affects the activity of the WRN gene product. An agonist will activate or increase the activity of the WRN gene product. An antagonist will inhibit or decrease the activity of the WRN gene product. The activity of the WRN gene product may be measured in an assay, such as a helicase assay or other assay that measures an activity of the WRN gene product. Other assays measure the binding of protein that interacts with WRN and is necessary for its activity.

Agonists and antagonists of the WRN gene product may be used to enhance activity or inhibit activity of the gene product. Such agonists and antagonists may be identified in a variety of methods. For example, proteins that bind and activate WRN may be identified using a yeast 2-hybrid detection system. In this system, the WRN gene is fused to either a DNA-binding domain or an activating domain of a yeast gene such as GAL4. A cDNA library is constructed in a vector such that the inserts are fused to one of the domains. The vectors are co-transfected into yeast and selected for transcriptional activation of a reporter gene (Fields and Song, Nature 340: 245, 1989). The protein(s) that bind to WRN are candidate agonists. Three different proteins that bind WRN have been identified in an initial screen using the 2-hybrid system.

When the binding site on WRN gene product is determined, molecules that bind and activate WRN protein may be designed and evaluated. For example, computer modeling of the binding site can be generated and mimetics that bind can be designed. Antibodies to the binding site may be generated and analogues of native binding proteins generated as well. Any of these molecules is tested for agonist or antagonist activity by a functional assay of the WRN gene product. For example, to test for antagonist activity, yeast are co-transfected with the WRN and binding protein each fused to a DNA binding domain or an activation domain. The test molecule is administered and activation is monitored. An antagonist will inhibit the activation of the reporter gene by at least 50%. Similarly, agonist activity may be measured by either enhancing WRN activity in a yeast 2-hybrid system or by coupling the test compound to a DNA binding or activation domain and monitoring activity of the reporter gene.

Labels

WRN proteins, nucleic acid molecules which encodes such proteins, anti-WRN protein antibodies and agonists or antagonists, as described above and below, may be labeled with a variety of molecules, including for example, fluorescent molecules, toxins, and radionuclides. Representative examples of fluorescent molecules include fluorescein, Phycobili proteins, such as phycoerythrin, rhodamine, Texas red and luciferase. Representative examples of toxins include ricin, abrin diphtheria toxin, cholera toxin, gelonin, pokeweed antiviral protein, tritin, Shigella toxin, and Pseudomonas exotoxin A. Representative examples of radionuclides include Cu-64, Ga-67, Ga-68, Zr-89, Ru-97, Tc-99m, Rh-105, Pd-109, In-111, I-123, I-125, I-131, Re-186, Re-188, Au-198, Au-199, Pb-203, At-211, Pb-212 and Bi-212. In addition, the antibodies described above may also be labeled or conjugated to one partner of a ligand binding pair. Representative examples include avidin-biotin, and riboflavin-riboflavin binding protein.

Methods for conjugating or labeling the WRN proteins, nucleic acid molecules which encode such proteins, anti-WRN protein antibodies and agonists or antagonists, as discussed above, with the representative labels set forth above may be readily accomplished by one of ordinary skill in the art (see Trichothecene Antibody Conjugate, U.S. Pat. No. 4,744,981,; Antibody Conjugate, U.S. Pat. No. 5,106,951; Fluorogenic Materials and Labeling Techniques, U.S. Pat. No. 4,018,884; Metal Radionuclide Labeled Proteins for Diagnosis and Therapy, U.S. Pat. No. 4,897,255; and Metal Radionuclide Chelating Compounds for Improved Chelation Kinetics, U.S. Pat. No. 4,988,496; see also Inman, Methods In Enzymology , Vol. 34 , Affinity Techniques, Enzyme Purification: Part B , Jakoby and Wilchek (eds.), Academic Press, New York, p. 30, 1974; see also Wilchek and Bayer, “The Avidin-Biotin Complex in Bioanalytical Applications,” Anal. Biochem . 171:1-32, 1988).

Pharmaceutical Compositions

As noted above, the present invention also provides a variety of pharmaceutical compositions, comprising one of the above-described WRN proteins, nucleic acid molecules, vectors, antibodies, host cells, agonists or antagonists, along with a pharmaceutically or physiologically acceptable carrier, excipients or diluents. Generally, such carriers should be nontoxic to recipients at the dosages and concentrations employed. Ordinarily, the preparation of such compositions entails combining the therapeutic agent with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin are exemplary appropriate diluents.

›Definitions · 11 of 11

In addition, the pharmaceutical compositions of the present invention may be prepared for administration by a variety of different routes. In addition, pharmaceutical compositions of the present invention may be placed within containers, along with packaging material which provides instructions regarding the use of such pharmaceutical compositions. Generally such instructions will include a tangible expression describing the reagent concentration, as well as within certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) which may be necessary to reconstitute the pharmaceutical composition.

Methods of Treating or Preventing Werner's Syndrome

The present invention also provides methods for treating or preventing Werner's Syndrome (or related diseases), comprising the step of administering to a patient a vector (e.g., expression vector, viral vector, or viral particle containing a vector) or nucleic acid molecules alone, as described above, thereby reducing the likelihood or delaying the onset of Werner's Syndrome (or the related disease).

Similarly, therapeutic peptides, peptidomimetics, or small molecules may be used to delay onset of Werner's Syndrome, lessen symptoms, or halt or delay progression of the disease. Such therapeutics may be tested in a transgenic animal model that expresses mutant protein, wild-type and mutant protein, or in an in vitro assay system (e.g., a helicase assay such as that described by Bjornson et al., Biochem . 3307:14306-14316, 1994).

As noted above, the present invention provides methods for treating or preventing Werner's Syndrome through the administration to a patient of a therapeutically effective amount of an antagonist or pharmaceutical composition as described herein. Such patients may be identified through clinical diagnosis based on the classical symptoms of Werner's Syndrome.

As will be evident to one of skill in the art, the amount and frequency of administration will depend, of course, on such factors as the nature and severity of the indication being treated, the desired response, the condition of the patient, and so forth. Typically, the compositions may be administered by a variety of techniques, as noted above.

Within other embodiments of the invention, the vectors which contain or express the nucleic acid molecules which encode the WRN proteins described above, or even the nucleic acid molecules themselves may be administered by a variety of alternative techniques. including for example administration of asialoosomucoid (ASOR) conjugated with poly-L-lysine DNA complexes (Cristano et al., PNAS 92122-92126, 1993), DNA linked to killed adenovirus (Curiel et al., Hum. Gene Ther . 3(2):147-154, 1992), cytofectin-mediated introduction (DMRIE-DOPE, Vical, Calif.), direct DNA injection (Acsadi et al., Nature 352:815-818, 1991); DNA ligand (Wu et al., J. of Biol. Chem . 264:16985-16987, 1989); lipofection (Felgner et al., Proc. Natl. Acad. Sci. USA 84:7413-7417, 1989); liposomes (Pickering et al., Circ . 89(1):13-21, 1994; and Wang et al., PNAS 84:7851-7855, 1987); microprojectile bombardment (Williams et al., PNAS 88:2726-2730, 1991); and direct delivery of nucleic acids which encode the WRN protein itself either alone (Vile and Hart, Cancer Res . 53: 3860-3864, 1993), or utilizing PEG-nucleic acid complexes.

The following examples are offered by way of illustration, and not by way of limitation.

EXAMPLES
›Examples59
›Example 1

Cloning of the WRN Gene From Chromosome 8

The WS locus (WRN) was initially localized to 8p12 by conventional mapping methods (Goto et al., Nature 355:735-738, 1992) and the genetic position refined using both meiotic and homozygosity mapping (Schellenberg et al., 1992; Nakura, et al., Genomics 23:600-608, 1994; Thomas, Genomics 16:685-690, 1993). The latter approach is possible since many WS subjects are the offspring of consanguineous marriages (Table 1). Initial mapping work (Nakura, et al., Genomics 23:600-608, 1994; Oshima et al., Genomics 23:100-113, 1994) placed the WRN locus in an 8.3 cM interval flanked by D8S137 and D8S87 (FIG. 1 ). D8S339, a marker within this interval, was the closest locus tested (q=0.001, Z max =15.93). Multipoint analysis placed WRN within 0.6 cM of D8S339, although the region between D8S87 and FGFR could not be excluded. Subsequently, the short tandem repeat polymorphism (STRP) markers at glutathione reductase (GSR) and D8S339 were found to be in linkage disequilibrium with WS in Japanese WS subjects (Yu, American Journal of Human Genetics 55:356-364, 1994).

To clone the WRN gene, a yeast artificial chromosome (YAC) P1, and cosmid contig was generated starting at the GSR/D8S339 region and extended by walking methods to cover approximately 3 Mb. An additional 16 STRP markers in the YAC contig (FIG. 1B) were identified to define recombinants and to delineate the boundaries of the linkage disequilibrium region. For marker ordering and gene identification, cosmids and P1 clones were also isolated and used to construct a small-clone partial contig of the region (FIG. 1 E). The WRN region was defined by obligate recombinants at C41C3S3 excluding the region telomeric to this marker, and at y896R9 excluding the region centormeric to this marker. Thus, the region from C41C3S2 to y896R9, which is approximately 1.2 Mb (FIG. 1 C), was considered the minimal WRN region.

Genes in the WRN region were identified by exon trapping using vector pSL3 (Buckler et al., Proc. Natl. Acad. Sci. USA 88:4005-4009, 1991; Church et al., Nat. Genet . 6:98-105, 1994), hybridization of cDNA libraries to immobilized YACs (Parimoo et al., Proc. Natl. Acad Sci USA 87:3166-3169, 1991), and comparison of the genomic sequence to DNA sequence databases using BLAST (Altschul et al. J. Mol. Biol . 215:403-410, 1990) and the exon-finding program GRAIL (Uberbacher and Mural, Proc. Natl. Acad Sci. USA 88:1261, 1991). The genomic sequence was determined for the region defined by P1 clones 2233, 2253, 3833, 2236, 2237, 2932, 6738 and 2934 and cosmid clone 176 C6. Each method identifies short segments of expressed sequences, which were then used to screen an arrayed fibroblast cDNA library to identify longer cDNA clones. This library was selected because WS fibroblasts have a premature senescence phenotype in vitro, indicating that the WRN gene is probably expressed in this cell type. Genes identified by this process were screened for WRN mutations using reverse transcriptase-polymerase chain reaction (RT-PCR). Seven subjects were initially screened for mutations; 5 WRN subjects (2 Caucasians and 3 Japanese) and 2 control subjects (1 Caucasian and 1 Japanese). Prior to identification of the WRN gene, the following genes from the region were screened for mutations; GSR, PP2AB, TFIIEB, and genes corresponding to other expressed sequence tagged sites (ESTs).

The candidate WRN locus gene was initially detected by using the genomic sequence of P1 clone 2934 to search the EST database. A single 245 bp EST, R58879, was detected which is homologous to 3 segments of the genomic sequence separated by presumed intronic sequence. Sequence from R58879 was used to identify longer cDNA clones from a normal fibroblast cDNA library. An initial 2.1 kb cDNA clone containing EST R58879, which corresponds to the 3′ end of the gene, was obtained by screening an array of clones by PCR, using the primers A and B (see below). Primers A and B are derived from R58879 sequence and yield a 145 bp fragment after amplification. Longer clones were identified by PCR screening with primers SEA and SEB, which were derived from sequences within a predicted exon located in p2934 and 5′ to sequences contained in the initial 2.1 kb clone. Six additional clones were identified. An additional 8 clones were obtained by plaque hybridization. The longest clone is 4.0 kb in length. Additional sequence was obtained by the RAGE method using primer 5EA to prime first strand cDNA synthesis. A 2.5 kb product was obtained that contained an additional 1.4 kb of sequence.

Evidence that R58879 is expressed was obtained by Northern blot analysis, in which 6.5 kb and 8 kb transcripts were detected in a variety of tissues, including heart, placenta, muscle, and pancreas. Also, transcripts were detected by RT-PCR products from fibroblast and lymphoblastoid cell line RNA.

›Example 2

Cloning of the WRN Gene From Subjects

The WRN gene may be isolated from patients and mutations or polymorphisms determined by sequence analysis. Peripheral blood cells are obtained by venipuncture and hypotonic lysis of erythrocytes. DNA or RNA is isolated from these cells and the WRN gene isolated by amplification. The gene sequence may be obtained by amplification of the exons from genomic DNA or by RT-PCR, followed by determination of the DNA sequence. Primers suitable for determining the DNA sequence and for performing RT-PCR are listed below (Primers A-R are SEQ ID Nos. 1-18 respectively, and primers 5EA-5EG are SEQ ID Nos. 19-25 respectively). Two cDNAs were identified and are shown in FIGS. 2 and 3. There is some uncertainty regarding the identity of a few bases in the 5′ untranslated region in FIG. 2 .

Two RT-PCR reactions are used to obtain the gene from different tissues. First strand cDNA synthesis is carried out according to standard procedures (e.g., with a Stratascript Kit from Stratagene). The cDNA is subjected to a pair of nested PCR amplifications, the first with primers I and J (SEQ ID Nos. 9 and 10), followed by primers K and L (SEQ ID Nos. 11 and 12), and the second with primers SED and P (SEQ ID Nos. 22 and 16), followed by primers 5EE and B (SEQ ID Nos. 23 and 2). These fragments are isolated and used for sequencing to identify differences in the gene sequence or splicing pattern. Primers A-H (SEQ ID Nos. 1-8)and K-R (SEQ ID Nos. 11-18) are used for sequencing the first RT-PCR fragment. Primers B, 5EA, 5EB, 5EC, 5EE, 5EF and 5EG (SEQ ID Nos. 2, 19, 20, 21, 23, 24, and 25, repectively) are used for sequencing the second RT-PCR fragment. Sequencing is done on an ABI373A using Applied Biosystems Division of Perkin-Elmer FS sequencing kits according to the instructions of the manufacturer.

The exons of the 3′-end of the WRN gene can be amplified from DNA samples using the primers listed below (Primers EIA-E13B are SEQ ID Nos. 26-57, respectively). The DNA sequence is determined using the same primers and an ABI373A automated sequencer using Applied Biosystems Division of Perkin-Elmer FS sequencing kits according to the instructions of the manufacturer.

›Example 3

Identification of Mutant Alleles

The cDNA sequence (FIG. 2) was aligned to the genomic sequence to identify the exon structure, and primers synthesized for PCR amplification of each exon. DNA sequence of all 13 exons were determined for 5 patients and two unaffected individuals. In 4 of 5 patients single base pair changes lead to splicing defects or stop codons in the open reading frame of the gene. In the fifth patient, a single base pair change results in a cysteine to arginine transition, which may disrupt gene function. Each of the exons was also sequenced in 96 unaffected control individuals (48 Caucasians and 48 Japanese), and none of the mutations were found in any of the control individuals.

The first mutation is a mutation at a splice acceptor site. In the sequence below, the GGTAGAAA sequence begins at nucleotide 2030 (FIG. 2 ). The g to c change results in a deletion of 95 bp.

Preparation of DNA for RT-PCR mutational analysis revealed that for one subject, the amplification product was shorter than observed in products from other WS and control subjects. DNA sequence analysis of the RT-PCR product revealed that 95 bp were missing compared to other samples. The missing sequence corresponds to a single exon. This exon and flanking genomic segments were sequenced from the WS subject and controls and a single base change (G→C) at the splice donor site was detected. The subject was the offspring of a first cousin marriage and was, as expected, homozygous for this mutation. The same mutation was found in a total of 18 out of 30 Japanese WS subjects and, thus, is the most common Japanese WS mutation. Deletion of this exon results in a change in the predicted open-reading frame and a premature stop codon. This mutation was not observed in 46 Japanese and 46 Caucasian controls. Among mutation carriers, 12/16 had the 141 bp allele at the GSR2-STRP.

wild type: ttttaatagGGTAGAAA (SEQ ID No. 58)

Werners: ttttaatacGGTAGAAA (SEQ ID No. 59)

The second mutation changes a C to T at nucleotide 2384 (FIG. 2) changing a glutamine to a stop codon, which results in a predicted truncated protein. This mutation was observed in a single subject. Primers E 11 A and E 11 B flank this sequence and amplify a 360 bp fragment.

The third mutation changes a C to T at nucleotide 2804 (FIG. 2 ), which alters an arginine codon to a stop codon resulting in a predicted truncated protein. Four Japanese WS subjects and 1 Caucasian W5 subject had this mutation. Primers E8A and E8B flank this sequence and amplify a 267 bp product.

The fourth mutation is a 4 bp deletion across a splice junction. The exon sequence shown below begins at nucleotide 2579 (FIG. 2 ). This mutation was identified in a Syrian W5 kindred. Primers E4A and E4B flank this mutation and amplify a 267 bp fragment.

wild type: ctgtagACAGACACCTC (SEQ ID No. 68)

Werners: ctgt - - - AGACACCTC (SEQ ID No. 69)

The fifth mutation is a missense mutation. A T is altered to a G at nucleotide 2113 (FIG. 2 ), changing the wild-type phe codon to a leu codon. This change is a polymorphism with each allele present at a frequency of approximately 0.5 It does not appear to correlate with WS.

The sixth mutation is a missense mutation changing a T to a C at nucleotide 2990 (FIG. 2) and a cys codon to an arg codon.

These point mutations may also be identified by PCR using primers that contain as the 3′-most base either the wild type or the mutant nucleotide. Two separate reactions are performed using one of these primers and a common second primer. Amplification is detectable in the reaction containing a matched primer.

›Example 4

Characterizarion of WRN Gene and Gene Product

The 2 kb WRN cDNA hybridizes to a 6.5 kb RNA and a less abundant 8 kb RNA on a Northern blot, suggesting that a full length coding region is about 5.2 kb long. An overlapping cDNA clone has been isolated that extends the sequence by 2 kb. The insert from this clone is used to probe cDNA libraries to identify other clones that contain the 5′ end of the cDNA or full length sequence. Alternate splicing events are detected by sequencing the full cDNA sequence from a number of different tissues, including fully differentiated cells and stem cells, and the full range of gene transcripts identified by sequence comparison. Additional exons are identified as above by further genomic sequencing and GRAIL analysis.

The predicted amino acid sequence is shown in FIGS. 2B and 3. FIG. 2 shows cDNA and predicted amino acid sequences of the WRN gene. FIG. 3 presents cDNA and predicted amino acid sequences of a less abundant transcript of the WRN gene. The longest open reading frame is shown from the first methionine in that frame. The predicted WRN protein consists of 1,432 amino acids divided into three regions: an N-terminal region, a central region containing 7 motifs (I, Ia, II, III, IV, V and VI) characteristic of the DNA and RNA superfamily of helicases (Gorbalenya et al. Nucleic Acid Res . 17: 4713, 1989), and a C-terminal region (FIG. 8 ). Unlike the central region, the N-terminal and C-terminal domains of the predicted protein do not show amino acid identity to other helicases or to any previously described protein. Because many helicases function as part of a multiprotein complex, the N-terminal and/or the C-terminal domain may contain interaction sites for these other proteins, while the central helicase domain functions in the actual enzymatic unwinding of DNA or RNA duplexes.

The N-terminal region, encompassing approximately codons 1 to 539, is acidic; there are 109 aspartate or glutamate residues, including a stretch of 14 acidic residues in a 19 amino acid sequence (codons 507-526). Stretches of acidic residues are found in the Xeroderma pigmentosum (XP) complementation group B helicase, the Bloom's syndrome helicase, and the X-chromosome-linked α-thalassemia mental retardation syndrome helicase. In the WRN gene, this region also contains a tandem duplication of 27 amino acids in which each copy is encoded by a single exon. Because this duplication is exact at the nucleotide level, and because flanking intronic sequences for the two exons that encode the duplication are also highly similar, this duplication is presumed to be the result of a relatively recent event. The duplicated regions are also highly acidic with 8 glutamate or aspartate residues out of 27 amino acids and only 2 basic amino acids (one histidine and one lysine residue).

The central region of the WRN gene, spanning approximately codons 540-963, is highly homologous to other helicases from a wide range of organisms including the ReqQ gene from E. coli , the SGS1 gene from S. cerevisiae , a predicted helicase (F18C5C) from C. elegans , and several human helicases. Thus, by sequence similarity, the WRN gene is a member of a superfamily of DExH-box DNA and RNA helicases. The principle conserved sequences consist of 7 motifs found in other helicases. These motifs include a predicted nucleotide binding site (motif I) and a Mg 2+ binding site (sequence DEAH, motif II). Some or all of the 7 motifs are presumed to form the enzymatic active site for DNA/RNA unwinding. The presence of the DEAH sequence and an ATP-binding motif further suggests that the WRN gene product is a functional helicase.

The C-terminal end of the WRN gene, from codons 964 to 1432, has limited identity to other genes. The only identity identified is a loose similarity to E. coli ReqQ gene and C. elegans gene F18C5.2.

›Example 5

Identifying and Detecting Mutations in the WRN Gene

Mutations or polymorphisms of WRN may be identified by various methods, including sequence analysis. Although any cell (other than erythrocytes) may be used to isolate nucleic acids, peripheral blood mononuclear cells (PBMC) are preferred. Peripheral blood mononuclear cells are obtained by venipuncture and subsequent hypotonic lysis of erythrocytes. RNA is isolated and first strand cDNA synthesis is performed using a Strata-script RT-PCR kit according to the manufacturers instructions (Stratagene, La Jolla, part numbers 200347 and 200420). Three RT-PCR fragments are amplified using an LA PCR Kit Ver. 2 using buffer containing 1.5 mM Mg+2 (TaKaRa Shuzo Co., Ltd., Japan, part number RRO13A). Nested PCR is performed. In this reaction, a second PCR is performed using a pair of primers within the sequence amplified by the first PCR reaction. The cycling conditions for each amplification are: 10 min at 95° C., 35 cycles of 1 min at 60° C., 1 min at 72° C., and 1 min at 95° C., followed by 7 min at 72° C. in a Perkin-Elmer 9600 PCR machine. The amplified fragments are purified using 96-well plate spin columns (Wang et al., Anal. Biochem . 226:85-90, 1995). DNA sequence is determined using an FS Dye-Terminator sequencing kit (Applied Biosystems Division of Perkin Elmer) and the specific primers described below. An automated Applied Biosystems AB1373A DNA Sequencer is used to determine the sequence. The amplified fragments and the appropriate primers are listed in Table 1, and the primer sequences are listed in Table 2.

The DNA sequences are aligned with the known sequence (FIG. 2A) using the program Sequencher (Gene Codes, Michigan) to identify any discrepancies between patient samples and the reference sequence.

›Example 6

Isolation of Genomic DNA Containing Werner's Syndrome Gene

To facilitate mutational analysis of the WRN gene, the intron-exon structure is determined. The WRN gene is located in the genomic sequence of P1 clone 2934. However, this clone only contains the 3′ end of the gene (exons 21 to 35). Genomic clones containing the 5′ end are obtained from a chromosome 8-specific cosmid library LA08NC01 (Wood et al. Cytogenet. Cell Genet . 59: 243, 1992) by screening for clones adjacent to P1 clone 2934. Briefly, this library is arrayed for PCR screening as described in Amemiya et al. ( Nucl. Acids Res . 20: 2559, 1992). WRN containing cosmids are identified using primer sets 5E6/5EY, 5ED/5E12, and CD-A/CD-B (Table 3), which are derived from the WRN cDNA sequence (FIG. 1; GenBank Accession No. L76937). Four walking steps yielded cosmids 193B5, 114D2, 78D8 and 194C3, which contained the remaining exons. Primers derived from the WRN cDNA were used for the initial sequence analysis of the cosmid clones. The resulting sequence (FIG. 5) is compared to the cDNA sequence to identify intron-exon boundaries. Sequencing primers are then designed from the intron sequences to obtain sequence in the reverse direction and to obtain the second boundary defining the intron-exon junction. This strategy is used to define the exons not present in P1 clone 2934.

The annealing temperature was 60° C. for all primer sets.

Table 4 presents a summary of the structure of the genomic WRN gene. The first column identifies the exon, the second column indicates the base numbers of the cDNA that are derived from the exon, the third column denotes the size of the exon in bp, the fourth column shows the sequence of the boundaries with intron sequences in lower case letters and exon sequences in upper case letters, the fifth column shows notable features of the exons.

As shown above, WRN contains a total of 35 exons ranging in size from 68 bp (exon 14) to 768 bp (exon 35). The coding region begins in the second exon (Table 23). As noted previously, there is a duplicated region in the WRN cDNA sequence which is 27 amino acids in length. This duplication is exactly conserved at the nucleotid level in cDNA. At the genomic level, the duplicated sequences were present as 2 exons (exons 10 and 11), each exon containing only the duplicated nucleotides. The intronic sequences adjacent to these 2 exons are also highly conserved, suggesting that the a relatively recent duplication event is responsible for these repeated exons. In addition, because the surrounding intronic sequences were conserved, it was not possible to design primers which could specifically amplify exons 10 and 11.

The helicase region of the WRN gene is contained in exons 14-21. Helicase motif 1 is split between exons 14 and 15 while the remaining motifs are each in an individual exon (Table 4). This region, from codon 569 to 859, has sequence similarity to the 7 signature helicase motifs. In addition, though the sequences between the motifs are not conserved, the spacing is very similar in genes from a wide range of speciese. For example, the helicase domains in the E. coli RecQ gene are found in a stretch of 288 amino acids compared to 291 amino acids for the WRN gene.

›Example 7 · 1 of 2

Identification of Mutations

Initially, 4 different mutations in the C-terrninal domain of WRN were identified. These mutations accounted for more than 80% of the Japanese WS patients examined. All 4 mutations are in the C-terminal domain region of WRN and the resulting predicted protein contained an intact helicase domain. Additional WS subjects are screened to identify further mutations. Genomic structure information is used to design PCR-primers for amplifying each exon, which is then subjected to DNA sequence analysis. Five additional WRN mutations are described; 2 are located in the consensus helicase motifs and another 2 are predicted to produce truncated proteins without the helicase domains. These mutations suggest that in at least some WS subjects, the enzymatic helicase activity is destroyed and support that complete loss-of-function of WRN gene product causes Werner's syndrome.

Although any cell may be used to isolate DNA, PBMC are preferred. As above, PBMC are obtained by venipuncture and subsequent hypotonic lysis of erythrocytes. PBMC are lysed by the addition of detergent, such as 0.5% NP-40, 0.5% Triton-X100, or 0.5% SDS. If a non-ionic detergent is used, no further purification of DNA is necessary, but proteinase K treatment, and subsequent heat killing of the enzyme (95° C. for 10 minutes) is required. Genomic DNA is amplified according to the PCR conditions recited above using the primers listed in Table 5. Exons 9 and 10 are contained in a region of DNA that is duplicated. The primer pair for exon 9 and 10 anneals to sequences outside the duplication. Amplified product is analyzed by DNA sequence determination, hybridization with allele-specific probe, or other mutation detection method. When DNA sequences are determined, the sequence of the amplified exon is aligned with the known sequence (FIG. 2A) and any discrepancies between patient samples and the reference sequence are identified.

The annealing temperature was 60° C. for all primer sets.

Mutations are detected by amplifying WRN exons from genomic DNA and directly cycle-sequencing the PCR products by dye-terminator cycle sequencing (Perkin Elmer) and an AB1373 automated DNA sequencer. Prior to sequencing, the PCR-amplified exon fragments were purified using a QIAquick 8 PCR purification kit (Qiagen). The resulting sequences are aligned by FASTA analysis (GCG). Nucleotide differences between WS and controls are subsequently confirmed by sequencing the reverse strand.

Reverse transcriptase PCR (RT-PCR) based methods used to identify some mutations (mutations 1-4 and 9, Table 6) and to confirm the predicted consequences of splice-junction mutations. RT-PCR products were synthesized from mRNA isolated from lymphoblastoid cell lines (Qiagen Oligotex, Qiagen). The large genomic deletion was detected in genomic DNA using long-range PCR (Expand Long Template PCR System, Boehringer Mannheim).

Diagnostic Criteria. WS patients were from an International Registry of Werner's Syndrome subjects. Diagnostic criteria are based on the following signs and symptoms (Nakura et al. 1994). Cardinal signs are: 1) bilateral cataracts; 2) characteristic dermatological pathology (tight skin, atrophic skin, pigmentary alterations, ulceration, hyperkeratosis, regional subcutaneous atrophy) and characteristic facies (“bird” facies); 3) short stature; 4) paternal consanguinity (3rd cousin or greater) or affected sibling; 5) premature greying and/or thinning of scalp hair; 6) positive 24-hour urinary hyaluronic acid test, when available). Further criteria are: 1) diabetes mellitus; 2) hypogonadism (secondary sexual underdevelopment, diminished fertility. testicular or ovarian atrophy); 3) osteoporosis; 4) osteosclerosis of distal phalanges of fingers and/or toes (X-ray diagnosis); 5) soft tissue calcification; 6) evidence of premature atherosclerosis (e.g. history of myocardial infarction): 7) mesenchymal neoplasms, rare neoplasms or multiple neoplasms; 8) voice changes (high pitched, squeaky or hoarse voice); 9) flat feet. Diagnostic classifications are as follows: “Definite”, all cardinal signs (#6 when available) and any 2 others; “Probable”, the first 3 cardinal signs and any 2 others; “Possible”, either cataracts or dermatological alterations and any 4 others; “Excluded”, onset of signs and symptoms before adolescence (except short stature since current data on pre-adolescent growth patterns is inadequate) or a negative hyaluronic acid test. Family designations are as previously used (Nakura et al. 1994; Goddard et al. 1996; Yu et al. 1996).

Mutations in WS Subjects. Initial screening of the WRN gene was based on sequence from only the 3′ end of the gene (exons 23-35). Thus the first 4 mutations (designated 1-4, Table 3) were in the region 3′ to the helicase domains. In this mutation screening, primers amplify exons 2-35 along with approximately 80 bp of flanking intronic sequence (Table 5). Initially, 9 WS subjects (Caucasian subjects DJG. EKL, and FES, and Japanese subjects IB, KO, OW, KUN, WKH, and WSF) were screened for mutations. These subjects were selected based on haplotype analysis that suggested that each subject might have a different mutation (Yu et al. 1994; Goddard et al. 1996). A totai of 30 Japanese and 36 Caucasian subjects were ultimately screened for each mutation by DNA sequence analysis of the appropriate exon.

Five new WS mutations were detected in the WRN gene (designated 5-9, Table 6). Two of the mutations (5 and 6) were single base substitutions creating nonsense codons. Mutation 5 results in a C→T transition changing an Arg to a termination codon (Table 6, FIG. 6 ). The predicted protein is truncated at 368 amino acids, excluding the helicase region, which begins at codon 569. Three Japanese and 3 Caucasian subjects were homozygous, and 1 Japanese and 4 Caucasians were heterozygous for this mutation (Table 7). Mutation 6 is also a C→T transition changing an Arg to a nonsense codon. One Caucasian WS subject was homozygous for this mutation, and a second was a compound heterozygote. The predicted protein product is 888 amino acids. A third substitution mutation (mutation 7) was a G→T change at a splice-receptor site, generating a truncated mRNA devoid of exon 20 and a prematurely terminated WRN protein at amino acid 760. A single Japanese WS subject was homozygous for this mutation.

›Example 7 · 2 of 2

Two deletions were observed. One (mutation 8) is a 1 bp deletion at codon 389 resulting in a frame shift and a predicted truncated protein 391 amino acids long. This mutation is found in one Caucasian patient as a heterozygote. The second (mutation 9) is a much larger deletion. This deletion was first observed in RT-PCR experiments when 2 different RT-PCR products were obtained from RNA prepared from subject DJG. RT-PCR products produced by primers SEE and B (Table 5) yielded 2 different products, one with the expected size of 2009 bp, and a second, shorter product approximately 700 bp smaller. The DNA sequence of the shorter product revealed that exons 19 through 23 were missing. To further establish the nature of this mutation, primers (exon 18A and exon 24A, Table 5) derived from the exons flanking this potential gross deletion (exons 18 and 24) were used to amplify genomic DNA from subject DJG using a long-range PCR protocol. A single 5 kb fragment was observed corresponding to the shorter RT-PCR product. (The normal fragment, which is estimated to be >20 kb was not observed.) The complete DNA sequence of this 5 kb fragment was determined and contained the expected 3′ and 5′ ends of exons 18 and 24, respectively. The exonic sequences were separated by intronic sequences adjacent to the 3′ and 5′ end of exons 18 and 24, respectively. No sequences from exons 19-23 were found in the 5 kb fragment. In other subjects and controls, the intronic sequence in the intron 3′ to exon 18 contained 531 bp of unique sequence followed by a 241 bp Alu repeat element. Likewise, for the region 5′ to exon 24, there is an Alu repeat element separated from exon 24 by 3,460 bp of unique sequence. The 4938 bp fragment from subject DJG contained these unique exon-flanking intronic sequences separated by a single Alu element. Thus, this deletion presumably occurred by a recombination error at 2 highly homologous Alu elements within the WRN gene. A primer set, GD-A and GD-D (Table 5) was designed to specifically amplify a short fragment (426 bp) across this junction point. A single additional Caucasian WS patient, SUG, was shown to contain this genomic deletion. Further PCR amplification of the exons within this deleted region demonstrated that both DJG and SUG are heterozygous for this mutation.

Origins of WRN Mutations. Because multiple subjects have the same mutation and because the same mutation was observed in different ethnic groups, at least some of the mutations likely originated in common founders. Evidence for a common founder was examined using 2 short tandem repeat polymorphisms (STRPs) within the WRN gene. These STRPs, D8S2162 and p2934AT1, were isolated from the same P1 clone (p2934) and are within 17.5 kb of each other. While D8S2162 is not particularly polymorphic (heterozygosity=54% in Japanese and 70% in Caucasians) and is primarily a 2 allele system (140 and 142 bp alleles), p2934AT1 is highly polymorphic (heterozygosity=78% in both Japanese and Caucasian populations). For mutation 4, which has only been observed in Japanese subjects, all but 1 subject had the D8S2164/p2934ATI haplotype of 140-148 (Table 8). The single exception, JO2. has the haplotype 140-150, with the p2934AT1 allele being 2 bp different from the 148 bp allele observed in other subjects with mutation 4. This 2 bp difference may be the result of a 2 bp mutation., as is commonly observed in dinucleotide repeat STRP loci (Weber and Wong, 1993). The haplotype data is consistent with a common Japanese founder and is consistent with the linkage disequilibrium observed in the same Japanese subjects for other markers in the WRN region (Yu et al. 1994; Goddard et al., 1996). For mutations 2 and 5, in the Japanese, the 896R18-p2934AT1 haplotypes for the small number of available subjects, are consistent with common founders for each mutation. However, the non-Japanese subjects with mutations 2 and 5 have discordant p2934AT1 genotypes when compared to Japanese subjects with the same mutations. These results do not support a common founder for both Japanese and non-Japanese subjects with mutations 2 and 5. Within the non-Japanese subjects, for mutation 5, there may be as many as 3 different founders since in both cases, different subjects with mutation 5 are discordant for p2934AT1 (e.g. compare AG00780 to EKL). It should be noted that absence of evidence for a common founder does not necessarily exclude the possibility of a single originating mutational event. Intragenic recombination and/or mutations creating new alleles at the 2 STRP loci could, over time, obscure the origins of the different WRN mutations.

The 5 mutations identified here demonstrate that WS mutations are not restricted to the 3′ end of the gene, but are also found in other regions of WRN. In addition, mutations 5 and 7-9 each disrupt either part or all of the helicase region. Thus the WS subjects homozygous for this mutation will completely lack the WRN helicase domains as well as the 3′ end of the protein. Though the possibility exists that the truncated 368 amino acid protein has some partial remaining function, mutation 5 probably results in complete loss of all activity of the WRN protein. However, the WS phenotype in these subjects is not appreciably distinct from the WS phenotype generated by the other mutations described here. Thus, all mutations in the WS gene may be complete loss of function mutations.

›Example 8

Identification of Mouse WRN Gene

The mouse WRN cDNA was isolated by screening a mouse splenocyte cDNA library at low strengency with human WRN cDNA as probe. The mouse cDNA sequence is presented in FIG. 9 . The homology between human and mouse WRN cDNA sequence is about 80%. On the amino acid level, the human and mouse WRN gene product show about 90% identity. Notably, the repeated exon in human WRN cDNA (exons 10 and 11) is only present once in mouse WRN cDNA.

Genomic mouse WRN clone was isolated by using mouse WRN specific primers to screen mouse genomic BAC library. The genomic DNA sequence is presented in FIG. 6 .

The genomic DNA sequence is presentd in FIG. 7 and SEQ ID NOS: 207-209. The DNA sequence is presented in FIG. 6 and SEQ ID NOS: 205 and 206.

›Example 9

Localization of the WRN Gene Product

A rabbit polyclonal antiserum raised to a peptide of WRN gene product is used in an indirect immunofluorescence assay to determine the intracellular localization of the WRN protein.

A rabbit polyclonal antiserum is raised to the peptide Phe-Pro-Gly-Ser-Glu-Glu-Ile-Cys-Ser-Ser-Ser-Lys-Arg (FPGSEEICSSSKR) (SEQ ID NO: 204) by standard methods (see Harlow and Lane, Antibodies, A Laboratory Manual , CSH Press, Cold Spring Harbor, 1989 ; Current Protocols in Immunology , Greene Publishing, 1995). The peptide corresponds to residues 1375 through 1387 of the WRN polypeptide.

Cells, such as epithelial cells, are grown on a plastic or glass surface, fixed with 3% paraformaldehyde and permeabilized for 2 min with a buffer containing 0.5% Triton X-100, 10 mM PIPES, pH 6.8, 50 mM NaCl, 300 mM sucrose, and 3 mM MgCl 2 (see for example, Fey et al., J. Biol. Chem . 98: 1973, 1984). The cells are then stained for 20 min with a suitable dilution of the anti-peptide antibody (1:1500), washed, stained with a suitable second antibody (e.g., FITC-conjugated goat anti-rabbit antibody), washed, and mounted for visualization by gluorescence microscopy. Control stains include bis-benzimidine (Sigma, St. Louis, Mo.), which stains DNA, and phalloidin (Molecular Probes, OR, BODIPY 558/568 phalloidin), which stains filamentous actin.

As seen in FIG. 9, the WRN gene product is almost entirely located in the nucleus. Nuclear staining is readily noted in the epithelial cells at the bottom left in panel A. These cells are close to the periphery of the expanding clone of human prostate epithelial cells. Cells that are not rapidly dividing (e.g., cells closer to the center of the clone), such as those seen in the upper right of panel A, are stained in both the cytoplasm and nucleus. The location and size of the nuclei in these cells is shown by staining DNA with the intercalating dye bis-benzimidine (Hoeschst 33258), panel B. The overall size of the cells and in some cases key cytoskeletal features are revealed by staining for F-actin as shown in panel C.

›Example 10 · 1 of 49

Isolation of a Protein That Binds to the WRN Gene Product

A yeast 2-hybrid interaction screen (Hollenberg et al., Mol. Cell Biol . 13: 3813, 1995) is used to identify and isolate a cellular protein that binds to the carboxy-terminal 443 amino acids (residues 990 through 1432) of the WRN gene product.

A library of 1.1×106 independent cDNA clones generated from RNA isolated from stimulated human peripheral blood mononuclear cells is generated in pACT-2 (Clontech, Palo Alto, Calif.) that creates cDNA/GAL4 activation domain fusions is co-transfected into yeast containing pLEXA with the WRN gene fragment to generate WRN/LEXA DNA-binding fusion. Host yeast cells, L40, are grown on medium lacking leucine, tryptophan, and histidine and containing 4 mM 3AT, a toxic catabolite for histidine. 67 colonies grew on this medium. Of these, 60 were cured of the pLEXA plasmid by growth on medium containing cycloheximide and mated with a yeast strain expressing a fusion of a “sticky” laminin and the GAL4 activation domain. 19 clones did not activate the sticky protein and underwent DNA sequence analysis. Of these, 6 contained sequences that did not match any sequence in GenBank by BLAST search. Two other clones encoded carnitine palmitoyl transferase I and prolyl 4-hydroxylase B subunit. Six independent clones encoded a 70K component of the U1 snRNP complex (GenBank Accession No. M22636). Moreover, all six derived from the RNA recognition motif region of the 70K protein.

From the foregoing, it will be appreciated that, although specific embodiments of this invention have been described herein for the pruposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims.

209

22 base pairs

nucleic acid

single

linear

1

CTGGCAAGGA TCAAACAGAG AG 22

23 base pairs

nucleic acid

single

linear

2

CTTTATGAAG CCAATTTCTA CCC 23

22 base pairs

nucleic acid

single

linear

3

TGGCAAATTG GTAGAAGCTA GG 22

26 base pairs

nucleic acid

single

linear

4

AAATAACTAT GCTTTCTTAC ATTTAC 26

22 base pairs

nucleic acid

single

linear

5

CTCCCGTCAA CTCAGATATG AG 22

26 base pairs

nucleic acid

single

linear

6

CTGTTTGTAA ATGTAAGAAA GCATAG 26

21 base pairs

nucleic acid

single

linear

7

GAGCTATGAT GACACCACTG C 21

21 base pairs

nucleic acid

single

linear

8

ACTGAGCAAC AGAGTGAGAC C 21

22 base pairs

nucleic acid

single

linear

9

GGATCTGGTC TCACTCTGTT GC 22

22 base pairs

nucleic acid

single

linear

10

TTGCCTAGTG CAATTGGTCT CC 22

22 base pairs

nucleic acid

single

linear

11

AGTGCAGTGG TGTCATCATA GC 22

24 base pairs

nucleic acid

single

linear

12

CCTATTTAAT GGCACCCAAA ATGC 24

23 base pairs

nucleic acid

single

linear

13

CAGTCTATGG CCATCACATA CTC 23

22 base pairs

nucleic acid

single

linear

14

ACCGCTTGGG ATAAGTGCAT GC 22

24 base pairs

nucleic acid

single

linear

15

GAGAAGAAGT CTAACTTGGA GAAG 24

23 base pairs

nucleic acid

single

linear

16

TTCTGGTGAC TGTACCATGA TAC 23

23 base pairs

nucleic acid

single

linear

17

CCAAAGGAAG TGATACCAGC AAG 23

24 base pairs

nucleic acid

single

linear

18

ACAGCAAGAA CATAATTGTT CTGG 24

23 base pairs

nucleic acid

single

linear

19

GAACTTTGAA GTCCATCACG ACC 23

24 base pairs

nucleic acid

single

linear

20

GCATTAATAA AGCTGACATT CGCC 24

24 base pairs

nucleic acid

single

linear

21

CATTACGGTG CTCCTAAGGA CATG 24

25 base pairs

nucleic acid

single

linear

22

GATGGATTTG AAGATGGAGT AGAAG 25

25 base pairs

nucleic acid

single

linear

23

TGAAAGAGAA TATGGAAAGA GCTTG 25

25 base pairs

nucleic acid

single

linear

24

GTAGAACCAA CTCATTCTAA ATGCT 25

23 base pairs

nucleic acid

single

linear

25

AATTTGCGTG TCATCCTTGC GCA 23

22 base pairs

nucleic acid

single

linear

26

TCCTAGTCAC CCATCTGAAG TC 22

23 base pairs

nucleic acid

single

linear

27

CATGAAACTT GCTTCTAGGA CAC 23

21 base pairs

nucleic acid

single

linear

28

CCCAGGAGTT CGAGACCATC C 21

23 base pairs

nucleic acid

single

linear

29

TTACAATCGG CCACATTCAT CAC 23

23 base pairs

nucleic acid

single

linear

30

TGTAATCCCA ACACTTTGGG AGG 23

24 base pairs

nucleic acid

single

linear

31

AGTGGAAGAA TTCATAGTGG ATGG 24

24 base pairs

nucleic acid

single

linear

32

TAGCTTTATG AACCAATTTC TACC 24

25 base pairs

nucleic acid

single

linear

33

AATCCAAAGA ATCAATAGAC AAGTC 25

22 base pairs

nucleic acid

single

linear

34

GCTTGAAGGA TGAGGCTCTG AG 22

22 base pairs

nucleic acid

single

linear

35

TGTTCAGAAT GAGCACGATG GG 22

23 base pairs

nucleic acid

single

linear

36

CTTGTGAGAG GCCTATAAAC TGG 23

22 base pairs

nucleic acid

single

linear

37

GGTAAACAGT GTAGGAGTCT GC 22

25 base pairs

nucleic acid

single

linear

38

GCCATTTTCT CTTTAATTGG AAAGG 25

25 base pairs

nucleic acid

single

linear

39

ATCTTATTCA TCTTTCTGAG AATGG 25

23 base pairs

nucleic acid

single

linear

40

TGAAATAGCC CAACATCTGA CAG 23

25 base pairs

nucleic acid

single

linear

41

GATTAATTTG ACAGCTTGAT TAGGC 25

25 base pairs

nucleic acid

single

linear

42

TGAAATATAA ACTCAGACTC TTAGC 25

24 base pairs

nucleic acid

single

linear

43

GTACTGATTT GGAAAGACAT TCTC 24

22 base pairs

nucleic acid

single

linear

44

GATGTGACAG TGGAAGCTAT GG 22

24 base pairs

nucleic acid

single

linear

45

GGAAAAATGT GGTATCTGAA GCTC 24

23 base pairs

nucleic acid

single

linear

46

AAGTGAGCAA ATGTTGCTTC TGG 23

23 base pairs

nucleic acid

single

linear

47

TCATTAGGAA GCTGAACATC AGC 23

24 base pairs

nucleic acid

single

linear

48

GTTGGAGGAA ATTGATCCCA AGTC 24

24 base pairs

nucleic acid

single

linear

49

TGTTGCTTAT GGGTTTAACT TGTG 24

25 base pairs

nucleic acid

single

linear

50

TAAAGGATTA ATGCTGTTAA CAGTG 25

23 base pairs

nucleic acid

single

linear

51

TCACACTGCG CATTTACTAC CTG 23

25 base pairs

nucleic acid

single

linear

52

GTAATCATAT CAGAATTCAT AACAG 25

22 base pairs

nucleic acid

single

linear

53

CTTTGGCAAC CTTCCACCTT CC 22

24 base pairs

nucleic acid

single

linear

54

GCAAAGGAAA TGTAGCACAT AGAG 24

23 base pairs

nucleic acid

single

linear

55

AGGCTATAGG CATTTGAAAG AGG 23

21 base pairs

nucleic acid

single

linear

56

GTAGGCTCCC AGAAGACCCA G 21

23 base pairs

nucleic acid

single

linear

57

GAAAGGATGG GTGTGTATTC AGG 23

17 base pairs

nucleic acid

single

linear

58

TTTTAATAGG GTAGAAA 17

17 base pairs

nucleic acid

single

linear

59

TTTTAATACG GTAGAAA 17

18 base pairs

nucleic acid

single

linear

60

GAAGCTAGGC AGAAACAT 18

18 base pairs

nucleic acid

single

linear

61

GAAGCTAGGT AGAAACAT 18

12 base pairs

nucleic acid

single

linear

62

TTGGAGCGAG CA 12

12 base pairs

nucleic acid

single

linear

63

TTGGAGTGAG CA 12

15 base pairs

nucleic acid

›Example 10 · 2 of 49

single

linear

64

AAGAAGTTTC TTCTG 15

15 base pairs

nucleic acid

single

linear

65

AAGAAGTTGC TTCTG 15

12 base pairs

nucleic acid

single

linear

66

CCTTCATGTG AT 12

12 base pairs

nucleic acid

single

linear

67

CCTTCACGTG AT 12

17 base pairs

nucleic acid

single

linear

68

CTGTAGACAG ACACCTC 17

13 base pairs

nucleic acid

single

linear

69

CTGTAGACAC CTC 13

5208 base pairs

nucleic acid

single

linear

70

TGTGCGCCGG GGAGGCGCCG GCTTGTACTC GGCAGCGCGG GAATAAAGTT TGCTGATTTG 60

GTGTCTAGCC TGGATGCCTG GGTTGCAGCC CTGCTTGTGG TGGCGCTCCA CAGTCATCCG 120

GCTGAAGAAG ACCTGTTGGA CTGGATCTTC TCGGGTTTTC TTTCAGATAT TGTTTTGTAT 180

TTACCCATGA AGACATTGTT TTTTGGACTC TGCAAATAGG ACATTTCAAA GATGAGTGAA 240

AAAAAATTGG AAACAACTGC ACAGCAGCGG AAATGTCCTG AATGGATGAA TGTGCAGAAT 300

AAAAGATGTG CTGTAGAAGA AAGAAAGGCA TGTGTTCGGA AGAGTGTTTT TGAAGATGAC 360

CTCCCCTTCT TAGAATTCAC TGGATCCATT GTGTATAGTT ACGATGCTAG TGATTGCTCT 420

TTCCTGTCAG AAGATATTAG CATGAGTCTA TCAGATGGGG ATGTGGTGGG ATTTGACATG 480

GAGTGGCCAC CATTATACAA TAGAGGGAAA CTTGGCAAAG TTGCACTAAT TCAGTTGTGT 540

GTTTCTGAGA GCAAATGTTA CTTGTTCCAC GTTTCTTCCA TGTCAGTTTT TCCCCAGGGA 600

TTAAAAATGT TGCTTGAAAA TAAAGCAGTT AAAAAGGCAG GTGTAGGAAT TGAAGGAGAT 660

CAGTGGAAAC TTCTACGTGA CTTTGATATC AAATTGAAGA ATTTTGTGGA GTTGACAGAT 720

GTTGCCAATA AAAAGCTGAA ATGTACAGAG ACCTGGAGCC TTAACAGTCT GGTTAAACAC 780

CTCTTAGGTA AACAGCTCCT GAAAGACAAG TCTATCCGCT GTAGCAATTG GAGTAAATTT 840

CCTCTCACTG AGGACCAGAA ACTGTATGCA GCCACTGATG CTTATGCTGG TTTTATTATT 900

TACCGAAATT TAGAGATTTT GGATGATACT GTGCAAAGGT TTGCTATAAA TAAAGAGGAA 960

GAAATCCTAC TTAGCGACAT GAACAAACAG TTGACTTCAA TCTCTGAGGA AGTGATGGAT 1020

CTGGCTAAGC ATCTTCCTCA TGCTTTCAGT AAATTGGAAA ACCCACGGAG GGTTTCTATC 1080

TTACTAAAGG ATATTTCAGA AAATCTATAT TCACTGAGGA GGATGATAAT TGGGTCTACT 1140

AACATTGAGA CTGAACTGAG GCCCAGCAAT AATTTAAACT TATTATCCTT TGAAGATTCA 1200

ACTACTGGGG GAGTACAACA GAAACAAATT AGAGAACATG AAGTTTTAAT TCACGTTGAA 1260

GATGAAACAT GGGACCCAAC ACTTGATCAT TTAGCTAAAC ATGATGGAGA AGATGTACTT 1320

GGAAATAAAG TGGAACGAAA AGAAGATGGA TTTGAAGATG GAGTAGAAGA CAACAAATTG 1380

AAAGAGAATA TGGAAAGAGC TTGTTTGATG TCGTTAGATA TTACAGAACA TGAACTCCAA 1440

ATTTTGGAAC AGCAGTCTCA GGAAGAATAT CTTAGTGATA TTGCTTATAA ATCTACTGAG 1500

CATTTATCTC CCAATGATAA TGAAAACGAT ACGTCCTATG TAATTGAGAG TGATGAAGAT 1560

TTAGAAATGG AGATGCTTAA GCATTTATCT CCCAATGATA ATGAAAACGA TACGTCCTAT 1620

GTAATTGAGA GTGATGAAGA TTTAGAAATG GAGATGCTTA AGTCTTTAGA AAACCTCAAT 1680

AGTGGCACGG TAGAACCAAC TCATTCTAAA TGCTTAAAAA TGGAAAGAAA TCTGGGTCTT 1740

CCTACTAAAG AAGAAGAAGA AGATGATGAA AATGAAGCTA ATGAAGGGGA AGAAGATGAT 1800

GATAAGGACT TTTTGTGGCC AGCACCCAAT GAAGAGCAAG TTACTTGCCT CAAGATGTAC 1860

TTTGGCCATT CCAGTTTTAA ACCAGTTCAG TGGAAAGTGA TTCATTCAGT ATTAGAAGAA 1920

AGAAGAGATA ATGTTGCTGT CATGGCAACT GGATATGGAA AGAGTTTGTG CTTCCAGTAT 1980

CCACCTGTTT ATGTAGGCAA GATTGGCCTT GTTATCTCTC CCCTTATTTC TCTGATGGAA 2040

GACCAAGTGC TACAGCTTAA AATGTCCAAC ATCCCAGCTT GCTTCCTTGG ATCAGCACAG 2100

TCAGAAAATG TTCTAACAGA TATTAAATTA GGTAAATACC GGATTGTATA CGTAACTCCA 2160

GAATACTGTT CAGGTAACAT GGGCCTGCTC CAGCAACTTG AGGCTGATAT TGGTATCACG 2220

CTCATTGCTG TGGATGAGGC TCACTGTATT TCTGAGTGGG GGCATGATTT TAGGGATTCA 2280

TTCAGGAAGT TGGGCTCCCT AAAGACAGCA CTGCCAATGG TTCCAATCGT TGCACTTACT 2340

GCTACTGCAA GTTCTTCAAT CCGGGAAGAC ATTGTACGTT GCTTAAATCT GAGAAATCCT 2400

CAGATCACCT GTACTGGTTT TGATCGACCA AACCTGTATT TAGAAGTTAG GCGAAAAACA 2460

GGGAATATCC TTCAGGATCT GCAGCCATTT CTTGTCAAAA CAAGTTCCCA CTGGGAATTT 2520

GAAGGTCCAA CAATCATCTA CTGTCCTTCT AGAAAAATGA CACAACAAGT TACAGGTGAA 2580

CTTAGGAAAC TTAATCTATC CTGTGGAACA TACCATGCGG GCATGAGTTT TAGCACAAGG 2640

AAAGACATTC ATCATAGGTT TGTAAGAGAT GAAATTCAGT GTGTCATAGC TACCATAGCT 2700

TTTGGAATGG GCATTAATAA AGCTGACATT CGCCAAGTCA TTCATTACGG TGCTCCTAAG 2760

GACATGGAAT CATATTATCA GGAGATTGGT AGAGCTGGTC GTGATGGACT TCAAAGTTCT 2820

TGTCACGTCC TCTGGGCTCC TGCAGACATT AACTTAAATA GGCACCTTCT TACTGAGATA 2880

CGTAATGAGA AGTTTCGATT ATACAAATTA AAGATGATGG CAAAGATGGA AAAATATCTT 2940

CATTCTAGCA GATGTAGGAG ACAAATCATC TTGTCTCATT TTGAGGACAA ACAAGTACAA 3000

AAAGCCTCCT TGGGAATTAT GGGAACTGAA AAATGCTGTG ATAATTGCAG GTCCAGATTG 3060

GATCATTGCT ATTCCATGGA TGACTCAGAG GATACATCCT GGGACTTTGG TCCACAAGCA 3120

TTTAAGCTTT TGTCTGCTGT GGACATCTTA GGCGAAAAAT TTGGAATTGG GCTTCCAATT 3180

TTATTTCTCC GAGGATCTAA TTCTCAGCGT CTTGCCGATC AATATCGCAG GCACAGTTTA 3240

TTTGGCACTG GCAAGGATCA AACAGAGAGT TGGTGGAAGG CTTTTTCCCG TCAGCTGATC 3300

ACTGAGGGAT TCTTGGTAGA AGTTTCTCGG TATAACAAAT TTATGAAGAT TTGCGCCCTT 3360

ACGAAAAAGG GTAGAAATTG GCTTCATAAA GCTAATACAG AATCTCAGAG CCTCATCCTT 3420

CAAGCTAATG AAGAATTGTG TCCAAAGAAG TTTCTTCTGC CTAGTTCGAA AACTGTATCT 3480

TCGGGCACCA AAGAGCATTG TTATAATCAA GTACCAGTTG AATTAAGTAC AGAGAAGAAG 3540

TCTAACTTGG AGAAGTTATA TTCTTATAAA CCATGTGATA AGATTTCTTC TGGGAGTAAC 3600

ATTTCTAAAA AAAGTATCAT GGTACAGTCA CCAGAAAAAG CTTACAGTTC CTCACAGCCT 3660

GTTATTTCGG CACAAGAGCA GGAGACTCAG ATTGTGTTAT ATGGCAAATT GGTAGAAGCT 3720

AGGCAGAAAC ATGCCAATAA AATGGATGTT CCCCCAGCTA TTCTGGCAAC AAACAAGATA 3780

CTGGTGGATA TGGCCAAAAT GAGACCAACT ACGGTTGAAA ACGTAAAAAG GATTGATGGT 3840

GTTTCTGAAG GCAAAGCTGC CATGTTGGCC CCTCTGTTGG AAGTCATCAA ACATTTCTGC 3900

CAAACAAATA GTGTTCAGAC AGACCTCTTT TCAAGTACAA AACCTCAAGA AGAACAGAAG 3960

ACGAGTCTGG TAGCAAAAAA TAAAATATGC ACACTTTCAC AGTCTATGGC CATCACATAC 4020

TCTTTATTCC AAGAAAAGAA GATGCCTTTG AAGAGCATAG CTGAGAGCAG GATTCTGCCT 4080

CTCATGACAA TTGGCATGCA CTTATCCCAA GCGGTGAAAG CTGGCTGCCC CCTTGATTTG 4140

GAGCGAGCAG GCCTGACTCC AGAGGTTCAG AAGATTATTG CTGATGTTAT CCGAAACCCT 4200

CCCGTCAACT CAGATATGAG TAAAATTAGC CTAATCAGAA TGTTAGTTCC TGAAAACATT 4260

GACACGTACC TTATCCACAT GGCAATTGAG ATCCTTAAAC ATGGTCCTGA CAGCGGACTT 4320

CAACCTTCAT GTGATGTCAA CAAAAGGAGA TGTTTTCCCG GTTCTGAAGA GATCTGTTCA 4380

AGTTCTAAGA GAAGCAAGGA AGAAGTAGGC ATCAATACTG AGACTTCATC TGCAGAGAGA 4440

AAGAGACGAT TACCTGTGTG GTTTGCCAAA GGAAGTGATA CCAGCAAGAA ATTAATGGAC 4500

AAAACGAAAA GGGGAGGTCT TTTTAGTTAA GCTGGCAATT ACCAGAACAA TTATGTTTCT 4560

TGCTGTATTA TAAGAGGATA GCTATATTTT ATTTCTGAAG AGTAAGGAGT AGTATTTTGG 4620

CTTAAAAATC ATTCTAATTA CAAAGTTCAC TGTTTATTGA AGAACTGGCA TCTTAAATCA 4680

GCCTTCCGCA ATTCATGTAG TTTCTGGGTC TTCTGGGAGC CTACGTGAGT ACATCACCTA 4740

ACAGAATATT AAATTAGACT TCCTGTAAGA TTGCTTTAAG AAACTGTTAC TGTCCTGTTT 4800

TCTAATCTCT TTATTAAAAC AGTGTATTTG GAAAATGTTA TGTGCTCTGA TTTGATATAG 4860

›Example 10 · 3 of 49

ATAACAGATT AGTAGTTACA TGGTAATTAT GTGATATAAA ATATTCATAT ATTATCAAAA 4920

TTCTGTTTTG TAAATGTAAG AAAGCATAGT TATTTTACAA ATTGTTTTTA CTGTCTTTTG 4980

AAGAAGTTCT TAAATACGTT GTTAAATGGT ATTAGTTGAC CAGGGCAGTG AAAATGAAAC 5040

CGCATTTTGG GTGCCATTAA ATAGGGAAAA AACATGTAAA AAATGTAAAA TGGAGACCAA 5100

TTGCACTAGG CAAGTGTATA TTTTGTATTT TATATACAAT TTCTATTATT TTTCAAGTAA 5160

TAAAACAATG TTTTTCATAC TGAATATTAA AAAAAAAAAA AAAAAAAA 5208

1432 amino acids

amino acid

<Unknown>

linear

71

Met Ser Glu Lys Lys Leu Glu Thr Thr Ala Gln Gln Arg Lys Cys Pr

1 5 10 15

Glu Trp Met Asn Val Gln Asn Lys Arg Cys Ala Val Glu Glu Arg Ly

20 25 30

Ala Cys Val Arg Lys Ser Val Phe Glu Asp Asp Leu Pro Phe Leu Gl

35 40 45

Phe Thr Gly Ser Ile Val Tyr Ser Tyr Asp Ala Ser Asp Cys Ser Ph

50 55 60

Leu Ser Glu Asp Ile Ser Met Ser Leu Ser Asp Gly Asp Val Val Gl

65 70 75 80

Phe Asp Met Glu Trp Pro Pro Leu Tyr Asn Arg Gly Lys Leu Gly Ly

85 90 95

Val Ala Leu Ile Gln Leu Cys Val Ser Glu Ser Lys Cys Tyr Leu Ph

100 105 110

His Val Ser Ser Met Ser Val Phe Pro Gln Gly Leu Lys Met Leu Le

115 120 125

Glu Asn Lys Ala Val Lys Lys Ala Gly Val Gly Ile Glu Gly Asp Gl

130 135 140

Trp Lys Leu Leu Arg Asp Phe Asp Ile Lys Leu Lys Asn Phe Val Gl

145 150 155 160

Leu Thr Asp Val Ala Asn Lys Lys Leu Lys Cys Thr Glu Thr Trp Se

165 170 175

Leu Asn Ser Leu Val Lys His Leu Leu Gly Lys Gln Leu Leu Lys As

180 185 190

Lys Ser Ile Arg Cys Ser Asn Trp Ser Lys Phe Pro Leu Thr Glu As

195 200 205

Gln Lys Leu Tyr Ala Ala Thr Asp Ala Tyr Ala Gly Phe Ile Ile Ty

210 215 220

Arg Asn Leu Glu Ile Leu Asp Asp Thr Val Gln Arg Phe Ala Ile As

225 230 235 240

Lys Glu Glu Glu Ile Leu Leu Ser Asp Met Asn Lys Gln Leu Thr Se

245 250 255

Ile Ser Glu Glu Val Met Asp Leu Ala Lys His Leu Pro His Ala Ph

260 265 270

Ser Lys Leu Glu Asn Pro Arg Arg Val Ser Ile Leu Leu Lys Asp Il

275 280 285

Ser Glu Asn Leu Tyr Ser Leu Arg Arg Met Ile Ile Gly Ser Thr As

290 295 300

Ile Glu Thr Glu Leu Arg Pro Ser Asn Asn Leu Asn Leu Leu Ser Ph

305 310 315 320

Glu Asp Ser Thr Thr Gly Gly Val Gln Gln Lys Gln Ile Arg Glu Hi

325 330 335

Glu Val Leu Ile His Val Glu Asp Glu Thr Trp Asp Pro Thr Leu As

340 345 350

His Leu Ala Lys His Asp Gly Glu Asp Val Leu Gly Asn Lys Val Gl

355 360 365

Arg Lys Glu Asp Gly Phe Glu Asp Gly Val Glu Asp Asn Lys Leu Ly

370 375 380

Glu Asn Met Glu Arg Ala Cys Leu Met Ser Leu Asp Ile Thr Glu Hi

385 390 395 400

Glu Leu Gln Ile Leu Glu Gln Gln Ser Gln Glu Glu Tyr Leu Ser As

405 410 415

Ile Ala Tyr Lys Ser Thr Glu His Leu Ser Pro Asn Asp Asn Glu As

420 425 430

Asp Thr Ser Tyr Val Ile Glu Ser Asp Glu Asp Leu Glu Met Glu Me

435 440 445

Leu Lys His Leu Ser Pro Asn Asp Asn Glu Asn Asp Thr Ser Tyr Va

450 455 460

Ile Glu Ser Asp Glu Asp Leu Glu Met Glu Met Leu Lys Ser Leu Gl

465 470 475 480

Asn Leu Asn Ser Gly Thr Val Glu Pro Thr His Ser Lys Cys Leu Ly

485 490 495

Met Glu Arg Asn Leu Gly Leu Pro Thr Lys Glu Glu Glu Glu Asp As

500 505 510

Glu Asn Glu Ala Asn Glu Gly Glu Glu Asp Asp Asp Lys Asp Phe Le

515 520 525

Trp Pro Ala Pro Asn Glu Glu Gln Val Thr Cys Leu Lys Met Tyr Ph

530 535 540

Gly His Ser Ser Phe Lys Pro Val Gln Trp Lys Val Ile His Ser Va

545 550 555 560

Leu Glu Glu Arg Arg Asp Asn Val Ala Val Met Ala Thr Gly Tyr Gl

565 570 575

Lys Ser Leu Cys Phe Gln Tyr Pro Pro Val Tyr Val Gly Lys Ile Gl

580 585 590

Leu Val Ile Ser Pro Leu Ile Ser Leu Met Glu Asp Gln Val Leu Gl

595 600 605

Leu Lys Met Ser Asn Ile Pro Ala Cys Phe Leu Gly Ser Ala Gln Se

610 615 620

Glu Asn Val Leu Thr Asp Ile Lys Leu Gly Lys Tyr Arg Ile Val Ty

625 630 635 640

Val Thr Pro Glu Tyr Cys Ser Gly Asn Met Gly Leu Leu Gln Gln Le

645 650 655

Glu Ala Asp Ile Gly Ile Thr Leu Ile Ala Val Asp Glu Ala His Cy

660 665 670

Ile Ser Glu Trp Gly His Asp Phe Arg Asp Ser Phe Arg Lys Leu Gl

675 680 685

Ser Leu Lys Thr Ala Leu Pro Met Val Pro Ile Val Ala Leu Thr Al

690 695 700

Thr Ala Ser Ser Ser Ile Arg Glu Asp Ile Val Arg Cys Leu Asn Le

705 710 715 720

Arg Asn Pro Gln Ile Thr Cys Thr Gly Phe Asp Arg Pro Asn Leu Ty

725 730 735

Leu Glu Val Arg Arg Lys Thr Gly Asn Ile Leu Gln Asp Leu Gln Pr

740 745 750

Phe Leu Val Lys Thr Ser Ser His Trp Glu Phe Glu Gly Pro Thr Il

755 760 765

Ile Tyr Cys Pro Ser Arg Lys Met Thr Gln Gln Val Thr Gly Glu Le

770 775 780

Arg Lys Leu Asn Leu Ser Cys Gly Thr Tyr His Ala Gly Met Ser Ph

785 790 795 800

Ser Thr Arg Lys Asp Ile His His Arg Phe Val Arg Asp Glu Ile Gl

805 810 815

Cys Val Ile Ala Thr Ile Ala Phe Gly Met Gly Ile Asn Lys Ala As

820 825 830

Ile Arg Gln Val Ile His Tyr Gly Ala Pro Lys Asp Met Glu Ser Ty

835 840 845

Tyr Gln Glu Ile Gly Arg Ala Gly Arg Asp Gly Leu Gln Ser Ser Cy

850 855 860

His Val Leu Trp Ala Pro Ala Asp Ile Asn Leu Asn Arg His Leu Le

865 870 875 880

Thr Glu Ile Arg Asn Glu Lys Phe Arg Leu Tyr Lys Leu Lys Met Me

885 890 895

Ala Lys Met Glu Lys Tyr Leu His Ser Ser Arg Cys Arg Arg Gln Il

900 905 910

Ile Leu Ser His Phe Glu Asp Lys Gln Val Gln Lys Ala Ser Leu Gl

915 920 925

Ile Met Gly Thr Glu Lys Cys Cys Asp Asn Cys Arg Ser Arg Leu As

930 935 940

His Cys Tyr Ser Met Asp Asp Ser Glu Asp Thr Ser Trp Asp Phe Gl

945 950 955 960

Pro Gln Ala Phe Lys Leu Leu Ser Ala Val Asp Ile Leu Gly Glu Ly

965 970 975

Phe Gly Ile Gly Leu Pro Ile Leu Phe Leu Arg Gly Ser Asn Ser Gl

980 985 990

Arg Leu Ala Asp Gln Tyr Arg Arg His Ser Leu Phe Gly Thr Gly Ly

995 1000 1005

Asp Gln Thr Glu Ser Trp Trp Lys Ala Phe Ser Arg Gln Leu Ile Th

1010 1015 1020

Glu Gly Phe Leu Val Glu Val Ser Arg Tyr Asn Lys Phe Met Lys Il

1025 1030 1035 1040

Cys Ala Leu Thr Lys Lys Gly Arg Asn Trp Leu His Lys Ala Asn Th

1045 1050 1055

Glu Ser Gln Ser Leu Ile Leu Gln Ala Asn Glu Glu Leu Cys Pro Ly

1060 1065 1070

Lys Phe Leu Leu Pro Ser Ser Lys Thr Val Ser Ser Gly Thr Lys Gl

1075 1080 1085

His Cys Tyr Asn Gln Val Pro Val Glu Leu Ser Thr Glu Lys Lys Se

1090 1095 1100

Asn Leu Glu Lys Leu Tyr Ser Tyr Lys Pro Cys Asp Lys Ile Ser Se

1105 1110 1115 1120

Gly Ser Asn Ile Ser Lys Lys Ser Ile Met Val Gln Ser Pro Glu Ly

1125 1130 1135

Ala Tyr Ser Ser Ser Gln Pro Val Ile Ser Ala Gln Glu Gln Glu Th

1140 1145 1150

Gln Ile Val Leu Tyr Gly Lys Leu Val Glu Ala Arg Gln Lys His Al

1155 1160 1165

Asn Lys Met Asp Val Pro Pro Ala Ile Leu Ala Thr Asn Lys Ile Le

1170 1175 1180

Val Asp Met Ala Lys Met Arg Pro Thr Thr Val Glu Asn Val Lys Ar

1185 1190 1195 1200

›Example 10 · 4 of 49

Ile Asp Gly Val Ser Glu Gly Lys Ala Ala Met Leu Ala Pro Leu Le

1205 1210 1215

Glu Val Ile Lys His Phe Cys Gln Thr Asn Ser Val Gln Thr Asp Le

1220 1225 1230

Phe Ser Ser Thr Lys Pro Gln Glu Glu Gln Lys Thr Ser Leu Val Al

1235 1240 1245

Lys Asn Lys Ile Cys Thr Leu Ser Gln Ser Met Ala Ile Thr Tyr Se

1250 1255 1260

Leu Phe Gln Glu Lys Lys Met Pro Leu Lys Ser Ile Ala Glu Ser Ar

1265 1270 1275 1280

Ile Leu Pro Leu Met Thr Ile Gly Met His Leu Ser Gln Ala Val Ly

1285 1290 1295

Ala Gly Cys Pro Leu Asp Leu Glu Arg Ala Gly Leu Thr Pro Glu Va

1300 1305 1310

Gln Lys Ile Ile Ala Asp Val Ile Arg Asn Pro Pro Val Asn Ser As

1315 1320 1325

Met Ser Lys Ile Ser Leu Ile Arg Met Leu Val Pro Glu Asn Ile As

1330 1335 1340

Thr Tyr Leu Ile His Met Ala Ile Glu Ile Leu Lys His Gly Pro As

1345 1350 1355 1360

Ser Gly Leu Gln Pro Ser Cys Asp Val Asn Lys Arg Arg Cys Phe Pr

1365 1370 1375

Gly Ser Glu Glu Ile Cys Ser Ser Ser Lys Arg Ser Lys Glu Glu Va

1380 1385 1390

Gly Ile Asn Thr Glu Thr Ser Ser Ala Glu Arg Lys Arg Arg Leu Pr

1395 1400 1405

Val Trp Phe Ala Lys Gly Ser Asp Thr Ser Lys Lys Leu Met Asp Ly

1410 1415 1420

Thr Lys Arg Gly Gly Leu Phe Ser

1425 1430

TTTGGAATTG GGCTTCCAAT TTTATTTCTC CGAGGATCTG GTCTCACTCT GTTGCTCAGT 60

CTGTAGTGCA GTGGTGTCAT CATAGCTCAC TGCAGTCTTG ATCTCCTGAG CTCAAACGAT 120

TCTCCTGCCT CAGCTCCTGC TTCAGCCTCC TGAGTAGCGG AACAACAGAA TTCTCAGCGT 180

CTTGCCGATC AATATCGCAG GCACAGTTTA TTTGGCACTG GCAAGGATCA AACAGAGAGT 240

TGGTGGAAGG CTTTTTCCCG TCAGCTGATC ACTGAGGGAT TCTTGGTAGA AGTTTCTCGG 300

TATAACAAAT TT ATG AAG ATT TGC GCC CTT ACG AAA AAG GGT AGA AAT 348

Met Lys Ile Cys Ala Leu Thr Lys Lys Gly Arg Asn

1065 1070

TGG CTT CAT AAA GCT AAT ACA GAA TCT CAG AGC CTC ATC CTT CAA GCT 396

Trp Leu His Lys Ala Asn Thr Glu Ser Gln Ser Leu Ile Leu Gln Ala

1075 1080 1085 1090

AAT GAA GAA TTG TGT CCA AAG AAG TTT CTT CTG CCT AGT TCG AAA ACT 444

Asn Glu Glu Leu Cys Pro Lys Lys Phe Leu Leu Pro Ser Ser Lys Thr

1095 1100 1105

GTA TCT TCG GGC ACC AAA GAG CAT TGT TAT AAT CAA GTA CCA GTT GAA 492

Val Ser Ser Gly Thr Lys Glu His Cys Tyr Asn Gln Val Pro Val Glu

1110 1115 1120

TTA AGT ACA GAG AAG AAG TCT AAC TTG GAG AAG TTA TAT TCT TAT AAA 540

Leu Ser Thr Glu Lys Lys Ser Asn Leu Glu Lys Leu Tyr Ser Tyr Lys

1125 1130 1135

CCA TGT GAT AAG ATT TCT TCT GGG AGT AAC ATT TCT AAA AAA AGT ATC 588

Pro Cys Asp Lys Ile Ser Ser Gly Ser Asn Ile Ser Lys Lys Ser Ile

1140 1145 1150

ATG GTA CAG TCA CCA GAA AAA GCT TAC AGT TCC TCA CAG CCT GTT ATT 636

Met Val Gln Ser Pro Glu Lys Ala Tyr Ser Ser Ser Gln Pro Val Ile

1155 1160 1165 1170

TCG GCA CAA GAG CAG GAG ACT CAG ATT GTG TTA TAT GGC AAA TTG GTA 684

Ser Ala Gln Glu Gln Glu Thr Gln Ile Val Leu Tyr Gly Lys Leu Val

1175 1180 1185

GAA GCT AGG CAG AAA CAT GCC AAT AAA ATG GAT GTT CCC CCA GCT ATT 732

Glu Ala Arg Gln Lys His Ala Asn Lys Met Asp Val Pro Pro Ala Ile

1190 1195 1200

CTG GCA ACA AAC AAG ATA CTG GTG GAT ATG GCC AAA ATG AGA CCA ACT 780

Leu Ala Thr Asn Lys Ile Leu Val Asp Met Ala Lys Met Arg Pro Thr

1205 1210 1215

ACG GTT GAA AAC GTA AAA AGG ATT GAT GGT GTT TCT GAA GGC AAA GCT 828

Thr Val Glu Asn Val Lys Arg Ile Asp Gly Val Ser Glu Gly Lys Ala

1220 1225 1230

GCC ATG TTG GCC CCT CTG TTG GAA GTC ATC AAA CAT TTC TGC CAA ACA 876

Ala Met Leu Ala Pro Leu Leu Glu Val Ile Lys His Phe Cys Gln Thr

1235 1240 1245 1250

AAT AGT GTT CAG ACA GAC CTC TTT TCA AGT ACA AAA CCT CAA GAA GAA 924

Asn Ser Val Gln Thr Asp Leu Phe Ser Ser Thr Lys Pro Gln Glu Glu

1255 1260 1265

CAG AAG ACG AGT CTG GTA GCA AAA AAT AAA ATA TGC ACA CTT TCA CAG 972

Gln Lys Thr Ser Leu Val Ala Lys Asn Lys Ile Cys Thr Leu Ser Gln

1270 1275 1280

TCT ATG GCC ATC ACA TAC TCT TTA TTC CAA GAA AAG AAG ATG CCT TTG 1020

Ser Met Ala Ile Thr Tyr Ser Leu Phe Gln Glu Lys Lys Met Pro Leu

1285 1290 1295

AAG AGC ATA GCT GAG AGC AGG ATT CTG CCT CTC ATG ACA ATT GGC ATG 1068

Lys Ser Ile Ala Glu Ser Arg Ile Leu Pro Leu Met Thr Ile Gly Met

1300 1305 1310

CAC TTA TCC CAA GCG GTG AAA GCT GGC TGC CCC CTT GAT TTG GAG CGA 1116

His Leu Ser Gln Ala Val Lys Ala Gly Cys Pro Leu Asp Leu Glu Arg

1315 1320 1325 1330

GCA GGC CTG ACT CCA GAG GTT CAG AAG ATT ATT GCT GAT GTT ATC CGA 1164

Ala Gly Leu Thr Pro Glu Val Gln Lys Ile Ile Ala Asp Val Ile Arg

1335 1340 1345

AAC CCT CCC GTC AAC TCA GAT ATG AGT AAA ATT AGC CTA ATC AGA ATG 1212

Asn Pro Pro Val Asn Ser Asp Met Ser Lys Ile Ser Leu Ile Arg Met

1350 1355 1360

TTA GTT CCT GAA AAC ATT GAC ACG TAC CTT ATC CAC ATG GCA ATT GAG 1260

Leu Val Pro Glu Asn Ile Asp Thr Tyr Leu Ile His Met Ala Ile Glu

1365 1370 1375

ATC CTT AAA CAT GGT CCT GAC AGC GGA CTT CAA CCT TCA TGT GAT GTC 1308

Ile Leu Lys His Gly Pro Asp Ser Gly Leu Gln Pro Ser Cys Asp Val

1380 1385 1390

AAC AAA AGG AGA TGT TTT CCC GGT TCT GAA GAG ATC TGT TCA AGT TCT 1356

Asn Lys Arg Arg Cys Phe Pro Gly Ser Glu Glu Ile Cys Ser Ser Ser

1395 1400 1405 1410

AAG AGA AGC AAG GAA GAA GTA GGC ATC AAT ACT GAG ACT TCA TCT GCA 1404

Lys Arg Ser Lys Glu Glu Val Gly Ile Asn Thr Glu Thr Ser Ser Ala

1415 1420 1425

GAG AGA AAG AGA CGA TTA CCT GTG TGG TTT GCC AAA GGA AGT GAT ACC 1452

Glu Arg Lys Arg Arg Leu Pro Val Trp Phe Ala Lys Gly Ser Asp Thr

1430 1435 1440

AGC AAG AAA TTA ATG GAC AAA ACG AAA AGG GGA GGT CTT TTT AGT 1497

Ser Lys Lys Leu Met Asp Lys Thr Lys Arg Gly Gly Leu Phe Ser

1445 1450 1455

TAAGCTGGCA ATTACCAGAA CAATTATGTT TCTTGCTGTA TTATAAGAGG ATAGCTATAT 1557

TTTATTTCTG AAGAGTAAGG AGTAGTATTT TGGCTTAAAA ATCATTCTAA TTACAAAGTT 1617

CACTGTTTAT TGAAGAACTG GCATCTTAAA TCAGCCTTCC GCAATTCATG TAGTTTCTGG 1677

GTCTTCTGGG AGCCTACGTG AGTACATCAC CTAACAGAAT ATTAAATTAG ACTTCCTGTA 1737

AGATTGCTTT AAGAAACTGT TACTGTCCTG TTTTCTAATC TCTTTATTAA AACAGTGTAT 1797

TTGGAAAATG TTATGTGCTC TGATTTGATA TAGATAACAG ATTAGTAGTT ACATGGTAAT 1857

TATGTGATAT AAAATATTCA TATATTATCA AAATTCTGTT TTGTAAATGT AAGAAAGCAT 1917

AGTTATTTTA CAAATTGTTT TTACTGTCTT TTGAAGAAGT TCTTAAATAC GTTGTTAAAT 1977

GGTATTAGTT GACCAGGGCA GTGAAAATGA AACCGCATTT TGGGTGCCAT TAAATAGGGA 2037

AAAAACATGT AAAAAATGTA AAATGGAGAC CAATTGCACT AGGCAAGTGT ATATTTTGTA 2097

TTTTATATAC AATTTCTATT ATTTTTCAAG TAATAAAACA ATGTTTTTCA TACTGAATAT 2157

TAAAAAAAAA AAAAAAAAAA A 2178

395 amino acids

amino acid

linear

protein

73

Met Lys Ile Cys Ala Leu Thr Lys Lys Gly Arg Asn Trp Leu His Lys

1 5 10 15

Ala Asn Thr Glu Ser Gln Ser Leu Ile Leu Gln Ala Asn Glu Glu Leu

›Example 10 · 5 of 49

20 25 30

Cys Pro Lys Lys Phe Leu Leu Pro Ser Ser Lys Thr Val Ser Ser Gly

35 40 45

Thr Lys Glu His Cys Tyr Asn Gln Val Pro Val Glu Leu Ser Thr Glu

50 55 60

Lys Lys Ser Asn Leu Glu Lys Leu Tyr Ser Tyr Lys Pro Cys Asp Lys

65 70 75 80

Ile Ser Ser Gly Ser Asn Ile Ser Lys Lys Ser Ile Met Val Gln Ser

85 90 95

Pro Glu Lys Ala Tyr Ser Ser Ser Gln Pro Val Ile Ser Ala Gln Glu

100 105 110

Gln Glu Thr Gln Ile Val Leu Tyr Gly Lys Leu Val Glu Ala Arg Gln

115 120 125

Lys His Ala Asn Lys Met Asp Val Pro Pro Ala Ile Leu Ala Thr Asn

130 135 140

Lys Ile Leu Val Asp Met Ala Lys Met Arg Pro Thr Thr Val Glu Asn

145 150 155 160

Val Lys Arg Ile Asp Gly Val Ser Glu Gly Lys Ala Ala Met Leu Ala

165 170 175

Pro Leu Leu Glu Val Ile Lys His Phe Cys Gln Thr Asn Ser Val Gln

180 185 190

Thr Asp Leu Phe Ser Ser Thr Lys Pro Gln Glu Glu Gln Lys Thr Ser

195 200 205

Leu Val Ala Lys Asn Lys Ile Cys Thr Leu Ser Gln Ser Met Ala Ile

210 215 220

Thr Tyr Ser Leu Phe Gln Glu Lys Lys Met Pro Leu Lys Ser Ile Ala

225 230 235 240

Glu Ser Arg Ile Leu Pro Leu Met Thr Ile Gly Met His Leu Ser Gln

245 250 255

Ala Val Lys Ala Gly Cys Pro Leu Asp Leu Glu Arg Ala Gly Leu Thr

260 265 270

Pro Glu Val Gln Lys Ile Ile Ala Asp Val Ile Arg Asn Pro Pro Val

275 280 285

Asn Ser Asp Met Ser Lys Ile Ser Leu Ile Arg Met Leu Val Pro Glu

290 295 300

Asn Ile Asp Thr Tyr Leu Ile His Met Ala Ile Glu Ile Leu Lys His

305 310 315 320

Gly Pro Asp Ser Gly Leu Gln Pro Ser Cys Asp Val Asn Lys Arg Arg

325 330 335

Cys Phe Pro Gly Ser Glu Glu Ile Cys Ser Ser Ser Lys Arg Ser Lys

340 345 350

Glu Glu Val Gly Ile Asn Thr Glu Thr Ser Ser Ala Glu Arg Lys Arg

355 360 365

Arg Leu Pro Val Trp Phe Ala Lys Gly Ser Asp Thr Ser Lys Lys Leu

370 375 380

Met Asp Lys Thr Lys Arg Gly Gly Leu Phe Ser

385 390 395

1269 amino acids

amino acid

single

linear

74

Glu Asp Gly Phe Glu Asp Gly Val Glu Asp Asn Lys Leu Lys Glu As

1 5 10 15

Met Glu Arg Ala Cys Leu Met Ser Leu Asp Ile Thr Glu His Glu Le

20 25 30

Gln Ile Leu Glu Gln Gln Ser Gln Glu Glu Tyr Leu Ser Asp Ile Al

35 40 45

Tyr Lys Ser Thr Glu His Leu Ser Pro Asn Asp Asn Glu Asn Asp Th

50 55 60

Ser Tyr Val Ile Glu Ser Asp Glu Asp Leu Glu Met Glu Met Leu Ly

65 70 75 80

His Leu Ser Pro Asn Asp Asn Glu Asn Asp Thr Ser Tyr Val Ile Gl

85 90 95

Ser Asp Glu Asp Leu Glu Met Glu Met Leu Lys Ser Leu Glu Asn Le

100 105 110

Asn Ser Gly Thr Val Glu Pro Thr His Ser Lys Cys Leu Lys Met Gl

115 120 125

Arg Asn Leu Gly Leu Pro Thr Lys Glu Glu Glu Glu Asp Asp Glu As

130 135 140

Glu Ala Asn Glu Gly Glu Glu Asp Asp Asp Lys Asp Phe Leu Trp Pr

145 150 155 160

Ala Pro Asn Glu Glu Gln Val Thr Cys Leu Lys Met Tyr Phe Gly Hi

165 170 175

Ser Ser Phe Lys Pro Val Gln Trp Lys Val Ile His Ser Val Leu Gl

180 185 190

Glu Arg Arg Asp Asn Val Ala Val Met Ala Thr Gly Tyr Gly Lys Se

195 200 205

Leu Cys Phe Gln Tyr Pro Pro Val Tyr Val Gly Lys Ile Gly Leu Va

210 215 220

Ile Ser Pro Leu Ile Ser Leu Met Glu Asp Gln Val Leu Gln Leu Ly

225 230 235 240

Met Ser Asn Ile Pro Ala Cys Phe Leu Gly Ser Ala Gln Ser Glu As

245 250 255

Val Leu Thr Asp Ile Lys Leu Gly Lys Tyr Arg Ile Val Tyr Val Th

260 265 270

Pro Glu Tyr Cys Ser Gly Asn Met Gly Leu Leu Gln Gln Leu Glu Al

275 280 285

Asp Ile Gly Ile Thr Leu Ile Ala Val Asp Glu Ala His Cys Ile Se

290 295 300

Glu Trp Gly His Asp Phe Arg Asp Ser Phe Arg Lys Leu Gly Ser Le

305 310 315 320

Lys Thr Ala Leu Pro Met Val Pro Ile Val Ala Leu Thr Ala Thr Al

325 330 335

Ser Ser Ser Ile Arg Glu Asp Ile Val Arg Cys Leu Asn Leu Arg As

340 345 350

Pro Gln Ile Thr Cys Thr Gly Phe Asp Arg Pro Asn Leu Tyr Leu Gl

355 360 365

Val Arg Arg Lys Thr Gly Asn Ile Leu Gln Asp Leu Gln Pro Phe Le

370 375 380

Val Lys Thr Ser Ser His Trp Glu Phe Glu Gly Pro Thr Ile Ile Ty

385 390 395 400

Cys Pro Ser Arg Lys Met Thr Gln Gln Val Thr Gly Glu Leu Arg Ly

405 410 415

Leu Asn Leu Ser Cys Gly Thr Tyr His Ala Gly Met Ser Phe Ser Th

420 425 430

Arg Lys Asp Ile His His Arg Phe Val Arg Asp Glu Ile Gln Cys Va

435 440 445

Ile Ala Thr Ile Ala Phe Gly Met Gly Ile Asn Lys Ala Asp Ile Ar

450 455 460

Gln Val Ile His Tyr Gly Ala Pro Lys Asp Met Glu Ser Tyr Tyr Gl

465 470 475 480

Glu Ile Gly Arg Ala Gly Arg Asp Gly Leu Gln Ser Ser Cys His Va

485 490 495

Leu Trp Ala Pro Ala Asp Ile Asn Leu Asn Arg His Leu Leu Thr Gl

500 505 510

Ile Arg Asn Glu Lys Phe Arg Leu Tyr Lys Leu Lys Met Met Ala Ly

515 520 525

Met Glu Lys Tyr Leu His Ser Ser Arg Cys Arg Arg Gln Ile Ile Le

530 535 540

Ser His Phe Glu Asp Lys Gln Val Gln Lys Ala Ser Leu Gly Ile Me

545 550 555 560

Gly Thr Glu Lys Cys Cys Asp Asn Cys Arg Ser Arg Leu Asp His Cy

565 570 575

Tyr Ser Met Asp Asp Ser Glu Asp Thr Ser Trp Asp Phe Gly Pro Gl

580 585 590

Ala Phe Lys Leu Leu Ser Ala Val Asp Ile Leu Gly Glu Lys Phe Gl

595 600 605

Ile Gly Leu Pro Ile Leu Phe Leu Arg Gly Ser Asn Ser Gln Arg Le

610 615 620

Ala Asp Gln Tyr Arg Arg His Ser Leu Phe Gly Thr Gly Lys Asp Gl

625 630 635 640

Thr Glu Ser Trp Trp Lys Ala Phe Ser Arg Gln Leu Ile Thr Glu Gl

645 650 655

Phe Leu Val Glu Val Ser Arg Tyr Asn Lys Phe Met Lys Ile Cys Al

660 665 670

Leu Thr Lys Lys Gly Arg Asn Trp Leu His Lys Ala Asn Thr Glu Se

675 680 685

Gln Ser Leu Ile Leu Gln Ala Asn Glu Glu Leu Cys Pro Lys Lys Ph

690 695 700

Leu Leu Pro Ser Ser Lys Thr Val Ser Ser Gly Thr Lys Glu His Cy

705 710 715 720

Tyr Asn Gln Val Pro Val Glu Leu Ser Thr Glu Lys Lys Ser Asn Le

725 730 735

Glu Lys Leu Tyr Ser Tyr Lys Pro Cys Asp Lys Ile Ser Ser Gly Se

740 745 750

Asn Ile Ser Lys Lys Ser Ile Met Val Gln Ser Pro Glu Lys Ala Ty

755 760 765

Ser Ser Ser Gln Pro Val Ile Ser Ala Gln Glu Gln Glu Thr Gln Il

770 775 780

Val Leu Tyr Gly Lys Leu Val Glu Ala Arg Gln Lys His Ala Asn Ly

785 790 795 800

Met Asp Val Pro Pro Ala Ile Leu Ala Thr Asn Lys Ile Leu Val As

805 810 815

Met Ala Lys Met Arg Pro Thr Thr Val Glu Asn Val Lys Arg Ile As

820 825 830

Gly Val Ser Glu Gly Lys Ala Ala Met Leu Ala Pro Leu Leu Glu Va

835 840 845

Ile Lys His Phe Cys Gln Thr Asn Ser Val Gln Thr Asp Leu Phe Se

850 855 860

Ser Thr Lys Pro Gln Glu Glu Gln Lys Thr Ser Leu Val Ala Lys As

865 870 875 880

Lys Ile Cys Thr Leu Ser Gln Ser Met Ala Ile Thr Tyr Ser Leu Ph

885 890 895

Gln Glu Lys Lys Met Pro Leu Lys Ser Ile Ala Glu Ser Arg Ile Le

900 905 910

Pro Leu Met Thr Ile Gly Met His Leu Ser Gln Ala Val Lys Ala Gl

915 920 925

Cys Pro Leu Asp Leu Glu Arg Ala Gly Leu Thr Pro Glu Val Gln Ly

›Example 10 · 6 of 49

930 935 940

Ile Ile Ala Asp Val Ile Arg Asn Pro Pro Val Asn Ser Asp Met Se

945 950 955 960

Lys Ile Ser Leu Ile Arg Met Leu Val Pro Glu Asn Ile Asp Thr Ty

965 970 975

Leu Ile His Met Ala Ile Glu Ile Leu Lys His Gly Pro Asp Ser Gl

980 985 990

Leu Gln Pro Ser Cys Asp Val Asn Lys Arg Arg Cys Phe Pro Gly Se

995 1000 1005

Glu Glu Ile Cys Ser Ser Ser Lys Arg Ser Lys Glu Glu Val Gly Il

1010 1015 1020

Asn Thr Glu Thr Ser Ser Ala Glu Arg Lys Arg Arg Leu Pro Val Tr

1025 1030 1035 1040

Phe Ala Lys Gly Ser Asp Thr Ser Lys Lys Leu Met Asp Lys Thr Ly

1045 1050 1055

Arg Gly Gly Leu Phe Ser Ala Gly Asn Tyr Gln Asn Asn Tyr Val Se

1060 1065 1070

Cys Cys Ile Ile Arg Gly Leu Tyr Phe Ile Ser Glu Glu Gly Val Va

1075 1080 1085

Phe Trp Leu Lys Asn His Ser Asn Tyr Lys Val His Cys Leu Leu Ly

1090 1095 1100

Asn Trp His Leu Lys Ser Ala Phe Arg Asn Ser Cys Ser Phe Trp Va

1105 1110 1115 1120

Phe Trp Glu Pro Thr Val His His Leu Thr Glu Tyr Ile Arg Leu Pr

1125 1130 1135

Val Arg Leu Leu Glu Thr Val Thr Val Leu Phe Ser Asn Leu Phe Il

1140 1145 1150

Lys Thr Val Tyr Leu Glu Asn Val Met Cys Ser Asp Leu Ile Ile Th

1155 1160 1165

Asp Leu His Gly Asn Tyr Val Ile Asn Ile His Ile Leu Ser Lys Ph

1170 1175 1180

Cys Phe Val Asn Val Arg Lys His Ser Tyr Phe Thr Asn Cys Phe Ty

1185 1190 1195 1200

Cys Leu Leu Lys Lys Phe Leu Asn Thr Leu Leu Asn Gly Ile Ser Pr

1205 1210 1215

Gly Gln Lys Asn Arg Ile Leu Gly Ala Ile Lys Gly Lys Asn Met Ly

1220 1225 1230

Met Asn Gly Asp Gln Leu His Ala Ser Val Tyr Phe Val Phe Tyr Il

1235 1240 1245

Gln Phe Leu Leu Phe Phe Lys Asn Asn Val Phe His Thr Glu Tyr Ly

1250 1255 1260

Lys Lys Lys Lys Lys

1265

607 amino acids

amino acid

single

linear

75

Ala Gln Ala Glu Val Leu Asn Leu Glu Ser Gly Ala Lys Gln Val Le

1 5 10 15

Gln Glu Thr Phe Gly Tyr Gln Gln Phe Arg Pro Gly Gln Glu Glu Il

20 25 30

Ile Asp Thr Val Leu Ser Gly Arg Asp Cys Leu Val Val Met Pro Th

35 40 45

Gly Gly Gly Lys Ser Leu Cys Tyr Gln Ile Pro Ala Leu Leu Leu As

50 55 60

Gly Leu Thr Val Val Val Ser Pro Leu Ile Ser Leu Met Lys Asp Gl

65 70 75 80

Val Asp Gln Leu Gln Ala Asn Gly Val Ala Ala Ala Cys Leu Asn Se

85 90 95

Thr Gln Thr Arg Glu Gln Gln Leu Glu Val Met Thr Gly Cys Arg Th

100 105 110

Gly Gln Ile Arg Leu Leu Tyr Ile Ala Pro Glu Arg Leu Met Leu As

115 120 125

Asn Phe Leu Glu His Leu Ala His Trp Asn Pro Val Leu Leu Ala Va

130 135 140

Asp Glu Ala His Cys Ile Ser Gln Trp Gly His Asp Phe Arg Pro Gl

145 150 155 160

Tyr Ala Ala Leu Gly Gln Leu Arg Gln Arg Phe Pro Thr Leu Pro Ph

165 170 175

Met Ala Leu Thr Ala Thr Ala Asp Asp Thr Thr Arg Gln Asp Ile Va

180 185 190

Arg Leu Leu Gly Leu Asn Asp Pro Leu Ile Gln Ile Ser Ser Phe As

195 200 205

Arg Pro Asn Ile Arg Tyr Met Leu Met Glu Lys Phe Lys Pro Leu As

210 215 220

Gln Leu Met Arg Tyr Val Gln Glu Gln Arg Gly Lys Ser Gly Ile Il

225 230 235 240

Tyr Cys Asn Ser Arg Ala Lys Val Glu Asp Thr Ala Ala Ala Leu Gl

245 250 255

Ser Lys Gly Ile Ser Ala Ala Ala Tyr His Ala Gly Leu Glu Asn As

260 265 270

Val Arg Ala Asp Val Gln Glu Lys Phe Gln Arg Asp Asp Leu Gln Il

275 280 285

Val Val Ala Thr Val Ala Phe Gly Met Gly Ile Asn Lys Pro Asn Va

290 295 300

Arg Phe Val Val His Phe Asp Ile Pro Arg Asn Ile Glu Ser Tyr Ty

305 310 315 320

Gln Glu Thr Gly Arg Ala Gly Arg Asp Gly Leu Pro Ala Glu Ala Me

325 330 335

Leu Phe Tyr Asp Pro Ala Asp Met Ala Trp Leu Arg Arg Cys Leu Gl

340 345 350

Glu Lys Pro Gln Gly Gln Leu Gln Asp Ile Glu Arg His Lys Leu As

355 360 365

Ala Met Gly Ala Phe Ala Glu Ala Gln Thr Cys Arg Arg Leu Val Le

370 375 380

Leu Asn Tyr Phe Gly Glu Gly Arg Gln Glu Pro Cys Gly Asn Cys As

385 390 395 400

Ile Cys Leu Asp Pro Pro Lys Gln Tyr Asp Gly Ser Thr Asp Ala Gl

405 410 415

Ile Ala Leu Ser Thr Ile Gly Arg Val Asn Gln Arg Phe Gly Met Gl

420 425 430

Tyr Val Val Glu Val Ile Arg Gly Ala Asn Asn Gln Arg Ile Arg As

435 440 445

Tyr Gly His Asp Lys Leu Lys Val Tyr Gly Met Gly Arg Asp Lys Se

450 455 460

His Glu His Trp Val Ser Val Ile Arg Gln Leu Ile His Leu Gly Le

465 470 475 480

Val Thr Gln Asn Ile Ala Gln His Ser Ala Leu Gln Leu Thr Glu Al

485 490 495

Ala Arg Pro Val Leu Ala Glu Ser Ser Leu Gln Leu Ala Val Pro Ar

500 505 510

Ile Val Ala Leu Lys Pro Lys Ala Met Gln Lys Ser Phe Gly Gly As

515 520 525

Tyr Asp Arg Lys Leu Phe Ala Lys Leu Arg Lys Leu Arg Lys Ser Il

530 535 540

Ala Asp Glu Ser Asn Val Pro Pro Tyr Val Val Phe Asn Asp Ala Th

545 550 555 560

Leu Ile Glu Met Ala Glu Gln Met Pro Ile Thr Ala Ser Glu Met Le

565 570 575

Ser Val Asn Gly Val Gly Met Arg Lys Leu Glu Arg Phe Gly Lys Pr

580 585 590

Phe Met Ala Leu Ile Arg Ala His Val Asp Gly Asp Asp Glu Glu

595 600 605

1328 amino acids

amino acid

single

linear

76

Met Thr Val Thr Lys Thr Asn Leu Asn Arg His Leu Asp Trp Phe Ph

1 5 10 15

Arg Glu Ser Pro Gln Lys Ile Glu Asn Val Thr Ser Pro Ile Lys Th

20 25 30

Leu Asp Phe Val Lys Val Lys Val Ser Ser Ser Asp Ile Val Val Ly

35 40 45

Asp Ser Ile Pro His Lys Ser Lys Asn Val Phe Asp Asp Phe Asp As

50 55 60

Gly Tyr Ala Ile Asp Leu Thr Glu Glu His Gln Ser Ser Ser Leu As

65 70 75 80

Asn Leu Lys Trp Lys Asp Val Glu Gly Pro Asn Ile Leu Lys Pro Il

85 90 95

Lys Lys Ile Ala Val Pro Ala Ser Glu Ser Glu Glu Asp Phe Asp As

100 105 110

Val Asp Glu Glu Met Leu Arg Ala Ala Glu Met Glu Val Phe Gln Se

115 120 125

Cys Gln Pro Leu Ala Val Asn Thr Ala Asp Thr Thr Val Ser His Se

130 135 140

Thr Ser Ser Ser Asn Val Pro Arg Ser Leu Asn Lys Ile His Asp Pr

145 150 155 160

Ser Arg Phe Ile Lys Asp Asn Asp Val Glu Asn Arg Ile His Val Se

165 170 175

Ser Ala Ser Lys Val Ala Ser Ile Ser Asn Thr Ser Lys Pro Asn Pr

180 185 190

Ile Val Ser Glu Asn Pro Ile Ser Ala Thr Ser Val Ser Ile Glu Il

195 200 205

Pro Ile Lys Pro Lys Glu Leu Ser Asn Asn Leu Pro Phe Pro Arg Le

210 215 220

Asn Asn Asn Asn Thr Asn Asn Asn Asn Asp Asn Asn Ala Ile Glu Ly

225 230 235 240

Arg Asp Ser Ala Ser Pro Thr Pro Ser Ser Val Ser Ser Gln Ile Se

245 250 255

Ile Asp Phe Ser Thr Trp Pro His Gln Asn Leu Leu Gln Tyr Leu As

260 265 270

Ile Leu Arg Asp Glu Lys Ser Glu Ile Ser Asp Arg Ile Ile Glu Va

275 280 285

Met Glu Arg Tyr Pro Phe Ser Ser Arg Phe Lys Glu Trp Ile Pro Ly

290 295 300

Arg Asp Ile Leu Ser Gln Lys Ile Ser Ser Val Leu Glu Val Leu Se

305 310 315 320

Asn Asn Asn Asn Ser Asn Asn Asn Asn Gly Asn Asn Gly Thr Val Pr

325 330 335

Asn Ala Lys Thr Phe Phe Thr Pro Pro Ser Ser Ile Thr Gln Gln Va

›Example 10 · 7 of 49

340 345 350

Pro Phe Pro Ser Thr Ile Ile Pro Glu Ser Thr Val Lys Glu Asn Se

355 360 365

Thr Arg Pro Tyr Val Asn Ser His Leu Val Ala Asn Asp Lys Ile Th

370 375 380

Ala Thr Pro Phe His Ser Glu Ala Val Val Ser Pro Leu Gln Ser As

385 390 395 400

Ile Arg Asn Ser Asp Ile Ala Glu Phe Asp Glu Phe Asp Ile Asp As

405 410 415

Ala Asp Phe Thr Phe Asn Thr Thr Asp Pro Ile Asn Asp Glu Ser Gl

420 425 430

Ala Ser Ser Asp Val Val Val Ile Asp Asp Glu Glu Asp Asp Ile Gl

435 440 445

Asn Arg Pro Leu Asn Gln Ala Leu Lys Ala Ser Lys Ala Ala Val Se

450 455 460

Asn Ala Ser Leu Leu Gln Ser Ser Ser Leu Asp Arg Pro Leu Leu Gl

465 470 475 480

Glu Met Lys Asp Lys Asn His Lys Val Leu Met Pro Ser Leu Asp As

485 490 495

Pro Met Leu Ser Tyr Pro Trp Ser Lys Glu Val Leu Gly Cys Leu Ly

500 505 510

His Lys Phe His Leu Lys Gly Phe Arg Lys Asn Gln Leu Glu Ala Il

515 520 525

Asn Gly Thr Leu Ser Gly Lys Asp Val Phe Ile Leu Met Pro Thr Gl

530 535 540

Gly Gly Lys Ser Leu Cys Tyr Gln Leu Pro Ala Val Ile Glu Gly Gl

545 550 555 560

Ala Ser Arg Gly Val Thr Leu Val Ile Ser Pro Leu Leu Ser Leu Me

565 570 575

Gln Asp Gln Leu Asp His Leu Arg Lys Leu Asn Ile Pro Ser Leu Pr

580 585 590

Leu Ser Gly Glu Gln Pro Ala Asp Glu Arg Arg Gln Val Ile Ser Ph

595 600 605

Leu Met Ala Lys Asn Val Leu Val Lys Leu Leu Tyr Val Thr Pro Gl

610 615 620

Gly Leu Ala Ser Asn Gly Ala Ile Thr Arg Val Leu Lys Ser Leu Ty

625 630 635 640

Glu Arg Lys Leu Leu Ala Arg Ile Val Ile Asp Glu Ala His Cys Va

645 650 655

Ser His Trp Gly His Asp Phe Arg Pro Asp Tyr Lys Gln Leu Gly Le

660 665 670

Leu Arg Asp Arg Tyr Gln Gly Ile Pro Phe Met Ala Leu Thr Ala Th

675 680 685

Ala Asn Glu Ile Val Lys Lys Asp Ile Ile Asn Thr Leu Arg Met Gl

690 695 700

Asn Cys Leu Glu Leu Lys Ser Ser Phe Asn Arg Pro Asn Leu Phe Ty

705 710 715 720

Glu Ile Lys Pro Lys Lys Asp Leu Tyr Thr Glu Leu Tyr Arg Phe Il

725 730 735

Ser Asn Gly His Leu His Glu Ser Gly Ile Ile Tyr Cys Leu Ser Ar

740 745 750

Thr Ser Cys Glu Gln Val Ala Ala Lys Leu Arg Asn Asp Tyr Gly Le

755 760 765

Lys Ala Trp His Tyr His Ala Gly Leu Glu Lys Val Glu Arg Gln Ar

770 775 780

Ile Gln Asn Glu Trp Gln Ser Gly Ser Tyr Lys Ile Ile Val Ala Th

785 790 795 800

Ile Ala Phe Gly Met Gly Val Asp Lys Gly Asp Val Arg Phe Val Il

805 810 815

His His Ser Phe Pro Lys Ser Leu Glu Gly Tyr Tyr Gln Glu Thr Gl

820 825 830

Arg Ala Gly Arg Asp Gly Lys Pro Ala His Cys Ile Met Phe Tyr Se

835 840 845

Tyr Lys Asp His Val Thr Phe Gln Lys Leu Ile Met Ser Gly Asp Gl

850 855 860

Asp Ala Glu Thr Lys Glu Arg Gln Arg Gln Met Leu Arg Gln Val Il

865 870 875 880

Gln Phe Cys Glu Asn Lys Thr Asp Cys Arg Arg Lys Gln Val Leu Al

885 890 895

Tyr Phe Gly Glu Asn Phe Asp Lys Val His Cys Arg Lys Gly Cys As

900 905 910

Ile Cys Cys Glu Glu Ala Thr Tyr Ile Lys Gln Asp Met Thr Glu Ph

915 920 925

Ser Leu Gln Ala Ile Lys Leu Leu Lys Ser Ile Ser Gly Lys Ala Th

930 935 940

Leu Leu Gln Leu Met Asp Ile Phe Arg Gly Ser Lys Ser Ala Lys Il

945 950 955 960

Val Glu Asn Gly Trp Asp Arg Leu Glu Gly Ala Gly Val Gly Lys Le

965 970 975

Leu Asn Arg Gly Asp Ser Glu Arg Leu Phe His His Leu Val Ser Gl

980 985 990

Gly Val Phe Val Glu Lys Val Glu Ala Asn Arg Arg Gly Phe Val Se

995 1000 1005

Ala Tyr Val Val Pro Gly Arg Gln Thr Ile Ile Asn Ser Val Leu Al

1010 1015 1020

Gly Lys Arg Arg Ile Ile Leu Asp Val Lys Glu Ser Ser Ser Lys Pr

1025 1030 1035 1040

Asp Thr Ser Ser Arg Ser Leu Ser Arg Ser Lys Thr Leu Pro Ala Le

1045 1050 1055

Arg Glu Tyr Gln Leu Lys Ser Thr Thr Ala Ser Val Asp Cys Ser Il

1060 1065 1070

Gly Thr Arg Glu Val Asp Glu Ile Tyr Asp Ser Gln Met Pro Pro Va

1075 1080 1085

Lys Pro Ser Leu Ile His Ser Arg Asn Lys Ile Asp Leu Glu Glu Le

1090 1095 1100

Ser Gly Gln Lys Phe Met Ser Glu Tyr Glu Ile Asp Val Met Thr Ar

1105 1110 1115 1120

Cys Leu Lys Asp Leu Lys Leu Leu Arg Ser Asn Leu Met Ala Ile As

1125 1130 1135

Asp Ser Arg Val Ser Ser Tyr Phe Thr Asp Ser Val Leu Leu Ser Me

1140 1145 1150

Ala Lys Lys Leu Pro Arg Asn Val Lys Glu Leu Lys Glu Ile His Gl

1155 1160 1165

Val Ser Asn Glu Lys Ala Val Asn Leu Gly Pro Lys Phe Leu Gln Va

1170 1175 1180

Ile Gln Lys Phe Ile Asp Glu Lys Glu Gln Asn Leu Glu Gly Thr Gl

1185 1190 1195 1200

Leu Asp Pro Ser Leu Gln Ser Leu Asp Thr Asp Tyr Pro Ile Asp Th

1205 1210 1215

Asn Ala Leu Ser Leu Asp His Glu Gln Gly Phe Ser Asp Asp Ser As

1220 1225 1230

Ser Val Tyr Glu Pro Ser Ser Pro Ile Glu Glu Gly Asp Glu Glu Va

1235 1240 1245

Asp Gly Gln Arg Lys Asp Ile Leu Asn Phe Met Asn Ser Gln Ser Le

1250 1255 1260

Thr Gln Thr Gly Ser Val Pro Lys Arg Lys Ser Thr Ser Tyr Thr Ar

1265 1270 1275 1280

Pro Ser Lys Ser Tyr Arg His Lys Arg Gly Ser Thr Ser Tyr Ser Ar

1285 1290 1295

Lys Arg Lys Tyr Ser Thr Ser Gln Lys Asp Ser Arg Lys Thr Ser Ly

1300 1305 1310

Ser Ala Asn Thr Ser Phe Ile His Pro Met Val Lys Gln Asn Tyr Ar

1315 1320 1325

659 amino acids

amino acid

single

linear

77

Met Ala Ser Val Ser Ala Leu Thr Glu Glu Leu Asp Ser Ile Thr Se

1 5 10 15

Glu Leu His Ala Val Glu Ile Gln Ile Gln Glu Leu Thr Glu Arg Gl

20 25 30

Gln Glu Leu Ile Gln Lys Lys Lys Val Leu Thr Lys Lys Ile Lys Gl

35 40 45

Cys Leu Glu Asp Ser Asp Ala Gly Ala Ser Asn Glu Tyr Asp Ser Se

50 55 60

Pro Ala Ala Trp Asn Lys Glu Asp Phe Pro Trp Ser Gly Lys Val Ly

65 70 75 80

Asp Ile Leu Gln Asn Val Phe Lys Leu Glu Lys Phe Arg Pro Leu Gl

85 90 95

Leu Glu Thr Ile Asn Val Thr Met Ala Gly Lys Glu Val Phe Leu Va

100 105 110

Met Pro Thr Gly Gly Gly Lys Ser Leu Cys Tyr Gln Leu Pro Ala Le

115 120 125

Cys Ser Asp Gly Phe Thr Leu Val Ile Cys Pro Leu Ile Ser Leu Me

130 135 140

Glu Asp Gln Leu Met Val Leu Lys Gln Leu Gly Ile Ser Ala Thr Me

145 150 155 160

Leu Asn Ala Ser Ser Ser Lys Glu His Val Lys Trp Val His Asp Gl

165 170 175

Met Val Asn Lys Asn Ser Glu Leu Lys Leu Ile Tyr Val Thr Pro Gl

180 185 190

Lys Ile Ala Lys Ser Lys Met Phe Met Ser Arg Leu Glu Lys Ala Ty

195 200 205

Glu Ala Arg Arg Phe Thr Arg Ile Ala Val Asp Glu Val His Cys Cy

210 215 220

Ser Gln Trp Gly His Asp Phe Arg Pro Asp Tyr Lys Ala Leu Gly Il

225 230 235 240

Leu Lys Arg Gln Phe Pro Asn Ala Ser Leu Ile Gly Leu Thr Ala Th

245 250 255

Ala Thr Asn His Val Leu Thr Asp Ala Gln Lys Ile Leu Cys Ile Gl

260 265 270

Lys Cys Phe Thr Phe Thr Ala Ser Phe Asn Arg Pro Asn Leu Tyr Ty

275 280 285

Glu Val Arg Gln Lys Pro Ser Asn Thr Glu Asp Phe Ile Glu Asp Il

290 295 300

Val Lys Leu Ile Asn Gly Arg Tyr Lys Gly Gln Ser Gly Ile Ile Ty

›Example 10 · 8 of 49

305 310 315 320

Cys Phe Ser Gln Lys Asp Ser Glu Gln Val Thr Val Ser Leu Gln As

325 330 335

Leu Gly Ile His Ala Gly Ala Tyr His Ala Asn Leu Glu Pro Glu As

340 345 350

Lys Thr Thr Val His Arg Lys Trp Ser Ala Asn Glu Ile Gln Val Va

355 360 365

Val Ala Thr Val Ala Phe Gly Met Gly Ile Asp Lys Pro Asp Val Ar

370 375 380

Phe Val Ile His His Ser Met Ser Lys Ser Met Glu Asn Tyr Tyr Gl

385 390 395 400

Glu Ser Gly Arg Ala Gly Arg Asp Asp Met Lys Ala Asp Cys Ile Le

405 410 415

Tyr Tyr Gly Phe Gly Asp Ile Phe Arg Ile Ser Ser Met Val Val Me

420 425 430

Glu Asn Val Gly Gln Gln Lys Leu Tyr Glu Met Val Ser Tyr Cys Gl

435 440 445

Asn Ile Ser Lys Ser Arg Arg Val Leu Met Ala Gln His Phe Asp Gl

450 455 460

Val Trp Asn Ser Glu Ala Cys Asn Lys Met Cys Asp Asn Cys Cys Ly

465 470 475 480

Asp Ser Ala Phe Glu Arg Thr Asn Ile Thr Glu Tyr Cys Arg Asp Le

485 490 495

Ile Lys Ile Leu Lys Gln Ala Glu Glu Leu Asn Glu Lys Leu Thr Pr

500 505 510

Leu Lys Leu Ile Asp Ser Trp Met Gly Lys Gly Ala Ala Lys Leu Ar

515 520 525

Val Ala Gly Val Val Ala Pro Thr Leu Pro Arg Glu Asp Leu Glu Ly

530 535 540

Ile Ile Ala His Phe Leu Ile Gln Gln Tyr Leu Lys Glu Asp Tyr Se

545 550 555 560

Phe Thr Ala Tyr Ala Ala Ile Ser Tyr Leu Lys Ile Gly Pro Lys Al

565 570 575

Asn Leu Leu Asn Asn Glu Ala His Ala Ile Thr Met Gln Val Thr Ly

580 585 590

Ser Thr Gln Asn Ser Phe Arg Ala Glu Ser Ser Gln Thr Cys His Se

595 600 605

Glu Gln Gly Asp Lys Lys Asn Gly Gly Lys Lys Ile Gln Ala Thr Se

610 615 620

Arg Arg Arg Leu Gln Thr Cys Phe Ser Asn Leu Val Leu Arg Ile Gl

625 630 635 640

Glu Leu Arg Lys Glu Lys Ser Met Met Pro Asp Met Asn Val Thr Ly

645 650 655

Phe Ser Asn

1417 amino acids

amino acid

single

linear

78

Met Ala Ala Val Pro Gln Asn Asn Leu Gln Glu Gln Leu Glu Arg Hi

1 5 10 15

Ser Ala Arg Thr Leu Asn Asn Lys Leu Ser Leu Ser Lys Pro Lys Ph

20 25 30

Ser Gly Phe Thr Phe Lys Lys Lys Thr Ser Ser Asp Asn Asn Val Se

35 40 45

Val Thr Asn Val Ser Val Ala Lys Thr Pro Val Leu Arg Asn Lys As

50 55 60

Val Asn Val Thr Glu Asp Phe Ser Phe Ser Glu Pro Leu Pro Asn Th

65 70 75 80

Thr Asn Gln Gln Arg Val Lys Asp Phe Phe Lys Asn Ala Pro Ala Gl

85 90 95

Gln Glu Thr Gln Arg Gly Gly Ser Lys Ser Leu Leu Pro Asp Phe Le

100 105 110

Gln Thr Pro Lys Glu Val Val Cys Thr Thr Gln Asn Thr Pro Thr Va

115 120 125

Lys Lys Ser Arg Asp Thr Ala Leu Lys Lys Leu Glu Phe Ser Ser Se

130 135 140

Pro Asp Ser Leu Ser Thr Ile Asn Asp Trp Asp Asp Met Asp Asp Ph

145 150 155 160

Asp Thr Ser Glu Thr Ser Lys Ser Phe Val Thr Pro Pro Gln Ser Hi

165 170 175

Phe Val Arg Val Ser Thr Ala Gln Lys Ser Lys Lys Gly Lys Arg As

180 185 190

Phe Phe Lys Ala Gln Leu Tyr Thr Thr Asn Thr Val Lys Thr Asp Le

195 200 205

Pro Pro Pro Ser Ser Glu Ser Glu Gln Ile Asp Leu Thr Glu Glu Gl

210 215 220

Lys Asp Asp Ser Glu Trp Leu Ser Ser Asp Val Ile Cys Ile Asp As

225 230 235 240

Gly Pro Ile Ala Glu Val His Ile Asn Glu Asp Ala Gln Glu Ser As

245 250 255

Ser Leu Lys Thr His Leu Glu Asp Glu Arg Asp Asn Ser Glu Lys Ly

260 265 270

Lys Asn Leu Glu Glu Ala Glu Leu His Ser Thr Glu Lys Val Pro Cy

275 280 285

Ile Glu Phe Asp Asp Asp Asp Tyr Asp Thr Asp Phe Val Pro Pro Se

290 295 300

Pro Glu Glu Ile Ile Ser Ala Ser Ser Ser Ser Ser Lys Cys Leu Se

305 310 315 320

Thr Leu Lys Asp Leu Asp Thr Ser Asp Arg Lys Glu Asp Val Leu Se

325 330 335

Thr Ser Lys Asp Leu Leu Ser Lys Pro Glu Lys Met Ser Met Gln Gl

340 345 350

Leu Asn Pro Glu Thr Ser Thr Asp Cys Asp Ala Arg Gln Ile Ser Le

355 360 365

Gln Gln Gln Leu Ile His Val Met Glu His Ile Cys Lys Leu Ile As

370 375 380

Thr Ile Pro Asp Asp Lys Leu Lys Leu Leu Asp Cys Gly Asn Glu Le

385 390 395 400

Leu Gln Gln Arg Asn Ile Arg Arg Lys Leu Leu Thr Glu Val Asp Ph

405 410 415

Asn Lys Ser Asp Ala Ser Leu Leu Gly Ser Leu Trp Arg Tyr Arg Pr

420 425 430

Asp Ser Leu Asp Gly Pro Met Glu Gly Asp Ser Cys Pro Thr Gly As

435 440 445

Ser Met Lys Glu Leu Asn Phe Ser His Leu Pro Ser Asn Ser Val Se

450 455 460

Pro Gly Asp Cys Leu Leu Thr Thr Thr Leu Gly Lys Thr Gly Phe Se

465 470 475 480

Ala Thr Arg Lys Asn Leu Phe Glu Arg Pro Leu Phe Asn Thr His Le

485 490 495

Gln Lys Ser Phe Val Ser Ser Asn Trp Ala Glu Thr Pro Arg Leu Gl

500 505 510

Lys Lys Asn Glu Ser Ser Tyr Phe Pro Gly Asn Val Leu Thr Ser Th

515 520 525

Ala Val Lys Asp Gln Asn Lys His Thr Ala Ser Ile Asn Asp Leu Gl

530 535 540

Arg Glu Thr Gln Pro Ser Tyr Asp Ile Asp Asn Phe Asp Ile Asp As

545 550 555 560

Phe Asp Asp Asp Asp Asp Trp Glu Asp Ile Met His Asn Leu Ala Al

565 570 575

Ser Lys Ser Ser Thr Ala Ala Tyr Gln Pro Ile Lys Glu Gly Arg Pr

580 585 590

Ile Lys Ser Val Ser Glu Arg Leu Ser Ser Ala Lys Thr Asp Cys Le

595 600 605

Pro Val Ser Ser Thr Ala Gln Asn Ile Asn Phe Ser Glu Ser Ile Gl

610 615 620

Asn Tyr Thr Asp Lys Ser Ala Gln Asn Leu Ala Ser Arg Asn Leu Ly

625 630 635 640

His Glu Arg Phe Gln Ser Leu Ser Phe Pro His Thr Lys Glu Met Me

645 650 655

Lys Ile Phe His Lys Lys Phe Gly Leu His Asn Phe Arg Thr Asn Gl

660 665 670

Leu Glu Ala Ile Asn Ala Ala Leu Leu Gly Glu Asp Cys Phe Ile Le

675 680 685

Met Pro Thr Gly Gly Gly Lys Ser Leu Cys Tyr Gln Leu Pro Ala Cy

690 695 700

Val Ser Pro Gly Val Thr Val Val Ile Ser Pro Leu Arg Ser Leu Il

705 710 715 720

Val Asp Gln Val Gln Lys Leu Thr Ser Leu Asp Ile Pro Ala Thr Ty

725 730 735

Leu Thr Gly Asp Lys Thr Asp Ser Glu Ala Thr Asn Ile Tyr Leu Gl

740 745 750

Leu Ser Lys Lys Asp Pro Ile Ile Lys Leu Leu Tyr Val Thr Pro Gl

755 760 765

Lys Ile Cys Ala Ser Asn Arg Leu Ile Ser Thr Leu Glu Asn Leu Ty

770 775 780

Glu Arg Lys Leu Leu Ala Arg Phe Val Ile Asp Glu Ala His Cys Va

785 790 795 800

Ser Gln Trp Gly His Asp Phe Arg Gln Asp Tyr Lys Arg Met Asn Me

805 810 815

Leu Arg Gln Lys Phe Pro Ser Val Pro Val Met Ala Leu Thr Ala Th

820 825 830

Ala Asn Pro Arg Val Gln Lys Asp Ile Leu Thr Gln Leu Lys Ile Le

835 840 845

Arg Pro Gln Val Phe Ser Met Ser Phe Asn Arg His Asn Leu Lys Ty

850 855 860

Tyr Val Leu Pro Lys Lys Pro Lys Lys Val Ala Phe Asp Cys Leu Gl

865 870 875 880

Trp Ile Arg Lys His His Pro Tyr Asp Ser Gly Ile Ile Tyr Cys Le

885 890 895

Ser Arg Arg Glu Cys Asp Thr Met Ala Asp Thr Leu Gln Arg Asp Gl

900 905 910

Leu Ala Ala Leu Ala Tyr His Ala Gly Leu Ser Asp Ser Ala Arg As

915 920 925

Glu Val Gln Gln Lys Trp Ile Asn Gln Asp Gly Cys Gln Val Ile Cy

930 935 940

Ala Thr Ile Ala Phe Gly Met Gly Ile Asp Lys Pro Asp Val Arg Ph

›Example 10 · 9 of 49

945 950 955 960

Val Ile His Ala Ser Leu Pro Lys Ser Val Glu Gly Tyr Tyr Gln Gl

965 970 975

Ser Gly Arg Ala Gly Arg Asp Gly Glu Ile Ser His Cys Leu Leu Ph

980 985 990

Tyr Thr Tyr His Asp Val Thr Arg Leu Lys Arg Leu Ile Met Met Gl

995 1000 1005

Lys Asp Gly Asn His His Thr Arg Glu Thr His Phe Asn Asn Leu Ty

1010 1015 1020

Ser Met Val His Tyr Cys Glu Asn Ile Thr Glu Cys Arg Arg Ile Gl

1025 1030 1035 1040

Leu Leu Ala Tyr Phe Gly Glu Asn Gly Phe Asn Pro Asp Phe Cys Ly

1045 1050 1055

Lys His Pro Asp Val Ser Cys Asp Asn Cys Cys Lys Thr Lys Asp Ty

1060 1065 1070

Lys Thr Arg Asp Val Thr Asp Asp Val Lys Ser Ile Val Arg Phe Va

1075 1080 1085

Gln Glu His Ser Ser Ser Gln Gly Met Arg Asn Ile Lys His Val Gl

1090 1095 1100

Pro Ser Gly Arg Phe Thr Met Asn Met Leu Val Asp Ile Phe Leu Gl

1105 1110 1115 1120

Ser Lys Ser Ala Lys Ile Gln Ser Gly Ile Phe Gly Lys Gly Ser Al

1125 1130 1135

Tyr Ser Arg His Asn Ala Glu Arg Leu Phe Lys Lys Leu Ile Leu As

1140 1145 1150

Lys Ile Leu Asp Glu Asp Leu Tyr Ile Asn Ala Asn Asp Gln Ala Il

1155 1160 1165

Ala Tyr Val Met Leu Gly Asn Lys Ala Gln Thr Val Leu Asn Gly As

1170 1175 1180

Leu Lys Val Asp Phe Met Glu Thr Glu Asn Ser Ser Ser Val Lys Ly

1185 1190 1195 1200

Gln Lys Ala Leu Val Ala Lys Val Ser Gln Arg Glu Glu Met Val Ly

1205 1210 1215

Lys Cys Leu Gly Glu Leu Thr Glu Val Cys Lys Ser Leu Gly Lys Va

1220 1225 1230

Phe Gly Val His Tyr Phe Asn Ile Phe Asn Thr Val Thr Leu Lys Ly

1235 1240 1245

Leu Ala Glu Ser Leu Ser Ser Asp Pro Glu Val Leu Leu Gln Ile As

1250 1255 1260

Gly Val Thr Glu Asp Lys Leu Glu Lys Tyr Gly Ala Glu Val Ile Se

1265 1270 1275 1280

Val Leu Gln Lys Tyr Ser Glu Trp Thr Ser Pro Ala Glu Asp Ser Se

1285 1290 1295

Pro Gly Ile Ser Leu Ser Ser Ser Arg Gly Pro Gly Arg Ser Ala Al

1300 1305 1310

Glu Glu Leu Asp Glu Glu Ile Pro Val Ser Ser His Tyr Phe Ala Se

1315 1320 1325

Lys Thr Arg Asn Glu Arg Lys Arg Lys Lys Met Pro Ala Ser Gln Ar

1330 1335 1340

Ser Lys Arg Arg Lys Thr Ala Ser Ser Gly Ser Lys Ala Lys Gly Gl

1345 1350 1355 1360

Ser Ala Thr Cys Arg Lys Ile Ser Ser Lys Thr Lys Ser Ser Ser Il

1365 1370 1375

Ile Gly Ser Ser Ser Ala Ser His Thr Ser Gln Ala Thr Ser Gly Al

1380 1385 1390

Asn Ser Lys Leu Gly Ile Met Ala Pro Pro Lys Pro Ile Asn Arg Pr

1395 1400 1405

Phe Leu Lys Pro Ser Tyr Ala Phe Ser

1410 1415

87350 base pairs

nucleic acid

single

linear

79

TATATTATGG CTATTTTTCT TTCTTATCTA TTTGTATTTT TATTGTTATT ACCTAAAAAA 60

AAATTTTCTA TGTCTTATCA CTAATTCTTC CCTAAAATTT CCCACAATTG TGTAAACTTA 120

CCTCAGTATA TTCATAGATA TGAGACATTC TATCAATTTT ACCCTCTTAA AGATGCAGAA 180

ATAATGCATT ATGTTTCATC CCACCATCTT TAATGAGAAG CTTCCATCTT AGATTAATAT 240

TAGAGAATGT TAAAATACTC TGCAATCAGG TAAGGACGCT TGAAACTTCA TCATAATGCA 300

AAAGTTTTCT TTAACACAAT AAATATTTTG AACCCCTTTT GTGTCTTGTA TTCATAGGAG 360

TTCAGATAGA CCACTTTATT TACTATTTTT TATAGAGAGT GAACAGAAAT CCCATTTCTA 420

GTCACCAGTC CTTAATCTGT AAATCAGGCA GATAATCTGT AAATGATTGG TTGAAATCAC 480

ATTGAATTCC ACTTTGTGCC AGGGACTTAA GTTAACGAAC AAATTATTCT TACAAAAAGG 540

TATAAATGTA AGGTTTTCAT TCCGCTAAAT ATGTTTGTCA AACTGTGTTG TGATTTGTTC 600

TCAGTGTGTC ATAGCTACCA TAGCTTTTGG AATGGGCATT AATAAAGCTG ACATTCGCCA 660

AGTCATTCAT TACGGTGCTC CTAAGGACAT GGAATCATAT TATCAGGAGA TTGGTAGAGC 720

TGGTCGTGAT GGACTTCAAA GTTCTTGTCA CGTCCTCTGG GCTCCTGCAG ACATTAACTT 780

AAATAGGTAA AAAAAATTTA TTGTTTTTAC TCTTGCAGAT TTCTTTCTTT CTTTCCATAT 840

AAACCTCAAA AGTGTTTGAG GCTATTTCCA GTATCCCAAG TAATTTGTGA GTGCATTTAA 900

AGTAAAAAAA AAAAAAAAAG AAAAATAAAA CCTCCCCAAA TCCAGAGGAC ATGTAAGAAG 960

AACATTTGTG GTAAGAGTTG CCACTTGGAG ATGAGCTAAT TTCAGCATGC CTTAGTTAGT 1020

GTGAGGAATT AACTAAATCA GGACAATACT TGGGCCTGTC ACAGAGATCC TATGGAATAC 1080

TTTCCTACCA TTGTGCATTA ATGAACAGGT TCTTTTCCTC TCCTCAGATC CTGTCAAGTT 1140

GCGATGTCTT CAGCCATAGT TACTTCAACT ACCACTGATT TTGTTACTGA TTCTTTCTTC 1200

CCATGCTACA GTGGTGATTA TTCCAGAGGA TTTCTCTCAG TCCCTATTTG ACTCTTGTTA 1260

CTATTTGTTT TCTTGGTTAG TTCCATGAGA CCATGCCAGT TCTCCTTGAC TGTGTATGAA 1320

TCATTGTGTT GCACTGTACT GACAGACTGC CGTAAGTCAA TATTAAGTGT TCAGTATCTA 1380

AGTGCAGGAG AACCTTTCTA CTTAAGTACT CAACAAGTAG TTTGTTGGCA CTTAAGTTCT 1440

ATGAGATTTT TTGTTGTAAA GGAAAACATT ATCTTGCAAA GATTTTGGGG CAGCATTTAC 1500

CAATACTTTG TTCCTTCATC CGTAGGAAAA AGAATCTCAG GAGAAAAACC TATACATGGT 1560

AACCAATGGG GCTGCCAAGC TGATGAAGTA TTTTCAGAGT ACACCTTTGT GTAGCTGAAT 1620

AAATTGAGAT CTTGAATGGA CATATTAGCT CATTTTAGTA AAATGATAAG AGAGTGCCTC 1680

CCACTACAGT TTTTGTTTTT ATGCATCATT AAACAATGTG TTTTTGATTG TCCACTGTGT 1740

TCCATGAACT ATGCTATGTG TGGGAGATAT AGTAGTAAAG AAAAGCAAAG TACCTGCTTC 1800

CATAGAATTC AGTATAATGG GAATGGTAAT TCTTTAGAGA ATCACATAAC TATGGATACA 1860

TAGGCTTCAT TTTACTGTTC TCCTTTTGTG TTTGAAAATG TCAACAATCA AAATTTTGTA 1920

AAAAAGGAAT CATGCAACAT ATTTAAAATT ATAACTGTGT TAAGTGTAAT GAAGGGAAAT 1980

TGCACTGAGT AGTAAGAATA TATAATGGTG TGTGGTATTT CCCAAGTTAA AAAGGTCAGA 2040

TAAGGCTTCC TTGTGGAAGT GATAGTTCAA ATCTGAAAGA AGAATAGGAA TTAATTAGGT 2100

AAAAATGTTT GATGCAAATT TTAAGATTTT CCTTCTGAGT AGTCAGTAGC TTTTCCTTCT 2160

TAACATAGAA GATGACAAAA CCATCCTTTT TTTGTACATA ACAATTCTTG TTTTCCTTTA 2220

GACAGTTGTA TCTGTCAAGC TTCTTATGAT CTAATTTAAA TAATTGGGAT AGAACACAGC 2280

TGTACATGTT ACTATTAAAT ATGGAATATA TCAAACATAA GTTGATTCCT ACCAGTTCTG 2340

ATTTTATTTG TGTATTTTGT TAAAGGTACT GAGGACATTA ATATCCAGTT TTATATTGTG 2400

CATTTGAAGG TTCATCAATA AATACAATTC TTGTTTCTCT GGGTCTTAAA AGATATTTTA 2460

AATGGTTATC TCATTAAGAT TTAACAGGAA ATAACAGTGA TTCAAATCAA ATAGTGGTGC 2520

CAGAAACCCA TACTTGAATT TTGGGTATAG ACAGGTTACC CTTTGCATCA ATCCTGAGGA 2580

AACTAAAACT ATAGGATTAA TCAGGATAAA AAAGAATTGA GCAAGGATTC AGGAGGGATC 2640

TGTATCATCC TGGTGACAAC CCTCTTCTAG AAAAAACTAG AAAGTCTAAG AATAAATGAA 2700

GTTGCTGGTT CTCACCTGGA AAGGTCAGTT ACTCACAAAA TTTTTAGAGT CTATCTTATG 2760

CCATAATTCT ATCACTGAGA GAAGAAACTT GTCCAGTCAT CATGTAATCT TCATGTAAAT 2820

TTATGTTTTT AATTGCAGAA TTCATACCAC AGGCAAAGTC CCAATGTCTG CATTTGCTGT 2880

TACCTTAAAT AGTCAAACCC CAAAGTTATT GTAATCTTTT TTTAACAGAG AATAATTTGC 2940

AGAGTAATCT CGGTCCGGTA GATCTTTCAG TGGATCCCAA ATGATTGCCA TGAATGGTTT 3000

AGAATTTTTT TAATTTTCAA GTTGTTTTTA TTCTGTGGAA TACTGGCTTA TTTTTGTAGT 3060

CCCAAAAGAA AAATAAATAT TTATTTATTT GCCGTTAAGA GTTGTAGTTT TGTTTTCTCA 3120

AATTTGTCCT GACACTGACG AGATTAGTTA AATGTAGGTC ATCTGAACCA AATACAAGGA 3180

AGGAAGGACC CAGTTCTGAA GAGTGTGGGC ATTTCTTTTC TTGTTTTTTT TTTTTTTTTT 3240

›Example 10 · 10 of 49

TTTTTTTTTT CTATAGGAGG GGAACGAGGT GAACTAAACA AACAAAATAA AGCAAAAAAG 3300

AACTGATTTT TATCCCTTGA GGTAGAAAGA ATGAGATTAC AGTGGACCCC CTTGTCTGCA 3360

TTTTCACTTT CTATGTTTTA GTTACTCACA ACCACGTCCA AAATGTTAAA TAGAAAATTC 3420

CAGAAATAAA CAATTTATAA ATTTTAAATC AGTGGTGGCT TTGAGTACTG TAATGAAATG 3480

TTGTGCCATC CCACTCAGTC GGCCTCGACT TCCCTTAGAA TCATCCCTTT GTCCGGTGCA 3540

TTCACGTTGT ATTTACTCCC TGTCTGTTAG TCACTTGTTG CAGTATCACA GTGCTTGTGT 3600

TCAAGTAACG CTTATTTTAC TTAAGAATGA CCCCAAAGCA CAAGAGTACT GTGCCTAATT 3660

TATAAATTAA ACTTTTTCAT AGGTATATAC ATATAGGAAA AAACATAATA CATACAGGAT 3720

TTGGTTGGTA CTATTCTGCG GCTTCAGGCA TCCACTGGAC GTCTTGGAAT GTATCCCTTG 3780

TGGATAAGGA GGAACTGTAT ATGGTTAACC TAGGAGCTAG AGTCAACAGT TGGAAGAGAC 3840

TTTGGGGATA ATTACATGGA AGGGCATGGT GGGTGGTCGT TTCAGATGAC AAGAATGTTT 3900

TTGAATAACG GATCATTTGT GTCTTCAGAC TTTCCAGAAC TCCTTGAGAA TTATGCAGAG 3960

GTATTTAATC AGTCAGAAGG TTGAATAGTC AAATTATTAG TGAGTGAAGT CTATTTTGAT 4020

GAGGATTTTA CTAATGCTGT CCCTTAGATG TTATAAGTAA ATCGTTGTTT TCTTTTGAAA 4080

TATCTGAAAC CTAGTTAACA TGGACTTTCA TTTGTTCTTG TAAAGATATG CAAAGCTATT 4140

TGGGAGATTG TCATCATCTG ATATTTGATA TTCATGGGCT TTCTTCACAG AAGACTAGAA 4200

ATTAACAGAG TCATGATGAA TTATGGCTGC ATTGACTTTA AAAAACAAAC ACCTCCTTAA 4260

TGTTATTTAA CAATTTTGAA TAAATTTGAT ATGGCAAACA AATCAGTTAT AATCGATTGA 4320

GAAAGGAACT TAATTCTAAT ACTTGACTGG TGTCCCATAA TAACCCATAA TACTAAGAGA 4380

CAGTTTTGGA GGGCGAGAAG TCCTGAAGAG CTGATAGAGA TAAAGGTTCA AATTTGAGCT 4440

TCTTTCAGTG TTCCTTACGT CAATGCTTTT AGTTTCTCAT ACAAAATAAA ATAAAGAATA 4500

ACCTTTTTAC TGGGAAAAGG TAAAAATTAA TAAATTGTAG AAGCATTGTT TGAAGCCAAA 4560

AAGTGTGTGA CATGTAAATT GAAATGAAAA ACCTTAGAGT TTTTGATACT TTTTCAAAGC 4620

AGCTAAAGAA TTGATACTTG GACACAGGAA GAATTTTTTT TCAAAAGCAA TTTTTATAAA 4680

ATCAGAAAAA TGTTTACCTC TTGTTGGGGG CATTGACTGG AAAGGAATAC AACAGAACTT 4740

TCTGAGATGC TAGAAATGTT TTTTTATCTT GATGGGGTGT GGGTTTTGTA GATAATGAAA 4800

AATAAACAGT AAAAAATAAG TAAAAAAAAA AGTAAGAAAG TTGCCAATAC AGTTTTACAT 4860

ATTCCTGTGA TGTTTTTAAT CGACAGGCAC CTTCTTACTG AGATACGTAA TGAGAAGTTT 4920

CGATTATACA AATTAAAGAT GATGGCAAAG ATGGAAAAAT ATCTTCATTC TAGCAGATGT 4980

AGGAGACAGT ATGTATTATT TATTTTATGC CAATAGTATG GATTTATGGA TGATGCTCTT 5040

TTAAGACAAC AATTTGGCTA AATAATTATC AGTATTTTGA AAAAATATTT TGTTGCTGTT 5100

ACATGTGTGC TGAATTTTTA AGGCTAACTT CTTTGTGTCT GAGTAAACTG AAGTCAAATA 5160

ATGAAGTCCC AAGTGAATCA ATTAATGGTG ATTTTACCTC ATTATTTTCA GGAATGAACT 5220

TAACATATAC GTTTCTGTTC TTTTATTTAA TTTAAAATTT TGTCTTGGGT AGAATCATCT 5280

TGTCTCATTT TGAGGACAAA CAAGTACAAA AAGCCTCCTT GGGAATTATG GGAACTGAAA 5340

AATGCTGTGA TAATTGCAGG TCCAGGTAAA GATTTCTTAT TATAGATGGA CATTCTAAAA 5400

GTCTTTCTTT CTCTTCCTTT TCATGTTTAA CTGAATTTTT GTTGAATGAT AAGTATTTCA 5460

GTTTTTTAAA CAAAACAATG AATGTGTTTA GATATGAGAA AGCAAACAAT ATTAAAGTAT 5520

TTTGCTTAAA AAATAGATAA AGCAATAAAA TGGTAGCCCT AAATCTAAAC ATATCAATAG 5580

TTATGTTAAA TGTAAATGAT CTAAAATATT ATTTAAAGGC GTAAATTGTA AGAATTGGTT 5640

TAAAAACATG ACCCTGTTCT GTACGTTGTC CACAAGAAAT CCACTGTAAT TATATAGATA 5700

GGTTTAAAAA AGAATGAAAC ATTACATTCC ATGAAAACAT TAATCAAAAG GAAGTTGGAG 5760

TTACTTTAAT ATCAGACAAT GGACACTTTG GAGCAAAGAA TATTATCAGG ATAAAGAAGG 5820

ATATTATATG ATGTAAAAGA ATCATTTCAC CAATGTATCA GTCAGGGTTC ACCAGAGAAA 5880

TAGGACGATT GATATTATGG AGATATATAT ATATATATAT ATATATATAT ATATATATAT 5940

ATATATATAT ATATATATAT ATGGGGAGGG AAAGGAAGAA CAAATATGGG GAGAGAGGGA 6000

TGAGGCGACT GATTTTGAAG AATTAGCTCA CGAAATTGTG GGGGTTGGCA AGTCTGAAAT 6060

TTGTAGAGCA GGTCAATAGG CTGGAAACTC AGGCAAGAGG TGATGTTGCA GTCTTGAGGC 6120

AGAATTTCTT CTCTAGCAAA CCTAGTTTTT GCCCTTTAGT CCTGCCACTG AGTGGATGAG 6180

GCCCACCCAC ATTATTGACA ATAATCTCCT TTACTTAAAG TCAACTGATT ATAAATGTTA 6240

ATCACGTCTA CAAAATATTT TACAGCAACA TCTAGATTAG TGTTTGACCA AACAACTGAG 6300

CATCATAGGC TAGCCAAGTT GATGCATAAT ATTAATCATC ACAACCAAGA AGACATCATC 6360

CTAAATATAT ATATATATCT ACTTAACAAA AAGACTGACA GAACTGAAAG GAGAAATAGA 6420

GAAATCTACA GTTACATTTG GTGACTTCCA GCATCTCTCA ATAATCAATA AAACTGACAG 6480

ACCAAAAAAT CAGTAAGAAG ACAGAAGAAA TGAACAGGAT TATCAGCATG CTGGATCTCA 6540

TTGACCTTTT TAGAACATTC TACCCAACAA CAGTAGAGTA CACATTCAAG TGCAGATGCA 6600

GTATTCATGA ACATGGATTA TATTCAGAGT CATAAAACAA ACCTTAACAA ATTTAAGAAT 6660

CTTGTATTTG TATATTTTTT GACTAGAATG GAATTAAACT AGAAAACAAT AACAGAAAGA 6720

TAACAGAAAA GTCTCTAAAC CTTAGAAATT AAATAACACA CTTATAAATA AATCCATGAG 6780

TCAAAGAGGA AGTCTCAAGG CAAATCAGAA AATGTTTTGA ACTGAATGAA ATGAAAATAC 6840

AAAATGTGTG AGATGCAGCT AATGCAATAC TGAGAAGGAA ATTTATAGCA TTAAATACCT 6900

ATGTAATAAA AGAAGAAAGG TCTCAAATCA GTACCTAAGC TTACATCTTA AGCAACAAGC 6960

AAATAAGAGC AAAATAAATC AAAATGAAGT AAACATAAGG AAATAACAAA GAACATAAGT 7020

CAATGAATAG AAAAGCTATG GTCATACCAC TGCTGTCCAG CCTGGGTGAC AGAGTGAGAC 7080

CCTATGTCAA AAAAATTTAA AAACAAAGCA GCATGCAGCA TTCATTGTCA GTGAATAGAA 7140

AATGGGAAAA CAATAGAGAA AATCAACTCA AAAGCTCATT CTGTATAAAG ATCAACAAAA 7200

TTGATATAAA CTTCTAACAA GACTGACGGN AAAGANGAAA AGACACAGAA GACCAATACC 7260

AGGAATGAAA GAGGGAATTT CACTACAGAC CTCCCAGGTA TTACTAGGGA TGATAAGGGA 7320

ACACTATGAA CAACTCAGAA CATAACTTTA ATAATTTAGA TGAAATGGAT CAATTTCTTG 7380

ATAATCTCAA GCTAATTAAA CTTACAGTGA ATTAGATAAC CTGCATAGTG TTACAACCAT 7440

TAGAGGGATT GAATTCTATG TTAAAAATCT CTGAAAATAA AATCCCCTAG CCCAAAGAAT 7500

TTCAATGACA AATTCTACCA AACATTTAGA AGACAAAATA ATACCAATTC TATAGCATGA 7560

TTCCATTTAT ATAATAGTCT TTGAAACATA AAACTATACT AGAGGGATGA AGAAAAGATC 7620

AGTGGTTATT AGAGATTGGG GGAGGGAGAA GGTATGATTC CAAAGGATAG TACAAGGCAG 7680

TATTTTGGAG TGATAGATTT ATCGTGCCCT GATTGTGATG GGAGTTAGAT GAATCTATGG 7740

ATATCTTAAA ATGTGTAGAA CTTTACACAT ACATACAACC AATTTGCCTA TGTTAATTGA 7800

AAAAATAAAA TAAAAACAAA TTATTTACCT GGTGGGTTAG CTACGTACCT AAGTTCAATA 7860

GCTGCGTTAC TGTAAGACAA AAGAAGCATT ATTAGGGATG GAGTTGTTNC TCTGTGTAAT 7920

GACAAATACT TCCTTCACTA AGAAGACAGA ATTGTTTTAT GCACCTTTAA AAAAAAACAA 7980

AAACAAAAAA AATACAACCA ACAAACAGTA ACTTGCTGGT GCGGTGGCTC ACACTTGTAG 8040

TATTAGCACT TTGGGAGGCT GAGGTGGGAG GATCACTTGA GACCAGGATT TTTAAGACCA 8100

GTCTGGGCAA AAAACCGAGA CTGTGTCTCT ACAAAAATAA AAAATAAATA AAAAAAATTA 8160

GCTAGGCATA GCATTATGTG CCTCTAGTCC CAGCTACTCT GGAGGCTAAG GTGGAAAGAT 8220

CGCTTGAGCC TGGAAGGTTG AGACTGCAGT TGCAGTGAGC CATGATGGCA CCACTACACT 8280

CCAGGCTGGG CATCAGAGTA AGACTCTGTC TCACATAAAA AAAATAATAA TAATGATAAA 8340

AACTAGTCTG GGCATGGTGG CTCACACCTG TAGTCCCAGT CCTTTGGAAG GCCGAGGCAA 8400

›Example 10 · 11 of 49

GAGAATTGCT TGAACCCAAG ACTTTGAGAA CAGCCTGGGC AACATAGCAA GACCCCATCT 8460

CTATTTAAAA AAAAAAACAA ACTTAAAAAT CCAGCAAATA CATAAAGCAC AAAGCCGACA 8520

GAAGAGGTGG AGAAATCAAC AAATCCACCA TCAAAGTGGG AGAATTTGAT ATAATTTTAA 8580

GTTATTGGTA GGGTAAACAA TCCAAAAATT AGTACACTGT AGAAAATTTG GTCAACATAG 8640

TAATAAGTTT GCTTATTACT ATTTATCAGT ATACATAGTA TACTGATTTA TCAGATACAT 8700

AGTATATGGA GCCCTAGAGC AAGCAACTAT AGCAGTGTAT CTCAAGTATT TTTACTTCAT 8760

GACCCACATA GCAAATGATA TGTGTATATA ACACACTGGG CTAATTGTCA GAGTTCAGTT 8820

TCTGTCCAAA ACCCTAAGAT CTGGAGTGAT TAACCTTTCA GCACTCTTAG AACTCACTTG 8880

TTTGTAGCAC ACTGATTGAG AAGCACTGAA AGACTTCACT CCTCAAACAT ACATGGAATA 8940

TTTCTAAAAA CTATGTATTG GGCCGGGTGC AGTGGCTCAT GCCTGTAATC CCAGCACTTT 9000

GGGAGGCCGA GGCGGGTGGA TCCCGAGGTC AGGAGATCGA GACCATCCTG GCTAACATGA 9060

TGAAACGCCG TCTCTACTAA AAATACAAAA AATTAGCCGG ATGTGGTGGC GAGTGCCTGT 9120

AGTCCCAGCT ACTCGGGAGG CTGAGGCAGG AGAATGGTGT GAACCCAGGA GGCGGAGTTG 9180

CAGTGAGCCG AGATCGTGCC ACTGCACTCC AGCCTGGGCA ACAGAGCGAG ACTCTGTCTC 9240

AAAAAAAACC AACCAACTGA ACAAACAAAA AAACTAAAAA ACAAAAACAA AAAAACTATG 9300

TATTAGAGCA TGGGTTGGCA AACTATGGCC TGTAGGCAAA TCTGCATGCT GTTTTATTTT 9360

TTTTATTTTT TTGACATAGG GTCACTACAG GCTGTCACAC AGGCTGGAGA GCAGTGGTAT 9420

GATCATAGCT CACTGTAACC TCAAATTCCT GGGCTCAAGC AATTCTCTTG CCTCACCTCA 9480

GCTTCCCAAG TAGCTACAGG CATGCACTAC CAGACCCAGT TAATTAAAAC AAATTTTTTT 9540

TTGGTAGAGA CAGTCTCAGT ATGTTGCCCA GGCTGGTTTT CAAACTCCTT GCCTCAATCA 9600

GTCCTCCTAC TTCAGCCTCC TAAAGTGCTG GGATTATAGG CCTGAGCCAT CACGCTTGAC 9660

TAATGTTTTT GTAAATAAAG TTTTCTCAGA ACACAGCCAT GCCTTTTGTT TATGTGTTAT 9720

GTAGGGCTGC CTGAGTTAAG TAGTTGGCTA CAAAGCCTAT CATGGCCTAT AAAGCCTGAA 9780

ATACTTACTA TCTGGTCCTT TATAGAAAGT GTTTTCTGAC CCTGTACTAG ACTAGCTTGT 9840

CTCAAAATTC TTCAATGAAT TTGGAAGTTT TCTCACCACA TTTTCTGACC ATAATGCACT 9900

TGAGTTAGAA GTAAATAAGC AGATAAACAA CAAAATCCTC ATGCATTTGG AAATTAAAAA 9960

TAACACTTAA ATAATTCATA TTCAAAGAAA AAATCAAACT GGAAATTAAA AAAAATTTTA 10020

AACCTACAGA TAACTACATT AATATGCATT AACATTTTTA GAACTTAGGG ATAGTTACAA 10080

TGATATACAT TAAAACTGGT AAGAGGCTGG GTGCGTTGGC TCACGCCTGT AATCCCAGCA 10140

CTTTGGGAGG CCGAGGCTGG GGGATCACGA GGTCAAGAGA TTGAAACCAT CCTGGCCAAC 10200

ATGGTGAAAT CCCGTCTCTA CTAAAAATAC AAAAATCAGC TGGGCGTGGT GGCACGCGCC 10260

TGTAGTCCCA GCTACTTGGG AGGCTGAGGC AGGAGAATCG CTTGAACCTG GGAGGCGGAG 10320

GTTGCCGTGA GCCGAGATTG GGCCACTGCA CTCCAGCCTG GCGACAGAGC GACACTCTTG 10380

TCTCAAAAAA AAAACAAAAA AAAAAACAAA AAAAAAAACT AGTAAGAGGT CCCAGTGGCT 10440

CACACCTGTC ATTCTAGCTC TTTGGGAGAC TGAGGAGAGA GGATCAGTTG AGGCCAGGAT 10500

TCAAGACCAG TCTGGGCAAC ATAACGAGAC CGCATCTCTA CAAAATTTTA ATAACAACAA 10560

CAAAAAAACT GGTAAGAGGC AACATTGAAT AGTACTTTGT GGGAGTTTAT TAGCTTGAAA 10620

TACTCATAAT AGAAAAGAAA ATTAATCAGC TAAGCATCTC ACTAAAGAGA TTAGGAGAAT 10680

AAACCTAAGC ATAGTTTTTT TCCCCCAAAC ATTATTATAT CTGGAATATT GAATGCATTC 10740

TTATTGCTAT TTCAAAGATA CTTACTCTAA GGAAAGCAAT TGAATTAGGT AGTTGAACTC 10800

TATAGTAGAT TTTCTTTAAT GAGTCCTTTT GTTCTCAACC TACTTAAATA ATTCTCATTT 10860

GAATTTATGA TAGTTTCAGA TCTACCCAAA GGGTGACTTA GGAATTTAAC TTCTAAATCT 10920

ATTTAAATGA AAGGTTTATA ATCTTTGTGT CATATTTTAC AGTCGTTAGC GTTTAACAAT 10980

TTATAGCATA GGATTTGGGT TTTTTTTTTT TTCATTTTAA AGAAGAAGTT TATTTAAGCA 11040

AGACACTTGA CTAAGGGAAG ACTATCTTGG AGTTATTATT ACTAGAGTAA TTTATTTCTA 11100

CTTAAAGACA GATTGCCCCA CAAGTAACAG CTACATAAAA AACAGTTGTA AAATTGTCCT 11160

TGGTTTTACA ATGATAAATG AAAAACATTA AAATTCTCTA ATTGAACAAG GTATGCAAGG 11220

ATTTTTATAT TGTTTTTTGC TAAAACTATG ACAGCAAAAT AACATCCTGG AGTATAAAGA 11280

TAAGAGCTGA ATGAGCAGGC CACTAGGGGA CAAAGGGAGT CTTTTCACAG AACCAATGCT 11340

TCTTTTGCCC ACCCCATCTC CATCGAAGTC AATCTAAACA TATTATTGGC CATTTAGTTA 11400

AAAAAAGAAA GAAAAGNAAA AGCAATATGC TTGTGGACAT ACACCAGTTA CTTTATGTGC 11460

AATAAAAGAG TAGGAAGGGG AAGGTGAAAG AATAGAGAAA ACTATGTAGT CAGGATGTGG 11520

TGGAACCAAA TTGCAACTTT CTTTTTTTTT TTTTTTTTTT TTTTTGAGAC AGAGTTTTGC 11580

TCTTGTCACC CAGGCTGGAG TGTAGTGGTG GCCCAATCTT GGCTCACTGC AACCTCCGCC 11640

TCTCAGATTC AAGCCATTCT CCTGCCTCAG CCTTCTGAGT AGCTGGGATT ACAGGTGCAT 11700

GCCACCATGC CTGGCTAATT TTTGTATTTT TAGTAGAGAT GGGTTTTCAC CATGTTGGCC 11760

AGGCTGGTCT TGAATGCCTG ACTTCAAGTG ATCCACCCGC CTCAGCCTCC CAAAGTGCTG 11820

GGATTACAGG CGTGAGCACT GCGCCTGGCC AAATTGTAGC TTTCTAATTG AGACTGTCTT 11880

CTTGGTCTGG AAGAGCAGAG TTCTGCAGTA AAATAACAGG TCCCCCTTTT AGTAGACATC 11940

TCCATGTCTG CTGCTGGAAC ACATCAGTTT TGTCTTAAGC CTCACTTCCA AATGTGCAGA 12000

TGTGTCTGGT TCATTGATTG GCTGCCTGTC AAATTGAAAC CTGATCTGCC TCATTGGCAA 12060

ACCGTGCCCC TTACAATAGG CTTTCATTGG TTTACTAAGC GGTGTGGTGC GTGGCTGTTC 12120

ATCTTAAACT GCACCACAGT TTAAGATGAA CCTTCAAATG AACATTATCC TTGTTCTCAG 12180

TCTTGACTTT CCTTGGGCTT TTTGTGGACC CTGGTGAGTG TGGCAGTCTC CTCAGCTGCT 12240

GCTTCACAAA AGAGGTACCA GGTCTGCCCC GAATGAGTGA GCCCCTAAAC AGGACCAGGA 12300

GTGGCAGAAG AAAGAGGCAG CAACTGAGAT GTGTTTTTTC TAAGCTGAAA GGCTTTTTTT 12360

TTTTTTTTTT GCAACACACC TTTAACACTA AAGTCCAATA TTTATATAAT TNGGTCAAGT 12420

AAGTGGAGCT GTTCTAGCTA TAAATATGGC AACTCTGCTT GCTCGTCCTA TTATTGATTG 12480

TATTCCTTTC TGTGGTCTGA GGTGCCTCCC ATGAAACTTG CTTCTAGGAC ACTAGGATTG 12540

AGAACCATNC AGCGTAACAT ATCTGTTACG CTACAATAGT TTATTTTCAT ATTTTAGCTA 12600

CTTTACATAC TCGGGTATAA TGAACTTTAT TCATAGCTTC TGAAGCAGTT GGCACATTTG 12660

AGATATTTTT TACTTGGCTA ATTGTTATGC TAAATCTTTT GATTTCTAAA GATACATGCC 12720

TTTGCTAAGC TTTCTTCAAA TGTTATTATT TTTATTTAGA TTGGATCATT GCTATTCCAT 12780

GGATGACTCA GAGGATACAT CCTGGGACTT TGGTCCACAA GCATTTAAGC TTTTGTCTGC 12840

TGTGGACATC TTAGGCGAAA AATTTGGAAT TGGGCTTCCA ATTTTATTTC TCCGAGGATC 12900

TGTAAGTATA TATCTGTGAA TTCCCTTCAT AGATCTTCTT TTACTTCTAT TACACTTTTC 12960

TTCAGAGGTT TGCAGTATTA TGATTGTAAC TTTGACTTCA GATGGGTGAC TAGGAACTCA 13020

TAGAGTCTTA CTAAGTTCCA GTTAAACACT ACATTCATTA CTTTGGATAA AACCCGTGTG 13080

TATGGCATCT TCTGCTGTTT TCATGTTCAA GCCGATGTTC AGCTCTGCAG CTCAGTCTGG 13140

AAGCATTGTG TTAATTTATC ACATTGCATT TGGGTGAATC CCTAGACTAG TCTTGCTTAG 13200

GATAATTAGG AAAAGTTAAC TTTCATTGTA TCAAGGGACA GGTAGAACAA AATTGTCCTT 13260

TTGTCCAGGA AACTATTAAA TTCTTCAAGG AAAACTTTAG TTATAGGGAT TATTTTTTAA 13320

ATGTCTAATT TCAGTAACAA TATTTGGGAC ATATTTATTT TTCCTTCTGT TTCCTATCAG 13380

AAGTATTTAA AGTTATAAGA AAATTGTGGT TTTTGCCTTT ACTAATGAAT AAATAATCAA 13440

TTAAATTCAG TTACTTTTTT TTGGAGTGAT TGATGTTCCA GTATTCTTCT AAACAACCAC 13500

›Example 10 · 12 of 49

GGGTACAAAT GTGAATAAGA TAGGACCGTT GCAGTCCAAG AGCTTGTTCT GTAGTCCTTT 13560

CCTTTATATG ATTTTTTCCC CTGATTTAGA AGTCTATAAA GCAAAGCTAA GTATTACACA 13620

CTGATAATGG CTGAATAAAT CAAGAGCAAG AGATAGGATA CTTTGCAAAT ATGCATATTT 13680

ATTAAAAATG TACTTTAAAA TAGAGATTAA AATTCTCGTA TTGAATGTAG AATAGGTAAG 13740

CATTTATTTG TGAAATACTC GAATGCTTCA TGTAAATACT TTCTGAGTTT GTATTTTTAG 13800

AAAGGAACAT TTTGGAGGCT GAGGCAGGAG AATGGCGTGA ACGTGGGAGG CGGAGCTTGC 13860

AGTGAGCTGA GATTGTGCCA CTGCACTCCA GCCTGCGCGA CAGAGCAAGA TTCTGTCTCA 13920

ATAAAAAAAA AAAAAGAAAC ATATTTATTA AATTAGTTGT GAAATATTTT TAATGAAATA 13980

TATTGAAAAC TTCTGTTGAT TTTTCATGTA CTGATGTTTT TAGATTCTAA ATGGAGTTTA 14040

AAATTTTGTT TGTAAATCAC AAGTTGGATT AGAAATTTAA TAGTAGAAGT GTTGCCTAAG 14100

GACTATTTTA GGTGCTGTGA GTGAAACTGT ATTTTTTATA ACAAGAATTT TAGTTGTAAG 14160

GGACAGCTTA AATATAATTG AGATCTGTGA AAATGTATTC TGTCTCTATC ACCTTCAGAA 14220

CCTGTGTATC TCAGTTGAAT GTATAATTTA TAAAAATTAT TCTTGTTTTA ATTTGGTGTA 14280

ATCCAGCCAT ATCCAGTATC AACAAATAAG TCTAAGTAGG CTCCTTGACA AACTTGAACT 14340

GGCCACAAGA GAGATCAGAT TTCACCTATT AAAAAACCAA ATCAGACCAC TTACACTGAC 14400

AGTCTCTTCT GGGAGTCCTC AAATTAAGAA GTCTATCCTT TGTGAAATAT TACACTACCC 14460

TTGCTAGATA AAACTTTTCT AAAAGTACCA CTTAATGAAA ATCTGTAGAC ACTAAATGCA 14520

ATGAAAATAA GGCATTGTTT TTTTTTCTCC CCATTTCAGT GATCTTGGTA TCCTGGGATA 14580

TTGTTTTTAA AATTATCGTT ATAATTCCTT TGAGAATTTA GTGAAACGTT CCCTTTAACC 14640

AACTTAGGAA AAATTAATAT CTTTGTACAT GATTTTGAGC TGTAAAATAA ACATTTTAAA 14700

CTGGGAATAA TTGGAGTTTA GTTAAAGAGA TAATGTATAT AAATATATAA CATAGTAGCA 14760

GCATATAATT CTGTCTTACA CAAGATTTTT CTGAATAGTA TAAACAGTTA TGTAGCCTAT 14820

CTAGGAGTTT GTGAATAGAG TTTAAAATTT TGTTTTGAAG CTGCAAATTT GATTAGAAAT 14880

TAAACAGTAA AGTTATTACT TAAGGAACTT CGTTTTAGCT GTCTGAACAA CTTACTGTAT 14940

AAAAATCTTT AAACATTCTG TATAAATATG TGATAAGATA TGCAATGACC TTAATTTTAT 15000

AGATTAGAAA ATAAAAACAC ACTCATTAAT TTACATAACT GACAGATTAA GTGAAACTTC 15060

TCTTCTGATC ACGTTAGCAG AATGCCAAAT CTTGTCGTGG CACTAGAATT AGACGGTAGT 15120

TTTGATAATA CATGATTTGA CTATAGACAT TTGTTGAAAC TATTGGTAGT TTTAATCACT 15180

CTTGTAATTT TCAAACTATC TAACGGGAGA GGATTATCCA TCCTGTTTTC TAGACAAACT 15240

GTTTCATCTG AATGAAATAT ATTCCTAGAG ATAATTATCA CTACTTCATC TTTTGGTTTT 15300

ATTTTGCACA TAGAATTATA GTTCACAATG ACTTTCTGAA GCTCTAAAGT TGCAGCTGTG 15360

AGCTTCTTTG GCCTGTAGGG ACTGGGAAAA AGCACCCCCG TCCTCCCCCA AGCCCCCCCA 15420

CCAAAAAAAG TTAAAGTGTT TTTAACAATA GCTGTGGGCT TTTTGTAGTT TCAGAACTTA 15480

GGAGTTGCCC AGGCTGGAAT GCAGTGGTGT GATCATAGCT TGATGCAGCC TTGAACTCCT 15540

GGGTTCAAGC AATCCTCCCA CCTCAGCCTC CAGAGTAGCT GGGACCACAG GTGCCACCCC 15600

ACCCAGCTAT TTTTTTTATT TTTTAATTTT TTTGTAGGTA TGGGGTCTCC CCATGTTGCC 15660

CTGCCTGTCT CAAACTCCAG GGCTCTCAGG TGATACCCAC CACCCTTGGC CTCCCAAAGC 15720

ACCGAGAGTC ACTGTGCCAG GCTGAGTTTA AAATTTCTTG AGTTGGAGTT TATGGCTATT 15780

TTTTCCACTA GTTATTAAAC ATGTATTTTT GTATAAGGCA CTGTATTACA TTTTGTGGGG 15840

GGATTCAAAG CTAAATTAGA TGAGACGCAT CATCTATTAT GGAAGATGTT ACTTAAGAAG 15900

AAATGAGTGT AATGTAGCAG AGAATTAGAT AAGGGACGTA TGAATACATA TAAATGCTGT 15960

TGAAGTTCTG AAGAGAGAGA GTGTTTAGAG AAATTAGAGG AGTCTTTGTG AAGTTATCAC 16020

TAGAACTTCC TATTTTTGTG GAATATATAG TAGATTTTGG TGTGATACTG TGGATTTGGA 16080

CATTCACTCA GAGAAGGAAT GAGGGAAGAA TGGTGGAGAA GAATGGCATT CACAGTACTC 16140

AAAGCAACTG TGACTTTTAA AGAAGTTAAT ATGGAGAAGT GGCAAGTCTT TTCTTCTCTG 16200

TTCTCTTCTC TTCTCTTCTC TCTTCTTTTT CTTTTTTCTT TTTTTCTCTG TCAGATATCA 16260

TTGTAAAGAC TTTGCTTTTA CCGGAAACTG ATACGTTGGG TCATGTACCC TGGCCAGCAG 16320

GTTCTCTTTA TTCTAACACT TAGCCGATCA ATTAGATTTC CACATTCCAT GATATGTCCC 16380

TTTTGGTGAC CCTTATTTTT CCACCTGGTT TATAAAGGGA AAGAATGTGA TATGTCACAA 16440

AGGCTCTGGA GTACAGTGGC ATGATCATAG GTCACAGCAG CCTCAAAGTT TCCAGTTCCC 16500

GCGATCCTAC CTCCTTGGCT TCCTGAGTAT GTGGCACTAC AGGTGCATGC CACCATGCCT 16560

AGCTAACTTT TTTGTAGAGA CAGGGTCTCC CTATGTTTCC CAGGCTGGTC TTGAACCCCA 16620

GACCTCAAGT GATCCGCCCA CCTTGGCTTC CCAAGATATT GGCATTACAG GCATGAGTAG 16680

CTGTGCCGGC CTGAAAATTT CTCTTTTGAG ATGGCATCCC ACAGAAGTAT ACCTGCTATT 16740

AGCTAACACT GGTAAAAAGA CTATTTAACC CTATTGCCTT ATTTTACTGT AGTTGAGGTC 16800

GAGTTAAACT GAAAGCTGAA TGACCTGTCC TAGGTCATAC TGTTACTTTG TGCCAGATGT 16860

AGGATGAGCA AATGGATTTC CTGCCTGCTA GTCTAGTGTC TTTTCTATTT ATTGTGCTAA 16920

AACATACAGT TTTAAATTTG TATTTTTATG CCCAATGGAC ATGGTAGCTC ACACCTGTGA 16980

TTTCAGCACT TTTGGGAAGC CGAGGTGGGG GGATTGCTCG AGACCAGGAG TTCAAGATGA 17040

GCCTGGGCAA CATAGCGAGA CTCCGTCTCT ATAAAAAAAA ATTTAAAAAT TAGCTGAGTG 17100

GTGATGTGTG TGCGTGTAGT CCTCCTTGTG GGAGGTTGAG GTGGGAGGAT CGATTGAATC 17160

TAGGAATTCA GGACTGCAGT GAGCCATGAT TACACCACTG CACTCCAGCC TGGGTGACAG 17220

AGCAATACCC TGTCTCGAAT GAATGAATGA ATGAATGAAT GAATGAATGA ATGCCCAAAT 17280

CCGTAAGCTA TGTTCTGTAT AGCAGCTTTT TCATCATAGG CAGTTTTTAC TCTTATCAGT 17340

GGACAACCTA CAAAATTAAC TAAACACTTA AGCAATTAAC AGAGGAGGCC TTGTTCAGAG 17400

TGAGAAATCA TTAAGCATTT GTTGTTGAAA TTTCTTACTG TACTCTGTTT TAATTCTGTT 17460

TTTTTTTTTT TTTAATGTTA CTTGTTTTAG TTTGGATTCC TAGTTGAAAA GGGAATATGA 17520

TTCCTTTAAA ACAAAGATAC TCTGCTTTAA AGCAAAGGTA TATCATCCTC TTCATGGTGA 17580

TTGCCATGGA AACAAGACAA TGTAAATTTA TTCAAATAGT ACACAGTTTT TATAGTTATT 17640

GATCATGAGG GGAAGGGACA GTTAATCCCT ACTGATCAGA TAAAACCTCA TTGTTTCATA 17700

CTAATAAATG GTTTTTTTAT GCTTATGAAA GGAAAAGCCA GAAGGGTAAT TTTTAGTGTT 17760

TAGAGAGCTA GTGATTCTAG TTAGGGAACT TAATACCTTT GAAGTTATTA GTTTGCAAGC 17820

AATAGAATCT ACTACTACCA AGGTGACCCC TAGCAGATGT AGAGTACCAT TAACAAGTGT 17880

TCCAGGGAAG GAAAGCCAAC TAGATACCAA GTCATGCTTT TTACTCTTAG ATTAAGAAAT 17940

TCAGGTTGAG TTAAAGGATC AGCTGTTAAC TAATAAAAAG CAGATTAATA TTACAGAGCC 18000

AGGCTCTGTC CTGGTTATGG ACTTAATCTT CACAGCATCC TCAAGAGATA AAAATGAATA 18060

TACCTGCATA TTAGATGAGG AAATAGAAGA TAAGTAACTT GCCAGAGCTA TGACGTGAAC 18120

TCAGGTAATG TAGCTTAAGA GCCCCCACAT GTATGTATAT TGGGTGTGTG TGTGGAGGGG 18180

GTGCGTGTGA GTGCTTGTGC ATGCGTGTGG TATAATAAGA AAAAATTAGC ATTTATGCCT 18240

GTAATCCCAG CACTTTGGGA GACCGAGGCA CGAGGATCTC TCAACCCCAG GAGTTCAAGA 18300

CCAGTCTAGG CAACATAGCG AGACCCTACC TCTACAAAAA AAGTTTTAAA AATATTAGCG 18360

GGCATGGTGG AATACACCTG TAGTCTCAGC TGCTTGGGAC GCTGAGGTGG GAGGATCCTT 18420

GAGTCCAGGA GATTGAGGCT ACAGTGAGCT ATGATGACAC CTCTGCACTC CAGCTTGGGT 18480

GACAAAGAGA GACCCTGTCT CCAAAAAAAA AAATTAGAAC TAGTTATCTG GAGGCCTGTG 18540

TTCTAGTCCT AGCTTTAGTA CGGCTACACA GTGACACATT AGGCTACCAT TTAACATCTT 18600

›Example 10 · 13 of 49

TGAACCTCTG ATAATTTGTT AACAATATGG GTAAAAATGA CTAAGATAAA TCAAAGAGCT 18660

CCAGCATTCC CTCCAGCTCT GAAATTCTAT GATGTTTTAT CTTATTTTAC TTACAAAAAT 18720

AAATTATATT ATGTATATTT AAAGTATACA ATTTGATGTT ATGGGTTACC TATAGTAAAA 18780

TGATTACTAT AATGAAACTA ATTAACATAT CCATCATCTT ATATTGTTAA CCATTTTTTT 18840

GTTTTTGTGG CAAAAGCAGC TGAAATCCAC TCATTTAGCA GGAATCCCAA ATACAGTTCA 18900

GTTGTATTAA TTGTAATTCT CATGTTGTAC ATTCGATCTC TAGACTTGTT TATGCTACAT 18960

ATGTTTGACT TTTAAACATT CTACTCAAAT CAACCCTAAG TCAGGGTTAG CACAGACAGG 19020

ACTTGTTAAC AAGGTAGAAG GTGCCACATT GTACCTGGGT GTTTATATTT CTCTAAATCT 19080

TGTTCTGATC ATATTTTAAT AAATATAATC ATCAGGACAC CAAAATTCAT TCCTTAGCTA 19140

TTAAAAAATT CTATTCTATT TTATTGTTAA GATTTAGGAG AGCATGGTAC AGATTCTCTT 19200

AACTATACCT ATCAGAAGCC TATGTTTTAA GTCCAATGTA TAGGCACTGC TCTGTTTGTC 19260

TCTGGTGGGA ACTTACCCTG CTTTACCTAA TTTCATCCTA GCTTCCTTTT TGTGAAAGAT 19320

CACCCTTGCT TAGCCTATTT TTTGGCAAAT CTACACCTTG GAAATAGTAG TAAATGACAT 19380

AAGCATATTA ATATTTATGA TGTGATTTAT TTTTGTTTTC AAGTCATATA CTGGGGAAGA 19440

TTCTCAAATA TTAAAACAAT GTATCTTTAC ATTTATGTAT GTCGTTCTTG TTCTGTTTTA 19500

GAAGGCTTGT ATTTGCATTT TTAACATTCC AAAAGGTAAA CCTGTAATCA TAATGTTTTC 19560

ATCAATTCAA TAAAACCATT ACGTTTGTAA TAGAGAGCCC TATAGTTGCC TTAGTTAAGT 19620

TTGCTGCAAC TCATTTTATA TATTCTTTTA ATTTTGATCC CTGGATTTTT AATTGATTAT 19680

TAAACCTTCA TTAGGATATA TATGAAATGT AAAAATATTG AGTTATAATC TACCGTTTTC 19740

TAAAATTTTA TACTGCATTT TTATATAGAA ATTCAAATTG CTCATAATCA TTCTAGTGAA 19800

TTTAAGTAGA AAGGTATTTA TTACTAGGTA TTAAATGGCT TATAATATTG TTGACAAGGT 19860

TCCACTGCAA AATAGTTCAC CAAGGGAGCT GTGGCCTCTT CTGTGATCAA GAAGCCATCT 19920

GTCAACTTGG GAAGCTTCCA CTATAGCACC TAACCCCAGA CTACATTGAG TAGGAAGCTG 19980

TAATAATCAG GAAGCTTCTA CCTTTGCATG CTCTGCAAAC CAACGTGAAC CTGCTGTAAT 20040

TTGTAACCAC AAAATGGATG CCTGTTGATA CTTACGAAGC TCATCATTGT ATGCTGGGTT 20100

CTTTGCTAAT ACTTTCTTAT AAAAATTAAA TACCTCCACA ATCATGCATG CTAGCAGAAA 20160

CAGCAGAGGA GTAGCCTTAG CCTCACTTCC TGCTTATACC TGTCATGCAG ATATACAGAA 20220

CCCAGAACCC TAGCTGAAAG GGAGTTTGAG AACTAGTATT TGTATTGTCC CAGATTCTGC 20280

AGTGGAAGAA TTCATAGTGG ATGGAAGTTA GAATGACCCT TGAATTACAA TCGGCCACAT 20340

TCATCACAAA TACATTAAAT AAGAGTAATT TGCCATAAAG CTCTATGTTT GTATACTTCT 20400

TTGTTTTTTT TTTTTTTTTT TTTTTTTTTT GAGACAGGGT CTCACTCTGT TGCTCAGTCT 20460

GTAGTGCAGT GGTGTCATCA TAGCTCACTG CAGTCTTGAT CTCCTGAGCT CAAACGATTC 20520

TCCTGCCTCA GCTCCTGCTT CAGCCTCCTG AGTAGCGGAA CAACAGGTAC ACACCACCAC 20580

ACTTTGCTAA TTTTTTATTT TTTATTTTTT GTAGAGATGT GGGTCTCACT GTGTTGCCCA 20640

GGATGGTCTC GAACTCCTGG GCTTAAGTGA TCCTCCCAAA GTGTTGGGAT TACAGGCATG 20700

AACCACTGTG CCTGGCCCAT ATACTACATA TATTTAAAAG TAGTATTTAA ATGTGTAGAA 20760

TGAATGAAAG AGGCAGTAAG AGAACAAAGT GAATGAAAAA GTATTTCTAT ATGAAGTGAA 20820

AGCAGGAGAG TCCTCTCTGT TAGAGAACAA CAGAATTGCA TATGACAGAC TAGCTTTCTT 20880

AATATTTCTA GAACTTGATG GCTGTGAAGA GCGTCCCGTA GGAATTCTCC CTTCACTTAG 20940

GAAAACATAC CTCAAAACCA TCAGCTGTTT AGCATGCACC TGCTTTTCCT GGTATATCTC 21000

AGTGAAGCAG CTAAATTGTA AATGATTAAG TAAACTTTGC AGTGTATCAT GTGCAAAAGC 21060

ACAGTAAAAA CAAAAATGCA TTGGAAGCTG TGAGTTGTTG CACTGCACTC ATGGATGAAT 21120

AGCTGTTGGT TCGCATTGCG TTTTTTTGTT TTGTTTTGTT TTGTTTTTTT GAGATGGAGT 21180

CTTGCTCTGT TGCCCAGGCT GGAGTGCAGT GGCGTGATCT CGGCTCACTG CAAGCTCTGC 21240

CTCCCAGATT CACGCCATCC TCCTGCCTCA GCCTCCCGAG CAGCTGGGAC CACAGGTGCC 21300

CGCCACAACA CCTGGCTAAT TTTTTGTATT TTTAGTAGAG ACGGGGTTTC ACCATGTTAG 21360

CCATGATGGT CTCAATCTCC TGACCTCGTG ATCTGCCTGC CTTGGCCTCC CAAAGTGCTA 21420

GGATTACAGG CATGCCGCAT TGCGTTTTAT ATAATTCTCA TGGTTCTAGT CTCGAGCTGT 21480

AGGATTTTGA TCACTGTTTC AAACAATAAT GTGAGTTTGC TAAGAGGTCT AAATAACAAA 21540

AGCTAAGTGT CCAAACACAT ATCCAAACCT ATACACTGGG CAATGCATCT GAATTATATG 21600

TGAAATTTCC TGCCATTATT TAAGACACAA AAGGAACATT ATTTTGATAA TGTATTTATT 21660

TGTGAGTGGA GTGTTCAGAA TGAGCACGAT GGGTATAACA TTTTTGTAGG TTTTTAAAGT 21720

TGAAATTTAG TGTAAATCCA AAGAATCAAT AGACAAGTCT GTGTTTTACT TAACCTATAT 21780

GTTTAAATTA GCATTTTTAG ATACTGATTT TATTCCTAAT TTCAGAATTC TCAGCGTCTT 21840

GCCGATCAAT ATCGCAGGCA CAGTTTATTT GGCACTGGCA AGGATCAAAC AGAGAGTTGG 21900

TGGAAGGCTT TTTCCCGTCA GCTGATCACT GAGGGATTCT TGGTAGAAGT TTCTCGGTAT 21960

AACAAATTTA TGAAGATTTG CGCCCTTACG AAAAAGGTAA ACAGTGTAGG AGTCTGCCTG 22020

TTTGACTTAA TTTTGTTTCC CACTCCACAT TAAAAGATCC TTTTTGCTTT TAATAGGGTA 22080

GAAATTGGCT TCATAAAGCT AATACAGAAT CTCAGAGCCT CATCCTTCAA GCTAATGAAG 22140

AATTGTGTCC AAAGAAGTTT CTTCTGCCTA GGTTCATTTT TCAGTTTTTT TCTTGTAACT 22200

TCTGCATTTT TTGTTGCTAT TTATGTGATT CAAATTATAC CAGTTTATAG GCCTCTCACA 22260

AGTAAAATGA ATTGCCTGTT TGTTTTTGTA TGCCTATTTT AGTCAGTTTG GGGGAAGGGA 22320

TCTGTGAGGA AAGGATAAGT CATAGAGCAC TTTTCTTTTT TAAGAGACAG AGTCTCTCTG 22380

TGTTGCTCAA GCTGGAGTGC AGTGGTGCGA TCATAGCTTA CTGCAGCCTC GATCTCGTGG 22440

GCCCAAGTAA TCCTCAGCCA CCTGAGTAGA TGGGACTACA GACATGCACT ACTATGCCCA 22500

GCTAATATAT TTTAATTTTT TGTATAGAGA CAGGGTCTTC TAGTGCTTCC TAGGCTGGTC 22560

TTGAACTCCT GAGCTCAAGT GATCCTCCTG CCTCAGCCTC CCAAACTACT GGGATTACAG 22620

GCATGATCCA CCGCTCCCAG CCAGAACATT TTCTTGGTTG ATGGGAAGTA GCTGACCATG 22680

GTATTTAGAA AACTTCTTTC TCATCGATTA AAGAAGCAGT ACTGAAATCA ATGCGGAGGA 22740

ATCCATATAT CATATTTACT TCTGGTGTGT AGAAGTGGAA AGGGAATACA TTTGTTGCTT 22800

ACTTTTTTGT ACCTTTACAT GTGATTGATC ACTTGTGAGT TTTTTCTTTC AAACATCTTA 22860

AAGCTTCCAG AGCTTTTTCT AGAAAAAAAA ACCAGTTTTA AGAATCACCA GTTCTAAAAG 22920

GGTAATATCT TATTCATCTT TCTGAGAATG GAGTATCATG ATTCATGAAT TAGATACTTG 22980

CATCTTAACA TTTGAAATAA TTTAATTTTA TTATTTTTTA GTTCGAAAAC TGTATCTTCG 23040

GGCACCAAAG AGCATTGTTA TAATCAAGTA CCAGTTGAAT TAAGTACAGA GAAGAAGGTT 23100

TGTTTTAAAG AAATTGTTCT GACTTATTTC ATTCTTTATT GATTCAAATT CTGTTTAAAA 23160

TTTTATATTT TAATTCCTTT CCAATTAAAG AGAAAATGGC ATATATAACA AAGCATAAAA 23220

TTCGGCCAGG GAAGTGATGT GAACAGACTA AAATTTATTG TATATAATTT CTGGGGCTAA 23280

TAAAGAATTG GAGGTATTTG AGAAAGGAAT TAATTTGGGT TCTTTTAAAC CTATCTGCTA 23340

ACTCATTTGG CTTAGAGTAG TCACATGTTA TAATACTTAT AGTTGATCAA AAAATTGATT 23400

CCTAAGTGTT CTTATTAAAG ACACACACAC ACACACACAC ACACACACAC ATTCTTTCTC 23460

TCTCTCTCTC TCACACACAC ACACATGCAC ACACACTTAT GTACTTTCTT GCTTTTTTTG 23520

ACCTAAGATC TTAGATAACT ATTACAGATT AAATACTAAT CCACTGGCAG ACTTCAGCTA 23580

ATTAGAACAC TGGAATAATA GGCAAGCATA GTGAATTACA TTTTCTGGTG AACTTTTTCT 23640

GCTTTATTGA AGTATGCAGA ATGTAAATGA ATTGTTTTTA TAACTTTGGC ACTTGCTGTA 23700

›Example 10 · 14 of 49

TCTTAGAACA TTCTTTTGAT GATTTATTTT CTGTAGTTTT GGGAGAGATA AGACATTGGA 23760

ATGCGTTTCT AACTACCTTT AGAACTTTAG AAACTGATAA TTTAGGAGGT TATTTTCAGG 23820

TGATTAATTT GACAGCTTGA TTAGGCAAAG AAAAAATTGT GATTTTGAGA TTTTTGTTTC 23880

TTATTTTCTT CACATTTAAA AGTTTTTTGA AACTTTTTTT AATGGACCTT TATATGTTTA 23940

AATGCAGTCT AACTTGGAGA AGTTATATTC TTATAAACCA TGTGATAAGA TTTCTTCTGG 24000

GAGTAACATT TCTAAAAAAA GGTACAGAGT TCCATATTTC TATGTTCTAT ACTTGCTTTA 24060

TGAGTACTTT TTTTTCTAAA GAGAAAGAAC TGTCAGATGT TGGGCTATTT CATTGGCAAA 24120

AGGAAGTTAA ATTTAAAACA TAAGCTTTTC AGTATTAGAA TGATCAAAGT GAGCTATAAA 24180

AGAATAATGT TAATTTAATA GCTAACACTT CTTGGATATT ACTGTTTGTC AGGCATTATG 24240

TTAAATGCTA AGAACTTTAT ATGTGATATC TCATTTAATT CTTACAAGAG TCTAACAGCT 24300

GTTACTATTT ATCGCCATTT TATAGTTGAA GATACCAAGG GTTAAGAAGT TGACAAACTT 24360

GTTCAAGAGC ATACAGCTAA TGGCCGAGCT GGCTTTCAAG TCTATATTTG TCTACCTCTA 24420

GCATCAAGAC ACTATTTATT TTTCTTTGTA TGAAATATAT ACAGGCATAC TTTGTTTTAT 24480

TGTGCCTGGC TTTATTGTGA CTTGCAGATA TTGCATTTCT TATAAATTGA AGGTTTGTGG 24540

CAACCCTGCG TCAAACAGGT CATATTAGCC CCATTTTCCA ATAGCATGTT CTGTTGTCAT 24600

GTCTTTGTGT TATATTTTGG TAGTTCTTGA CTGGCCATTC ACCATTTCTC TCCCTCTCCT 24660

CGGGTCTCCC TGTTCCCTGA GATACAACAA AATTGAAATT AGGCCAATTA ATAACTCTAT 24720

AATAGTCTCT AAGTGTGTTT TTTTTTTTTT TCGAGACTGA GTCTCACTCT GTTGTTCAGG 24780

CTGGAGTGCA GTAGCACAAT CTCGGCTCAC TGCAATCTTC GCCTCCCGGG TTCAAGCGAT 24840

TCTCCTGTCT TAGCCTCCTG AGTAGCTGGG ACTACAGGCG CCCCCCGATC ATGTCTGGCT 24900

AATTTTTGTA TTTTTAGTAG AGATGGGTTT TTGCCGTGTT GGTCAGGTGG ATCTTGAACT 24960

CCTGAACTCA GGTGATCCGC CTGCCTTGGC CTCCCAAAGT GCTGGGATTA CAGGTGTGAG 25020

CCGCTGTGCC TGGCCCATCT CTAAGTGTTT AAGAGAAAGG AAGATTCACA TGTCTCTCAA 25080

TTTAAATCAA AAGCTAAAAG TGATTAGGCT TAGTGAGGAA GCCATGTCGA AAGCTGAGAT 25140

AGGCCAAAAG CTAGGCCCCT TGCACCAAAC AGTTAGTTTG CAAAGGCAAA AGTTCCTGAA 25200

GGAAATTAAA AATGCTACCC CAGTGAATAA AACAATGATA AGAAAGCAAA GCAGGCTTTT 25260

TGCTGATATG GAGAAAGTTT TAGTGGTCTT TATAGGAGAT TAAACCAGCC ACAACATTCC 25320

CTTGAGCCAA AGCCTAATCC AGAGCAAAGC CCTAACTCTC TTCAATTCTC TGAAAGCTGA 25380

GAGAGGTGAG GAAGCTGCAG AATAAAAGTT TGAGGCCAGC AGAGGTTGGT TCATGAGGTT 25440

TAAGGAAAGA AGCCATCTCC ATAACATAAA AGTGCAAAGT GAAACAGCAA GTGCTGGTAT 25500

AGAAGCTGTA GCAAGTTATC CAGAAGATCT AGCTAAGATC ATCGATGAAG GTGCCTGCAC 25560

TAACAGACTT TGAATGTAGA CCAAATGCTT TCTACCAGAA GAAGAAGCTG TCTAGTACTT 25620

TCATAGCTAG AGAGAAGTCA ATGCCTGGCT TCAAAGCTTC AAAGGACAAG CTGACTCTCT 25680

TGTTAGAAGC TGATGCAGCT GGTGACTTTA AGTTGAAGCC AGTGCTCAAT TAGCATTCTG 25740

AAAATCCTAG GGCCCTTAAG AATTATGCTA TATCTACTCT GCCTTTGCTA CATACATGTA 25800

ACAACAAAGT CTTGATGATA CCTGTTTACA GCATGGTTTC CTGAATACTT TAAGCCCATT 25860

GTTGAAACCT GCTTAGACAA AAGATTCCTT TCAAAATGTT ATTGCTCATT GACAACACTT 25920

AGTCACCAAG AGCCGTAATG GAGACATACA AGGAGACTAA CGTTGTTTTC ATGCCTGCTC 25980

GCTTAACATC CATTCTGTAG CTCATGGATC AAGAAGTAAA TTAACCTTTT AAGTATTATT 26040

ATTTAAGAAA TACAGTTTGT AATGCTTTAG CTTCTGTAGA TAGTGATTAT CAGAGATGGG 26100

TTTTTAAGAG GTTTTCCAGA AAACCTTCTG GAAAATATTC ACTATTCTAG AAGTCATGAA 26160

GAATATTTGT GATTCAGGAG AGTAGGTCAG AATATCAATA TTAATAGGAA TTTGGAAGAA 26220

GTCGATTCTT ATTAAAATCA AGAGTTTAGT GATAGACATA CTGAGTTTGG GATACCTGTG 26280

GAGTAGTCCA GAAGTTAATT TAAATATATG GGCTTAGTGT ACAGAAGTGA GCAGGGTGCT 26340

TATATATGAA TAAATATTAT TTTAAGATAT ATTTAAATTT TCCTTAAAAT AATACCTATA 26400

CTTGATATAA AAAGTTAATT GGAAATTAGT GGCTTATGAC AAGCATACCA GCCCACACTC 26460

TTCCCAAACC CACTTTGCTC TTATTCATAG AAGCTGTCAT CTTCAAATCT TCCAGCTGAT 26520

TTCCCTGGCG TGTGCCTTCT TATTTCTGAA TGACACGCTT AGAGTACTAT TTTTTTGACT 26580

TAGCAATTTT AGAAATTTTC TACTCATCTC CTATTATGGT AGATTTCCCC TCCTTCATTC 26640

CTCCTCCAAT ATAATTATAT TTCGTCATAT TAATAATTTG TTTATATATA TTTTTAATAT 26700

AATATGATAA TATTGTATTT ATATTATTAA AACTACACAA ATATTATATA CACACTACTA 26760

ACCCAACCGT GTTATTATGG CCACCACTAC CTTTATTTTT TTCCTTGTGT TAGTGATTGT 26820

CTTTGTTTTA TTTTCTTGGT TTTGAGTATT CCTTTTACTA ATTTTCTTTT TTCCTATTTC 26880

AATCTCTCAT TATTTGTTTA CTCATTTGGA GTGTTCCTTG ACTTTTATCC CCTCTTACCT 26940

AGTGACATTT TAATTTTAGT TATCAAATTT TTAATTTCTA AGAATGCTTC TTGTTCTCTT 27000

CTTGTTTCTT CTTCCCCACC AGCCAAAAAT CTATGATGTT ATAGCAAGGA TCATACATTG 27060

TTTCCCAGTA GGTTAAGAAA CCTTGGTTAA AACCTGTTGT ATCCCAGTAA GTTAAAAGAC 27120

GTTAACGTGT CATCTTCAGT ATGGATGAAA GAATATTTTC TTTCAAAAGC AGTTGGTTGA 27180

GGAAGAGAAT GGGACAAATG CTCTTTTTAA AACACCAATT TTGTGATGAA CTCAAATTGC 27240

AATTTTAACT TTACCATTAT AATGAATGTA TTTGATCCAA AATGTTTAAA ATCTAGGCTG 27300

TTGTCATTTA AATAACAAAT TACCTTACTG GTATCATGAA GAATAAATGT TTGTACTGAT 27360

TTGGAAAGAC ATTCTCATTT AGGGGATGAA ATAGAAAGTC AATGAGGAGA AAGAAAAGCT 27420

TTTATTATTT ATTTTCTTTT AAATATTTTA GTATCATGGT ACAGTCACCA GAAAAAGCTT 27480

ACAGTTCCTC ACAGCCTGTT ATTTCGGCAC AAGAGCAGGA GACTCAGGTA AGGCTTTTGT 27540

AAAAAGGTAA TTAGTTTATG ATAGGATAGT TATGATTCTA TGTATGCTTA AAATTCTGTA 27600

TTTTGCCAGC ATTTTAAAAA TTGTTCTTAA GCTAAGAGTC TGAGTTTATA TTTCAGTTTA 27660

TATTCATTCT AAGGAAAAAT GTGGTATCTG AAGCTCTAAA AATAAAGGAC TAGATCTTTT 27720

AAGTACACTT TAAAAAGTGT TGTTTCTTTG TTTTTTGTTC AGATTGTGTT ATATGGCAAA 27780

TTGGTAGAAG CTAGGCAGAA ACATGCCAAT AAAATGGATG TTCCCCCAGC TATTCTGGCA 27840

ACAAACAAGA TACTGGTGGA TATGGCCAAA ATGAGGTAAA CTATCTTTTG CATGTGTTCT 27900

CATTTATTTC CTTCTAACAA AATAGATTTG GAAAATATAT CTAAGTTGAT AATATGACCA 27960

TAGCTTCCAC TGTCACATCT GGGAGGTGAC TCAGATTCCC CCTGCTGCGA TGCTTATCTC 28020

TTTGCCAAGC TTTAGTACCG TGTTTCTGTA TGAATAAAAA CCAGTTACGT TTTCAGCAAT 28080

CATATTCAAT ATTTATAAAA TCTAACTCAT TATTTACCCA CCCTGCATTT TATCCAAATG 28140

CCGAAACTCC TCTTTTTGGA TTCTTTATTT TTGATTATCT TACCATCACA TTTGTAGTCA 28200

GAGGTTCCTA ATGCTTAAAA CCTCTGATCT GAATTTTCTC TCCTCCAATA TAAAACCCCT 28260

TCGTCTTCCT CTTCTTCTTC TTCATTTTTT TTTTTTTTTT TGTCTGAAGA CTTGTCTCAC 28320

TGTGTTGCCC AGGCTGGAGT GTAGTGGTGC GATCACTGCT CACTGCAGCC TTGACCCCCT 28380

GGACTCAAGC TATCCTCGCA CCTCAGCCTC CCGAGTAGCT GGGACTACAG AACATGCCAC 28440

CATGCTCAGC TAATTTTTGT ATTTTTTGTA GAGACAGGGT TTTGCCATAT TGCCTAGGCT 28500

GGTCTTGAAC TCCTAAGCTC AAGCAATCTT CCCGCCTCAG TCTCCAAAGT TCTGGCACTA 28560

CAGGTGTGAG CCACTGTGCC TGGCCTCTTT TTCTCATTTA AATACTTTTC ATACCTTTTG 28620

TAAAACGGGT TCCTTGTTGC CTGTCTATGC CTTCCTCCTC CTTCTTAATG ACACCACGTT 28680

AATTCTGACT GTTTTCCCTT GGCCTGTTGC AGAAGCCTCT TAACTATTAA CCCTTCATTC 28740

TCTCTCTCTG TTTCATCTGA TATATGAGTA CCAAACTAAA TCTTCCTTTA TCATATCTTA 28800

›Example 10 · 15 of 49

CTTCTGCTTA AATGTTTTTT TTCTAGCTTA GAATTCAAGG CCCTCTATTT ATGAACTTAA 28860

ACTTACTTTT CCCTCTAAGT TACAGAATTT GAAATGGTTT ATCTTACCTG GATTGTTTAT 28920

CACTTGTTGA AGATCCATTT TCAACTTCCA TATATTTATT TACAGTGTTG CTTCTCCTTG 28980

TAGTTTCCTT GATTCCTCAA AACTCCTTTT AAGAATTCTT GAAGATCTCG CTTTATTACT 29040

ATTTCTCGCT TTATTACTGT AAAGACTATG AGAAGGTCTT TCATGATCTT ATCAGCAAAG 29100

TAATTCCTCT CTCTTGAATT CATAGAGGAC TTTCAGATGA ATTCTAAAGA TGCTTCTGTA 29160

GCACTTACCA CACAATNGCT ATATTTTATT TTTTTGTAAT TAGTGGTAAA CAAGTATTAT 29220

TATATCTTNC TAGATTTTAA ACTCCAAATA AAGATACTAG CTCCTTACCT TTTTGTGTGT 29280

CTCCTGTAGC ACCTAGCACA ATGCCTCATA AACAGGAGGT GATCATTAAA TATTTAGAAG 29340

AAATTATTTC CCAAGAATAG TTGCTTGGTA ATTGTATTTG TCTTTTACTT CCTTTTAAAA 29400

AATTGTTTCT GTCACTAAAT TGCATCCAAT AGATGTTACT TGAGTGCAGA ATTTTCTAAT 29460

GACATTACAC AGTGCTACAT CTGACACTAA TTCTTTTGTT AAAAAATAAA TATTCTGGCC 29520

GGGCGCTGTG GCTCACGCTT GTAAATCCCA GGACTTTGGG AGGCCGAGGC GGGCGGATCA 29580

CGAGGTTAGG AGATCGAGGC CATCCTGGCT AACACGGTGA AACCCCGTTT CTACTAAAAA 29640

TACAAAAAAT TAGCCGGGCG TGGTGGCGGG TGCCTGTAGT CCCAGTTACT CTGGCGGCTG 29700

AGGCAGGAGA ATGGCGTGAA CCCGGGAGGC GGAGCTTGCA GTGAGCGGAG ATCGCGCCAC 29760

TGCACTCCAG CCTGGGTGAC AGAGCNNNAC TCCGTCTCAA AAAAAAATAA AAAATAAAAA 29820

TAAATAAATA TTCTAAGACC ATACTTTAAT GGAGGTGTTT TTTGTTTTTT TTTGTTTTTT 29880

TTTTTTTTTT TTGGTGATAG AGTTCTCACT CTGTCACCTA GGCTAGAGTG CAGTGGCGCG 29940

ATNCTCNGGC TCACTGCAAC CTCCGCCTCC TGGGTTCAAG CCATTCTCCT GCCTCAGCCT 30000

CCGGAATAGC TGGGACTACA GGTGCGCGCT GCCACCCCCG GCTAATTTTT TGTATTTTAG 30060

TAGAGATGAG GTTTCACTGT GTTGTCCAGG CTGGTGTTGA ACTCCTGAGC TCAGGCAATC 30120

CACCCGCCCC GGCCTCCCAA ATTGTTGGGA TTACAGGCGT GAGCCACAGT GCCTGGCCCA 30180

GAGGAGATAT TTAATGAAAA ATAATAATCA TTAGATAGGC AGATTTTTAG AAGGAGGGCA 30240

TCGAATGGGT TCTTGGATAT TGGACACAAT AAGAAATATT GAGCTAAAAG TCTGAAGGAA 30300

TTGGCAGATA TACTGTTACA GGTAAACACT TTGTAGAAGA AAATAATGAA TGAGACTTTC 30360

TTTTGAGATT TTCTTAGCCT CTTAGTTGTT CCCAGTTAAA GCCTCATATT TTTCCTTTTC 30420

ATGACAATAA AAATAATAAT AAAATCAGTA ATAAAGTGAA TATATGAGAT GTTAACCTGT 30480

TCCTTTATGA CAATGTCCTG TTTACCAATT AACAGTGTGT TTTTGTGGTG ATGGGGGCAA 30540

GACAAATCTT TAAATGGTGG AAAGCAAAGA AAGAAATTAT AAAACATGAT TAGTTGTATT 30600

ATACGTTGTT TTTGGTTGTT GGAAAAACTA TACATTTATT GAGAGAATCA TTAGGAAGCT 30660

GAACATCAGC TATATTGCTG GAGTGATACT GTTTCAGTGG TTTCTTGACC TTTTTGTTGT 30720

TGTTGTTGTT GTTGTTAAAC ACAGACCAAC TACGGTTGAA AACGTAAAAA GGATTGATGG 30780

TGTTTCTGAA GGCAAAGCTG CCATGTTGGC CCCTCTGTTG GAAGTCATCA AACATTTCTG 30840

CCAAACAAAT AGTGTTCAGG TAAAATACTG TGGTTTGCAG GAGCTCTTAG AGAATAAGCA 30900

TTTTTTGTAA CCATTTCAAA AGTACCCTCC AGAAGCAACA TTTGCTCACT TTATTTGCAT 30960

TTCCATACTG GACACTTAGA AAATGAATTA AAATTGTTTT TACAGTCAAT CNNTGTTGTA 31020

AAAACATGTC AGTTATCTAC TTTTAAAGAT GATACTAAAA AGTAGTTGTC CAGGCTGCTG 31080

ATGTCTTTCT ATTTCATTGG GAGGTTTTGT TTTTAAATTG GAAACATTAT TTTAGGTTGA 31140

TAAATTATAA TTTTACATTC AAATGTGGTA GTTGGAATTT AAAGCTGGAA AGTTATCCTT 31200

GCTATGAGTT GGTCAGGAGC TCAGCCACTT TCTTTTGGTT TAGCATCTTC TCTAATCTCC 31260

CTCCCCTTCC AGTAATGCTG TCTTTTGATA GTAAGTGGAT TTCATATTAT TCTCTTCAGT 31320

TTTAATAGTG TTTCCTTCAT ATCCTTTTAT TATTGCTTGT TCTGCCCTAA GTGACCATTT 31380

CCAGAAATGT CATTTAGGNA TTTTCTCTAA ACTCCACGTA GCAGACTCTA TAATGCATAC 31440

TCTGCAGAAG GTGAGGCAGT GGGAGGTAGA GGGGAGACTA CTAGACTAGG AGTCACGGAA 31500

TCAGGACTTT AGTTCTTCCT TACAGTTGTT CACCTGGTGA ACCTGCACAT GTCCTTTAAT 31560

TTCCTTGGGT CTCCATTTCC TCAGCTATAC AATGGAAATG ACACTTCCTC CCCCACATCC 31620

AGGAAACAAC AGATGACATT AGAAAATAGA AGACATGGGA TAAGTATAAA ATGTTGAAAG 31680

AGTTAAACAC ATTCAAGGCA ATATTAAGGG ATTATTTTTT ACTTCCAAGA AGCTCCTGGA 31740

AGCTTTGGGC AGGCACAGTT GGATCCTACT TTAGAAAAAT CTTTCTCTAA CTATAAGTAG 31800

AAAACCCTTC TGCTTTTTGA ATGTAGCATT TCCCTCTTTT GATATAGAGT ATCTTTGGCA 31860

ACTTTGAATT TTCTTTTTCA TACTCTTATA TAAGACATCA TGTGAAAATT CTTATTTCTT 31920

ACTGAGTTTT TGGAAATGAA ATTATAATGT CTTAATAGTT TGAGAAAGAA TATCATACCT 31980

ACCAGCGGTA ATTGAGTAAG TTCCCTCTCT TTGGACACTT GAAAGTAGTA TCTTCTTTCA 32040

TGAATTAGTG ATATTATTTA ATAATGAATG AGTGATCTCT CCTAACTCCC CTTCAGAAGA 32100

GGAAAATGAA GTAGGGGAAA AGGTAAATTC CCCAAGGGAT AGGTATGAAA CCTTTATGAA 32160

CCTTCTGGAT AGAGAAGATG ACTGCTGATT TCTGTGATTA GAAATTATAC TTGGGTTATT 32220

CTGCAAATTG AAATGAATTA TTTAAAAAAA AACAACTTTA ATGTTTATTA AGCAAGTTTT 32280

GTTATTCATG AGTTTCATTA GCCTTTTATT TTTTTTTTAA ATTTTGAAGT AAAATTTCTT 32340

GCTGTCACAA TACACATTAA AAATTACAAA TATGACACAT ATTAAACACA TTAAGATGGC 32400

CGAATAGGAA AAATATGCTA AAATATTTTT ATATAAATAC ATTTTTTGAG AATTTTGAGA 32460

ATTTCTGGAA CAAAGTAATG ATATAATCCA TAAATGTACA ATTAAAGAGT TTAAGGATAT 32520

CCAAAATACT TGGCAAAGTA ATCTGAAATA ATACTCTTAG GAAGGTAGGG CAAGAATGTG 32580

ATTCTAGTAA GCAAAAATGT AATCAAATCG TATTCTAGTC CCAGCTACTC GGGAGGCTGA 32640

GGCAGGAGAA TGGCGTGAAC CTGGGAGGCG GAGCTTGGAG TAAGCCGAGA TCGTGCCACT 32700

GCACTCCAGC CTGGGCGACA GAGCGAGACT CCATCTCAAA AAAAAAAAAA GACTATATGA 32760

ACTTGTATGG CATAAATATG TACAAATATT ATTTATTTTA AAAAAATTCA GGGGTAGGGA 32820

CAGGGTAGTT AGAAAATATC TAAGGATGTT CATGAAATAA TACTGGCTAT GAATGACAGT 32880

TGATGAAACC GGGTGGTGCC CNATCTTATT CCCTCGACTC GTGTATATGT TTGATATATC 32940

CCACAATAAA CCTTAAAAAA AAAAAGNATG AGTGGTCAAT TATAGGAAGA TATAAATAGA 33000

AAAGGCAATA AGGACAAAAG TTGGCAAAGC TTACCTAAGC ACTCTTCAGA TAAAAAGACA 33060

TTTTTGCTAA CTAGATTTGA ATATTATAGT TTAATTGTCA AGGAAAATGC CTCAACTTAA 33120

TCTTTGTTAA GAGACTACTT AAGGCACTAT CAGAAGTTCC CTCATGGCAA GGTGCAATCC 33180

CTCATGCCTG TAATCCCAGC ACTTTGGGAG GCCAAGGCAG GCAGGTTACC TGAGGCCAGG 33240

AGTTAGAAAA CAACCTGGGA AACATAGTGA GACCCGACCT CTACAAAAAC AATTTCTTAA 33300

AATTAGCCAG GCATGGTGGT GCTAGCCTGT AATCCCAGCT ATTTAGGATG CTTAGGCAGG 33360

AGGATTGCTT GAGCCCGGGG ATTTGAGGCT GCAGTGAGCC ATCATTGTGC CACAATACTC 33420

CAGCCTGAGT GATAGAAAAA AAAAAAAAAA GTGTCTTTGT TATATTCCAA ACTTGTTCTC 33480

AACTTTCAGG TGAGCTGGCT TCCTGTATAA CTCTTGTATA GGACAGAACA TACTGGTTGG 33540

GGCAAGTGAA ACTGTCTAGT TGTATGCCTC ATAAATTAAT GAATTTCCTT TCTAATATAT 33600

ACACTGATAT TTATACACAC ATACACATAA AACCAAGCTC AATAGATGGG TAGTGCAGCT 33660

CTATTCCCCA AAACCCAACT ACCCTGTAAC AAGACACATT AGACTTTTGA GATTGCAAGG 33720

ATGAGGACTG AAATGCTGGC CTAGACCATG GTGTTGCCAT AGTGGGGTGA CCAGTCTGAA 33780

TAGCCAACAA TGCTTCCTCA GTAAATACCC ATTTTGTCTT GGTGGGATTT CTACAAATTG 33840

CAAAATGCAG CTATTATGAA GCTGTAAAAG AGNAAACANG AAACATGTAA CACCTGGGAC 33900

›Example 10 · 16 of 49

TGTTTTATTA GGCCCACCGT ATGCTCAGAA CATGAAATCT CCACTGCTAG GGTTATTTGA 33960

TTGAAATTAT CTTTTGTGTT GATGTGAGAG TTTAGCTCTG AGATTCTTCC ACATGTAAAA 34020

TGTAATCCCC CAAAGTATTT GGCAAGCACA TTTTATTGCC TTGGGTCAGA TAATTGAAAC 34080

ATTAGGCATC ATATATATAG CATGTAAAAA GTAAAACAGA AACATTTATG TTTCTCACCA 34140

AGCAGTAAAT TAGTACTCAA CTAATAAATT TCTTAAACTC CCTAATAACA GAATATGGAA 34200

ACAAAAAATA AATCTTTCCA AAAGAAGAGC TCATGGACAC ATTTCCTCAT ATATGTATAC 34260

ATAATATAGT AGAACACATG ATAAATAACC TATAAAAATG ATACCAATAT CATTCATCAA 34320

GAGACGAGGC TCTTCTTTAA ATTATTAATT TCATCTGTTA CAGGTTTTAT TATGACTGTA 34380

GTATGCTGTT TTCATCTACC TTTTATGTGT AGTTAAAAAA ATAGTTTTCT ATCTCTTTAC 34440

CTTTATTTCA GCCTTTAAAA AGATTCCATT ATTTTTTCAT TAATCTTGTT TTTCAGTTTT 34500

TCCCATTTTT TCTTTTAAAC ATTTCTTAAG GAACCATATT TAAGATTTTA TAGAATACTT 34560

AGATTTCTAG TTGGGATGTA TCATTTAAAA TTAGATATGT AGAGAGAGTG TTATGATATA 34620

TTTCCTTACG ATATATTAGT GGTTATAGTA CCTAAATTTG AATAGTGATT CTGTTCATTC 34680

ATTCATTCAT TCATTCAATA TTCACTTCCA GGAGATTGGG GACTTATTTA AAGACAGAGT 34740

AGTTCACATT ATAGTTCCTT TTTTTAGTCC TTCTTATTCG TTAAAGAAAA GACTAGGAAA 34800

TGTTTGTTAT TACAAATATT TTATTAAAAT TTTGTGTGCT CTAGCATTAT TTTACCTTTT 34860

AAAATCAATA TGTTAAAAAT CCAACTTCTT TTTGAGCTCC CCATAAAAAG GGAATTATTT 34920

GTTGCTTATG GGTTTAACTT GTGTTATTTT TTTCTTAATG GCTAATTATC ATACATATAT 34980

TCTATTATTG TATTGATATT ACTGATCATT TGTGCTACAT TAAAAATTCT GTAGACAGAC 35040

CTCTTTTCAA GTACAAAACC TCAAGAAGAA CAGAAGACGA GTCTGGTAGC AAAAAATAAA 35100

ATATGCACAC TTTCACAGTC TATGGCCATC ACATACTCTT TATTCCAAGA AAAGAAGATG 35160

CCTTTGGTAA GTGTGACTTT CATGTTACAG GGAATTTTTT TAGTTTACTT AAACTTGTGT 35220

TTTATCAGCT TTTTAGTATT AAAGTTCTGA CTTGGGATCA ATTTCCTCCA ACCCTACAAT 35280

AAATCTCAGT TTATCTTTAA TTTTAAAAGA GAATGTTGTT TTCTTTTTCT GTTAAGCCTG 35340

CCTGTTAAGT AATAGCAGCA AGTTTAGTTT GGCCATGAAT ATCTTCTAGA GATTGTATCG 35400

GGGTACTGAT AAACACATTT ATAGCTCAGG GATACTGCAT CAGCCATATT TTAAAATGGG 35460

ACTAACAGTT TAAAAACTAT AAATATTCAC AGTGTTAAGA AACAATCTCA AGATGCATTA 35520

AGAAAAAGGA AGGTGCAAAA CAGAAAAACA AACGTAAACG TGTGTGCATA TGCATGCTTA 35580

TATAGTCACA TATTCTTGTA TGTGTACAAA AAATACACAC TGGATCTCTG CAAGCATAGC 35640

CAAGCAACTG GAAATATGTT TTTAAAAACT TGCTTTTCAT TCTATCTCTT CTAGTACTGT 35700

TTTGATGCTC TTTGAAAACA ATCTAATTGC TGTAACAAAT GACCATACGT AGGCCGGGTG 35760

TGGTGGCTCA TGCCTGTAAT CCCAGCACTT CGGGAGGCTG AGGCAGGCAG ATCATTTGAG 35820

GCCAGGGATT TGAGACCAGT TGGACAACAT AGGGAGACCC TGTCTTTACT AAAAATACAA 35880

AAATTAGCTG GGCGTAGTGA CGCATGCCTG TAATCCCAGA TACTTGGGAG GCGGAGACAT 35940

GGGACTTGCA TGAACCCAGG AGGCAGAGGT TGCAGTGAGC TGAGATTGCG ACACTGCATT 36000

CCAACCTGGG CGACCGAGCA AGACGCGGTC TCCAAAAAAA AAAAAAAAAA AGACCATATG 36060

TAATGTTTCT TCATTGTTCT AAGATAAATC TTTAAGGCTG TTGAGGTTTT TTGTATACAA 36120

AATGGAGAGT AAGTTTTAAT GGGATGGGAC AAAATGAGGC TTACAGTTGA GTTTAATTTG 36180

AGTTCACATC CTGTTGACAT TAAGTTGATT TGGAACAAGT GATATGGTCC AATGCCTGCT 36240

TTTCTATTGT CTGTGGTTCC ATCCACTAGT GCCTGTGTTA CACACCTCTT GTTCAGGTTT 36300

TATCATTTAA AATAAATAAG AATAAACAGT CCATAGCTTA TCTTACTTAC TGAATAAATG 36360

CTCTGATTTG ACAGTCATGT TTCTTAAAGT TCCTTACAAA GGCCATTGCC CAAGAAACCA 36420

AATAATTCCA TTATACTATT TTTGAAATAG AACACATAAT AAATGGGAAT TTTAAGTTCA 36480

GTTTCTTATG TAAACAATAA CTTCTATGTA CATGTTAAAT ATGCCTGTAT ATACCTAATT 36540

TGACCATGTA TGTATAGTAG AAATGAAAAC AGTTACTAAG AAAATTTGTT ATTGGCTCCA 36600

AATTTTCTGA ATTAAGTGTA TTNCTAATGC TCAGCCATAA TATGGGGTTT CATGTGTTAG 36660

TTTATGTATT CATGGTTAAA AATGTGAAGA CTGTTATATC TTCATTTGTG TCTTTTGGTA 36720

TTATTTGGTT GTATTTTATT GTGTGATATG GTGGTATAAT TATCCTTACC TCCCAGGAGT 36780

TTGAGAGGGT CTTGCCAGTT AACCGCAGAA TTAAACATGC CTAGGACTAA TTAATCAGGA 36840

GCAATACTAC AATTAATTGG AGGTAATTTG AAACCTGGTT TCAAATAACC CTGATATTAT 36900

GCACACATGG TGCACACTTT TCTAGTAGAC ATTTAATGAA AGTAATTTAA AACCTACCTT 36960

TGAAGGATGA AAAACATTGC CTTAAATGCT CTATTCTGTG AAAGTATCAA CATTTATGCA 37020

AATACAGTCT AAATTCAGAC TTTGAAAATG TATTGAAAGA GAGGATCATG AAATAAGTTA 37080

GAGCTGAGTG ACAAAGCTTT CTGAGTGTTT AAAAGAATGT TTTACCTAAT AAATATCTGA 37140

AATGTATTTG GAGCCACATT TGTTTAAAGA ACTGTATAAA TATGTAGCAC TGTTCATGTG 37200

AAGTTCAATA GTAGGAAAAT GCTGACAGCC CTTGTGGAAC TGTGGTTATT ATTATTTTAT 37260

GAATAGAGCC AATTTCAAAC ACCTATTAGA GTCTTCTCAG GAACATTTTA TAGAATGCAT 37320

CTGGAGCCTT ATGTTATCTC TAAGCATTTT AGGATTTGTC TTCTTGGAAA TTCATGTAAC 37380

CAAACCACCA TGTGTTATTT CAAGTGTATA TAGTATTGGG TTACAGTTTA CTATGTTTTC 37440

AGAAGGTTGT GACAACTATT AGACTTACAG AGAATGACTT CTCTGCCACT AACGGCTTTC 37500

TAAAGTGAAT AGAGAGGGGC GAGGATTGAA TTCTTCGGTA AAGCTGGGTG ATTTTGTTTT 37560

ATTCAATACA GTATAATAAG TATAAAAAGT AGAACCTATA GAGAGCTATA ATGGGGGTAG 37620

TTTTAAAGAA ATTCTGAAAA TGAAAAACTT AAGTAAAGGT TTAGTTCATT GTTTATTTCA 37680

CACTGAGCAT TTACTACCTG AATGTTTTGG ACATTTTATT TCCATGACTG GAGTGGACAC 37740

TTTTACAACT CACTGGGTTC TTTGCTGATC TTTCTCTAGA AGAGCATAGC TGAGAGCAGG 37800

ATTCTGCCTC TCATGACAAT TGGCATGCAC TTATCCCAAG CGGTGAAAGC TGGCTGCCCC 37860

CTTGATTTGG AGCGAGCAGG CCTGACTCCA GAGGTTCAGA AGATTATTGC TGATGTTATC 37920

CGAAACCCTC CCGTCAACTC AGGTGAGAGG CATGGCCTAG CTCTGCACCC TTAATGACTT 37980

GATGAAGTAA ACAAGCAATC CACTATATTT TTCACTGTTA ACAGCATTAA TCCTTTATGC 38040

TATTATGAAA ACCTTACTTT TGTGATTCTT TTTCTTGTTT TAGGAAAACA ATCTTTCTTC 38100

CCATTATCAC TCAGAGGAAA GTATACTGAG AAATTTTTTT GTTTTGTTTT GTTTTTTGAG 38160

ACAGAGTCTT GCTCTCTTGT CTAGGCTGGA GTGCAGTGGC GTGATCTTGG CTCGCTGCAA 38220

CCTCTATCTC CCAGGTTCAA GTGATTCTCT TGCCTCAGCT TCCTGAGTAG CTGGGACTAC 38280

AGGCGTGTGC CACCATGCCC AGCTACTTTT TGTATTTTTT GATAGAGACA GGGTTTTCCA 38340

TGTTGGCTAG GCAGGTCTCG AACTCCTGAC CTCTGATGAT CCGCCCACCT CAGCCTCCCA 38400

AAGTGCTGCG ATTACAGGTG TGAGCCATGG CACCTGGCCA ATACACTGAG AAATTTTTAT 38460

TTTCCTTTTC AGCTTAAGGT TACAACTTCC CCACCATCCA AAACGTGCAC TTTCATTTTT 38520

TTTCTAATTT CTATCTCATC ACTTGCAAAA ACCATATTTT TCTCCACATT CATTCCCAGT 38580

AGCTTCCTGA CTCCTAGTTC TTCCCTAAAT CCTTCTGAGT CCTTGTCATT GGTTTCGCTT 38640

GAGTAGCCTT TCTAATCAAC ACAGTCATTG GTATCAGTTA CTGTGACATG GAAGGGACAG 38700

ACCAAGTTCT GTGGGCCGCT ACGTAGAAGG ATTTCCTGTC ACTTTGCTGC AGAACCTCAG 38760

CTCGCGGAGA GCAAGCCCCT TTGCTTGCCC TGTAGAAATA TTTTAAATTA TTATCCTTTT 38820

TTTTTTNAAC AGAAGTAAAT AGGAGATACG TTAGAGGATT TTCTCTCCTA GATGTGTAAA 38880

TACAAACTTG GGGTCTTATA ACTCAATAAA TCTGATAAAT TTCTTTTGAC TGTTAGGATA 38940

GAGCAGTGGC CATACCAATA GCCTCATCTC CAAAGCTGCA GTGAAGATAC TTTTTACTAC 39000

›Example 10 · 17 of 49

CTTAAAGTCT TTCCCATTTG TGAACAACTT GTGAACAATT CCCCCCAAGA ATTTGGAAGA 39060

TCACTCTCTG AAAGCACAGT CAATACTGTA CTTAAATGGA TCTGAGCAAA AATAAGTCAC 39120

TTAGAAGACA GGATTATTTC TAGACTTGAG TGTGACTTGA CTGAAGGTCT AAAGAACAAA 39180

CAGCTCCTTC ACTTCCATTG ATCACGGTGG AAGCACAGGG AAAGGACAGA CACGGAGGCA 39240

AGTTGGAGTA GTGCTCATCT AAGTTCCAGG GATGCGGGGG AGTGGCCAGG GGACTTCAGG 39300

TATAGTAAAT AAATAACCTA TTTATAAGTT ATGTCAATGT CATGTTTGAA ATAGAAAACC 39360

AAATACTGCA TGTTCTTACT TACAAGCAGG AGCTAAAGTT GGTGCATATG GATATAAAAA 39420

TGAGAACAGG CCGGGCGTGG TGGCTTGTGT CTGTAATCCC AGCACTTTGG GAGACCTAGA 39480

TGGAAGGATT GCTTGAGCTC AGGAGTTCAA GACCAGCCTG AGCAACATAG TGTGACCCCC 39540

ATCTCTACAA AAAATAAGAA AATTAGCCAG ACGTGGTGGC ATATACCTAT AGTCTCAGCT 39600

ACTTGGGAGT CTGAGTCAGG AGGAGTGCTT GAGCTCAGGA GTTTGGGGTT ATAATAAGCT 39660

GTGATCATGC CACTGTGCTC CAGCCTGAGT GACACCCAGA GTGAGAACCT GTCTCAAAAG 39720

GAGAAAAAAA AAAAAGTAAC AGTAGACGCT GGGAACTACT GAGGGGAGGG AAGGAACAAT 39780

GGTTGAAAAG GTGGGAAGGG ACAGTGGTTG AAAAACTACG TGTTGGGTAC TATGCTCACT 39840

ATCTGGGTGA TGGGATCAAT TGTACCTCAA ACCTCAGCAT CCTGCAATAT ACTAATGTTA 39900

CAAACCTGCC CATGTACTAC CTGAATCTAA AGTAAAAGTT ATAATTTAAA AAAATTATAA 39960

TAAAATCAGA AAATAAAGGT CTGAGATGGA AAATTAAAAG ACCAAAGCCA CCCATAAGCA 40020

CAATAAATCC CTCCCCCCAA AAAATTATAT CTATTAAAAA AAGGTGTTGC GCCAGGCACT 40080

GTGGCTCATG CCTATTGCCT ATAATCCTAG CACTTTGGGA GGCCAAGACG GGCAGATGAC 40140

TTGACTTGAG GTCAGGAGTT CAAGACCAGC CTGGCCAACA TGGTGAAACC CTGTCTCTAC 40200

TGAAAATACA AAAATTAGCC AGCAGTGGTG GCATGCGCCT GTAATCCCAG CTACTCAGGA 40260

GACTGAGGCA GGAGAATCGC TTGAACTGGG GAGGCGGAGG TTGCAGTGAG CCGAGATCAT 40320

GCCACTGCAC TTCAGCCTGG GTGACAGAGT GAGACTCTGT CTCAAAAAAA AAAAAAAAAA 40380

AAGACCTTGT ACCCTGACAA GTTTTAGTTT GTGCAGGAAT GACACAATCT AGAATGACTC 40440

AAGATTGGAA AAATCTTTAA ATGTTAATTA CACAATAAGG GTAAAAGGAG AAAAATTACC 40500

TAATGTCATC TGAGCAACAA GAAGAAGAAA TGAAAGGCAT TAAAAATTGG GAAAAATTTA 40560

TATTTGACAG TATCTTAACA ACGAATTCTG CTTCTATATC ACTTCCTAGC TTTCTGATGA 40620

TAACTTCCCG TGCAGATCTG TATGTAAGGA ATGGACGTAG TAGTCATGCT AATCTGAGTA 40680

TTTATCTGTG TGATACTTAC GAATTAACGA TGTAAGTTAA TAAGTTAGCA TTTCGTGAAC 40740

CTGGTTAATA CCATTTGCTA AGGTTAAATT AGCCAAATCC TGAAGTAAGC TGTAAAACAT 40800

CCAAGGTAGG GTAGAGAGGC ATCTTATGAG AAAGCTGGCC AACTCTCCTG GTCACCTTCT 40860

AATCTTCCTA ACTTCAGAAA TCAAGGCAGA GAGAGGAAAA TAGTAATTAC TTTGTAGGAT 40920

TAGATTTATG GTTGTCGAAA CCTTTGTTTC TCCAGTGCAG AATGAGATAG CGTTTTAAGG 40980

AAAGCCAAAG ACTCAGATGT CTTCTTCATG CTCATCGTGT GGAATTTTTC TTCCTTTAGA 41040

AATGTATTGT CTCTCAGGGC TTAAAGCAAT TTGCATCTTT CGATGAGACA TTGAGTAATA 41100

GGCAATATTC TCTGAAATAA TTTGTGCAGG CTGGGCACAG TGGCTCACAC CTGTAATCCC 41160

AGCACTTTGG GAGGCCGAGG CGGGCAGGTC ACTGAGGTCA GGTGTTGGAG ACGAGCCTGA 41220

CCAACATGGT GAAACCCCGT CTCTACTAAA AATACCAAAA TTAGCTGGGC TTGGTGGCAC 41280

ACACCTGTAA TCCCAGCTAC TTGGGAGGCT GAGGCAGGAG AATTGCTTGA ACCCCCATGG 41340

AAGGTGGAGG TTGTGGTGAG CCAAGATTGT GTCATTGTAC TACAGTCTGG ACAACAGAGT 41400

GAGACTCTGT CTCAAAAAAA AAAAAATAGA ATTTGTGCAG TTCCCCCCAC CCCCTTTTTT 41460

TTTTCTGTTG GCATTTTTGC TATCATTTAG CTGCCTTCTT TATATCCTGA AACTTACAGG 41520

TGGTGTTGGT CTAGTCAGTA AGAGCAAAGG CTTTGGGAAT AGATAGATCT GTATTTAGAC 41580

CTTGGCTCTA GCATCTCATT GTTATGTGAC CTCCATCAAG TGACCTAATT TCCCTAATAT 41640

TCAATTTCCT CATCTCTAAG ACAGGGAGTT AATATTGCCT CTCTTATAGA ATTGTGAGAA 41700

ATATAGTCAT GTGTCGCTTG ATGATGGGGA TGAATTCTGA GAAATGTGTT GTTGGGCGAT 41760

TTCATTTTGT GGGAACCTCA CAGGGTGGAC TTAAACAAAC CTAGATGGTA TGGCCTACTA 41820

CACACCTAGG CTGTACGGTA TAGCTCCTGT CTTCAAACCT GTACAGCATG TGACTTTACT 41880

GAACACTGTA GGCAATTATA ACACAGTGGT ATTTGTATAT ATAAACATAG TGAAACATAG 41940

AAAAGGCCCA GTAGAAATAC AGTGTAAAAG NATTTTTTAA AAAAGCTGGG CATGGTGGCT 42000

CACGCCTGTA ATCCCAGCAC TTTGGGAGGC CGAGGCAGGC AGATCACTTG AGGTCAGGAG 42060

TTCAAGACCA GCCTGGCCAA CATGATGAAA CTCCGTTTCT ACTAAAAGTA CAAAAATTAG 42120

CTGGGCGTGG TGTTGGGTGC CTGTAATCCC AGCTATTCAG GAGGCTGAGG CAGGAGAATT 42180

GCTTGAACCC AGGAGGTGGA GGTTGCAGTG AGTCAAGATT GTGCCACTGC ACTTCAGCCT 42240

GGGAGACAGA GCGAGACTCT GTCTCNAAAA AAAAAAAAAA AAAAAAGAGA TAAAAAGGTA 42300

CATCTGTACA GGGCACTTAC CACGAATGGA GCTTGCACCC TGGGAGTTGC TCTGGGTAAG 42360

TCAGTGAGTG AGCGGTGAGT GAATGTGAAG ACCTAGGACT GTGCACTGCT GTAGACTTTA 42420

TAAACCCTGT GCACTTAGGC CACACTCACC CCTGTGATAC GAGTCTACCT ACTGTATAAC 42480

GTACCTGCAT ATGTACCCTT GAAACTAAAA CAAAAGTTAA AAAATTTATC TTCTTTTGCC 42540

AATAATAAAT TAACCTTAGC TTACTGTAAT GATTTTTCTT TATGAATTAA AATCTTTTTA 42600

CTCTTTTGTA ATAACACTTG GCTTAAAACA CAAACATATT GTACAGCTAT ACAAATATAT 42660

TTTCTTTATA TCCTTCTTCT CTAAGATTTT TTCTGTTTTT GATTTTGTTA AATTTGTTTT 42720

TACTTTTTAC ATTTTTTTTG TTAAAAACCA AGACAAAAAC CCACACATCA GCCTAGGCCT 42780

ACATGGGCTC AGGATCATCA GTCTCACTAT CTTCCACCTC CACATCTTGT CCCACCAGGT 42840

CTTCAGGGGC AGTCATATGC ATGGGGCTGT CATCTCCTGT GATAACAATG CCTTCTTCTG 42900

GACACCTCCA GAAGGGCCTG CGTGTTTTAC AGTGAACTTC TAAAAAATAA TAAAATGTAT 42960

AGTATAGCAA ACACATAAAC ATAGTAACAT AGTCATTTAT TATCATTTTC AAGTATTATA 43020

TACTGTACAT AATTGTACAT GCTAGACTTT TACACAGCTG GCAGCAAGGT GAGTTTGTTT 43080

ACACCATTAC CACCACAAAC ACATGGGTGA TGCTTTGCAT TGTGATGTTA CGATGGCATG 43140

ATGTCACTAG GTGGTAGGAA CTTTTCAGCT CCATGATAAT CTAATGGATA CTTGTTCCTG 43200

TTGGCTGCCC GTCGTTGACT GCAACATCAT TATGTGGTGC ATGACTGTAA ATTAGATACT 43260

GTTCAGAAAG CTTTGGCACA CTGGTAATAG CAAATGGTGG TGGCAAATAT GATGATGATG 43320

ATGATGATGA TTGAAGACAT AGATGGTAAA ATTTTATGGT GTCTTAAAAG TACCCTCTAA 43380

ATATGATTAT TTTTATAGTC TGTCCTTTTG AATAGGCACT TAAGAATGTA TGAACTTAAT 43440

AAGTATATAA GAAAGAATGT TCCCCAAAAT ATATCTTACA GAGGCATACA ATTTAAGAAT 43500

TCAAACAGGT TGTAATGGGG TGTGTGTGTG TGTGCACACG CGCACGCATG CGTGCTCAAT 43560

CACACTAAAG AATTCTTGGG CATATGTTCC TGAATGTCCT AAATGGACAT TCTAACATCA 43620

CTTCATTATG GGCAGAGGGA AATGGTAAAG AAAAATTTCA TATTATATTA TTCAGCCACA 43680

TATTGACAGC ATCTGTTTTA TTTGCCTATG GTAAAGAATT GAAGCACTGT TAATTTGCTT 43740

TTTAAATCAT GTAGGCACAA AGTTATCGAA CTTTAGATTT AGAAATGAAA CTGGAAATCA 43800

TTACACTTTC CCTTTCCTAT CCCCACCCTG TTTTGGAGAG AAAGAGTGTG AGGCTTAGAG 43860

AGTTATAAAA CTGTTTTAAT ACCATGTCTA AGATTAATAA CTGAACAAGT TTCTCTTTTT 43920

ACTCGTGTTA AAGTTGTACT GCCAATTAAC TTAAAAGAAA GAAATATGCA ATTTCTAATC 43980

CTGATATAGG ATATGGGTAT ATAAACTCTA ACTTGATGAG TGAAACAAAT TAACTTATTT 44040

ATAATCAGTT TCATATCTTT ATTTATTGAG TGTCTTTAAA TACCCCTTAC CTTTAAAGTA 44100

›Example 10 · 18 of 49

AGAAATATTA AAATCAAGCA GAATATAATA ATGAAAAATT CTTAAGATAT ACTTACTAAA 44160

AACTTATCGT TCGGTTAATA CACTGTATGT AGGTTGTACA TACAATATGA AAAAGTATAT 44220

TTTTGTAGCC TACTTTTAAA TCCAGAATAG AGGAGGTTAA GAAGGTTGTG ATAACCATGA 44280

GCTCTTTTTT TTTTTTTTTT GAGACAAGGT CTTACTCTGT TTCCCAGGCT GGAGTGCCGT 44340

GGCACAATCA TAGCTTACTG CAGCCTTGAA CTCTTGGGCT CAAGCAAGCC TTCCACTTCA 44400

GCCTTCCAAG TAGCTGGGAC CACACCTGGC TAATTTTTAA GTATTTTTGT AGAGATGAGT 44460

TCTCACTACA TTGCCCAGGC TAGTCTTGAA CCCCTAGCCT TAAGCGATCC TCCCACCTCA 44520

GCCTGCCTAA GTGCTGGGAT TACAGGTGTG AGCCACTGAG CCCAGCCCTC TTTTATTTCT 44580

TTTGATAGTA CACTCATAAT CATTAAACTA TCATTTCTGG ATGTGAGATT GTGCTTTTGG 44640

ATTCTTATTT TTTCTTTATA AAATACTTTT TGTTCTCTTA CTGGAGAAAA CATTGTTGGA 44700

TTATAAATGA TATAACAAGG AATGAGGATA TACATACTAT AATAACGATT CAGATATGTT 44760

ATTTTCATAT TTTATTTAAC TGTAGCCATG CCACAATAAT TTAGAGTTTT AAAGAACAAG 44820

TTTGATTGAA ATCTAAACTT TGTACAATCC TGAATTGAGA AGTTTCCTGT ATTTTATTAT 44880

GACACAATAT TTACCTAAAA ATAGGGTAAT TATGAATTGA GAAAACATAG CTATTAATTT 44940

CATACTCTTA TTTGTTAAGT AGATTTTGTC TGGAAAACTG TTCATATTTA AAGGAGCTTT 45000

GTACCTTTGT ATTCTTTTTG TTTTTCCTTG TTTATATAAT TTTAAACTCT GTTTATGGAT 45060

TTGGGATTCT AACTATGCTA AATAATAAAT TAAGGCATTG AATGAAGTAC CTAGACAGTA 45120

TTTTGATTAA TTTTATTCCC CCATTCTTAA TGTGCATGTA ACTGGAAAAT TAAGAGTGGC 45180

TTCCAAGGGA TCTACTACAA AAGTAAGGTT AATATGATCT CTTTTAAAAC ACTGAAGGCG 45240

TGTAGCCAGT GTTGTCATTA ATTCTGCAGT AGATATTTTC AGCACTTATT TACATGGGAA 45300

GTTAGAGCAG AGTAAGATGC ACCTGTAAAG CTAAATGCCA CTTATTTGCA TATATATAAA 45360

ACGCAGGATG AATTTACCAT AGAAATATAA AGGGTACTTA TAGAAATGTA TTAGAAAAAT 45420

ATATGAATTT TTAACTTATA TCTAGAAGTT AACTTTATAC ATTTAACTTT AAATCATTAA 45480

TAGTGGTTTA ACACCATAAG CGGATGTTTA TGCATCATCA TTTTATGAAC AAAAGACATT 45540

CTAATTTTAG AAATAAAGTG ATTCAAAAGA GAATAAAATA TCTTACTTTT TCTTTTAAAA 45600

TTAATTTGTT TAGCGCATTA CATGATAATA GCTCAAGCTT GTGTGATTTT TCCCTAAAAA 45660

ATTGGTTTAT AAATATTACA TTTATAGTAT GAAGAAATTA ATCATACATA GTTTATTTAT 45720

CTAATTTCTA AATACCCATG GAAGAAAATG AATTTAATGG AATGTAGTTG TGTATTACTT 45780

GGTTTCGAGT GTGGGAAAAT TTATATGGTC TTTCTAAAAC AGCACTGTCA GTAGAAATAC 45840

AATGTGAGCT ACATATGCAA TTTTAAATTT TCTAGTAGCC ACATTTTAAA AAGTAAATGG 45900

ATGCAATTTA TTTTGATAAT ATAATTTAAT TAGTCTACTA TATTTAAAAT TTTATCATTT 45960

CAACATGTAA TCAATATGAA AATTATTAAT GAGATATTTT ACATACTTTT TTCTGTAATA 46020

AGCCTTTGTA ATCAGGTATG TACTTTATAT ATACAACAAA TCTTCTGATG CTAAATTTTA 46080

ACTGGAAATA CTTGATCTGT GTTTAGCTTT TGTAAAATTT ACTGTTGAAC AACGTGGACT 46140

AATGTGCCTA AGTGGTTCCA AACATATTTT AAAATTTGAA GACAAATAAA AGGGAACTCA 46200

AAGTAAATTG GGATACATAC ATACAACAGA ATACTGAGCC ATTAAAAAAT GATGAAATAG 46260

TAAAATTGGG GGAATTTTGA TGATACTAGG ATGATATAAT GACCAAGAGA CAAATACAAT 46320

TTTAGTTTGG TTGAGAGATG TGATCATCAC GTTGCTGATT TTACTATGTA TAGAGGTTAT 46380

CTTTTCCTTT CTAAGATTTT GAAACTTTAA TTAGTTAACC CACTTACCTA GTTTCTATTA 46440

GCTGTGTAAC TTTCTCTTCC TGTTTTTTGT TTTGTTTTGT TTTGTTTTTT GCTTTTTAAC 46500

TGCAGTATTT TGAGGAGTCT TGGAGTAGCA AGCTAATCTT TGGAAGAAAG GAAAATATAA 46560

ACCTGAAAAC TAATAATTTA AAGAACGTCT TTTCAGGTTG TCATTTGAAA AATANCTTGA 46620

TTTCTGATCN ACNTGATTTG AATTGAGTGT CAAATATTTG ATATGTTTTG TAAATTAGGT 46680

GAAGATGAGT GAGTAGGTTC TAAACTGCTT GGGTTTACCG CACTCTGGAG CATTGCAGGA 46740

GAATGTGATG TTGGAAGGAA GTGCTGAAAC ATAATTATTG GCTTGCCTAT AGGAGGGTGC 46800

TACATAATTT TAGAAGGTGT CAAGAAATTG ACACAGTCTG AATTAGTTCT GTTGAGTTGC 46860

AAAAAATGTA AAGTTTCTTG ATTCTGAAAA TAAGAAATAT GTTCCCAGAA ATCTCATCTA 46920

GTTAATGTGC TTTTAAAATC ATTGATGTCT CTTGTTATTA CAATAATAGC CATTGAAAGA 46980

ATCTTTTTTA TTAGAATGTT ATTTACAGGT ACGATTAGCT TCTATTTAAA TAAATTATTT 47040

TTATACTTGA TCTTAGGCAA AAGGCCAACA AGTGATCAGA ATAAATTATT TTAAGAGNAA 47100

AACTAATTAT AATTGATATT TGGAATTGGA AGCACAATTT CCTTTAGAAC AATTCCACGA 47160

ATGGTTGTTT TGATTCTCAA GGCAGCCCAC AAAAGACAGT TTGAAACACA ATTTATGCAG 47220

TGTCAATAGT ACTGACCTGA CTTTGGATCT TGGAGGCAGG GGCTTCAGGT GATACCCGAG 47280

TGGAGTTTTT ACTCCATTTC CATTCCGTAA GGCTATAGGC ATTTGAAAGA GGAAACTTTT 47340

CTTTGGCAAC CTTCCACCTT CCTTTCTACA GAATATTTCA GTATTTCTAG CTCATAGGTT 47400

TTCTAAAATA TTCTCTGTAA TTTATTTTGA AATGGAGTTT TTTTATCGTT TACAGATATG 47460

AGTAAAATTA GCCTAATCAG AATGTTAGTT CCTGAAAACA TTGACACGTA CCTTATCCAC 47520

ATGGCAATTG AGATCCTTAA ACATGGTCCT GACAGCGGAC TTCAACCTTC ATGTGATGTC 47580

AACAAAAGGA GATGTTTTCC CGGTTCTGAA GAGATCTGTT CAAGTTCTAA GAGAAGCAAG 47640

GAAGAAGTAG GCATCAATAC TGAGGTATTA ATTATATATA GAATTTTCAT AAAGTGTCAG 47700

TTTGTTCAAT TTGCATATCC TAGTACTAGA ATGCTGTATT TTTTTGAACT GTTATGAATT 47760

CTGATATGAT TACTTTCTCT ATGTGCTACA TTTCCTTTGC TTTTCATAAA TATGATCTGA 47820

GAAAAGTGAT TAAAAAAAAG ACAGTAAAAG GGAGGTTTAG TCCATCTGTT TAGCTTATTA 47880

TGTAGAATGT CAGCTTAAAT TTTACCTGTA CCTCATATTG ACCGTATAGC CTGGAAAATC 47940

TTTCGGAGGT ATAGTTAATG GATTTAAGCA TATGGCAGTT TATGTAGTTA ATGAAAGTGA 48000

AAACAAATTG TATTATAAAT ACCTCCCAAA CTGGTTTATT ATCATTCTAT CATTCTTCAT 48060

GCTCTGTTAG TATGATATTG AATATCTGAG GTACCAGGAT TATTGTTGCT TGTGGCTCTG 48120

AGCATTTCGT AGTGCTTTTG CATGATGAGA GAAAGATTAC AAATTTAGTA TTATGTTAGA 48180

TGGTACGTTT TATTAAAATC AAATGCTTCA AAAATAATTG CTCTGTGTAT GGCATGAGAT 48240

AAATAGCAAT CAGATATATT GTTTAATAAT ATGACTCTAT TAAATGATGG CATAAATTTG 48300

AAAATTTGAC CTTCGGTATC TTCCGGGTCT AAAATTATAT GACTCCATTA TAAATATTTT 48360

GGAAATGATT AACTAAAAAA TTGTTTCAAT TCTTAGTTGG TAAATTCAAT GTGGTAGTAG 48420

GTGGTGGTGA TTATTTTGTA TTAGAGAATT AGGAATTACA CTTAGTTCTA AGGTAATCTT 48480

TATAGGATGT CCAGCAATTA AACCCCTACT TTTTTGAATT GCTTAAAAAT AAGGGAACTG 48540

ATCTTTTTAA ATTCTGTACT TGAGTTACGT CTGTATATAT AGTCATGTCC TAGATAATCT 48600

AATGGAACTT AATTAGTTGG AAATCTTTAT ATTGTTTATA ACTGAACTAG CTATAAGAGG 48660

AACATTAAAG AAAACATATT TTGAGTGGAG GTAATGAAAT TTAGCTTCTA ATGCTCAGCC 48720

TTTTATTTCT GTAATCTATA CCAGATACCT AAGACCCTCT TATTGTTTCC CAGCTTCAAC 48780

CTGTCAGTAT AGAAAACGGT GTAACTTACT ATTTTTTCTC AATATTGAAG CACATTTGTA 48840

GTGAAATATT ATTTTAACTA TATATTGCCA TTTTTGCTTT TTCCCTATTT CAGTAACATT 48900

TTTCGCTATT TCAGTAACAT TACATGTCAA CAAGAGAATG GTGGGTATTT TGGGGGGGGT 48960

TGGGTGGGAA GAAATTTTAC TAAGCTTGCT AGATTCTAAA AGGTATACCT TATTTGGCCC 49020

CTTTTCCCCA TTTAGGGGAA CAAGGGTGTT GGGGCTGGGA AGTAGATAAG AGGTGAAGTA 49080

AGTCATCCAA AGCATATGTC TTCATTAGCC TCCCTGTATG AAAAGCTGAT TTCTGTAGAG 49140

TGTTGGAGGC CTACTTTCAG AATCTGTCAT ATGTTAACAT TCATCTTCTC TACTGACCTG 49200

›Example 10 · 19 of 49

ATTTATATCC CTTAGTCTAT TTCATTTTAT AATTATGACA AAGGATAAAG TCATTAGAAC 49260

AAATTCTTTT TATTAGTTGA CGTATTGTTG TGTTTATATC TCTTGTGTTT GTTATTAAGA 49320

TGGAAGCTCA ATCATGTCCT TGTTTAACAG AAAGGTGATG TCTTGGCATT GATAATTCTG 49380

ATTCAATATC CATAGGTACA TGGTGGATTC TTTAAATATT TAGTATTCTT TTATTTCTGG 49440

AAAGTTTTCT TAAATGATAG TTTTTTTAAA ATTTCATTTC TATAAAGTTT TCTTAAATCA 49500

TACTTTTTAG TGTTTTATTC CATTACTTCA TATTTCTTCT TCAGGAACTC CTGCTATACA 49560

TGTATGTTGG ATCTTCATTA CCCAGCTTCA ATATTTTTCA CTTTTCATGC ATTCTTTTTA 49620

TTTCTTCATT TCTCTTTAAA TTTTTTTCTT CCTTTTCACC TTCTATTTCT CTTTTAACAT 49680

AATTGTATTT ATTTCTGTAT TCCACATAGC TTAGTATTCA CTTATTTTAA AATTATTTTA 49740

AAACGTTTTT TAGATTTAAA AATTCTTTTT TTATTTATAT ATACATATTT TATTTTTACC 49800

AAAGGAGCAA CACTATTAAC TGAAGACTTC TATAATTTTT TTCTTTTATT TCTGATTCTT 49860

TCTTCGGTTT TCCCCCTCAG TTTTGAACTT TTCTAATTTT GATTTGTGAT GTCCTTTTGT 49920

ATTTTAGATA ATTTTCCTAA TGTTTTCCAG CTCATTTGGA AAGGCTACAG TTTTATTCTG 49980

TACCTAAGCA AGTCTTTCTG GTGTCAAAGA TTTGACCTTG ATACTTTTCT TTTGCTCATT 50040

TTCGTATGAG ATTAGTTTTC CTGTACTTTC AAAAGAAGGC GTGGTTCAAG ATGGCTTTCC 50100

CAATTTCACA TCTGTCTCTA ATGTTTTTGT GTAATGTCTA AAATATGGAA ACTTGGTTTA 50160

TGAGATCTAC TCTGCCATTT TTATCTGGGC TTTCTCTTCC TTTTGTCTCT GTTGTACCTG 50220

TCCTGCTTGG TTCTGATTTA ACCCCAGTGG TTTCTCCTGA ATGTGGAGCC TTCTCCTAGA 50280

AGGCAGCCTC GGCTAGTCCC AGGGTTCAGA GTAGCCAGCT GCTCTCTTCA CCTAAGAGAC 50340

CACTGTGGAT TCCTTGTACT CACTTGCTAT TGGCTTGGAC AAAAGCCCTC CCATTTTCAG 50400

ATGCTATTAT CAGATTAATC TCTCATTAAT CTGTCTTTCC AGTGTATGCC TGTGGGCTAT 50460

CTTGGGGTTC TCTTGTTATC AGACACCTCC CTGCTGGCCT CTGCTTTCTC CCGTACAGAT 50520

GTCAGTACTG TGCAGGTCTT AATTGCTGTT GGTGGTTTGC CCCTACATTC TTACAGTTTT 50580

AGTTTCCCAA GGATACCTTT AAACTTGGTT TTATTGTAAA TGTCGACAAT GGATTTTGGG 50640

TTTTACTATC TAGTTCTGTC TTAATTCTGG AATTCAGAAA GATTAAAAGC TCTGTTGTTG 50700

CAGCTGCTGC CACCTCTTCC CAGTACCCTC TCCTCCTATG TCATTTTTTT CTTCTTATTT 50760

TTCTTGACTG TATAAGAGAG AATGTATGAC ATTTCCTGCT TGACCGCTGA GTTTGATTAT 50820

AAATTAAAAT ACACAATATT TTATACAAAT TGTTTTGTAG AAGATTTATT TACAGATGCT 50880

CATTCACAGG TAAAATTGAC TTATGAAAAT AGTTTTCATG ACAAATGTAT CAGGCTCGGT 50940

AACTAAATAT ATGGATTGAT CTTGTTTATA AATGAAATTA AATGTGAATG TAACTTACAT 51000

ATTTCTGTAT TTGCTTACAT CCGTATGTAC ACATATAATC AGCAAATGAG TTGATGTTTC 51060

CTATTCGTAA CTTAATGGTA ATAGCTTGGT AACAGAGTTG GGAGTATTAA AAAGATGTAA 51120

AGAGCCCCTT AAAATTTTGT TGCTGGGAAT TTTAGTGTTC TACTGATGAA GGAAATAGAC 51180

ACTGGAAGGT GTTGTTTCTA TTAGGTAACT TAGATATCAT ACTGAAGACT TCAAATACTT 51240

ATTGTTGACA CTCAAAAGAC ACACTTAGTG TAAGTAAGCA TTTCCCCGCT TTTCCCAATG 51300

AAATAAGATC ATTATTATAA TTCCATTATA AATGCTGATG ATCATATTTA TAGAAATATA 51360

GAAGATAAGA CTTGAAATGA TATTCGCTAC CAATTAATGA GTTTGAAGAA GAAATCAGGA 51420

TGTGTTTTGC TATTTTACAT TTATTCTTAT TTAACTCCAA AGAATTCAGT GATGTTATGT 51480

ACTATTATTT CCATTTCTCT GTGAAGACGT TGAAGCTTAA GTAACACGCA TAATAAGGTC 51540

ATACATTTAG CAAGTGGCTC AATTAAAGTT CAAACCTGGT TCTGCCTGGT TTCAAAGTCT 51600

GTGCTACTCC ATGGTATTAG GCTACAACAT GACTTAGGGT TTCTTCCTCT GCTCTATTGC 51660

TGTTCAGATG TACTCCTCTT TTGGCAGAGT GGGAGAAAAT TTTTGCAATC TATGCATCTG 51720

ACAAAGGCCC AATATCCAGA ATCTACAAGG AACCTAAACA AATTTACAAG AAAAAAAAAA 51780

AAACATTAAA AAGTGGGCAA AGGACTTGAT CAGACACATC TCAAAAGAAG ACATTTATGT 51840

AGCCAACAAA CATATGAAGA AAAGCTCAAC ATCACTGATC ATTAGAAAGA TGCAAAATGC 51900

CTTTTCTGTA TGCCACCTTA TATCCCCAGT ATTTATTATT TCTAAGTCAT AGTATCTTAC 51960

AGTGTATATA AGTCTCATCC GTTCTTTTGA TTTTCTCTTC CCTGCTTGCA ATTGGGTACC 52020

TAGGAACAAA GTTGCAATCT TAGCCAGTTT TTTCTTTAGC CTTTGCTGAT GTGTGAAAAG 52080

CCCTTTTTTC TACCCTGGAT TTCTGTACTT AAGCTGGAAC AGCTAAGTTT TTACCTTTTT 52140

TAAATATAAA GTTTCAGAGT CTTCTGCCAA GGATCTTTTG CTGTTTTCCT ACTGTTAAAT 52200

ATTTCAAAGC CTTTTTTAAA CATAGGGAAT ATAATCAAAC ATAGCAAGCA GCTGATGAAC 52260

AATATCTAGA TAGTCTTCAT TATTGAAATG GAATAAATGG TATTTTTGTA TTTTAGGCTA 52320

ACAGACACCT TGTACCTTAG ATAAGGCCAA CCTTCTCATA AAATCCCTCA GTTACTTTTA 52380

TTAATAATAA CCAAATTAAC TCTGGATTCC AGGGTGTACT CATGATGGAA TGATTTCTCT 52440

GTCATGTTAT CCTGAGGATC TAGTACTCTG AGATAACATA AGTGTATGAC ACTTTAGGCT 52500

TATGAAACAC TTAGCTACTT AAATTATTTA ATTTTTTTTC ATGTGCAGAT GGTATTGTAC 52560

CCAAACACTA CCTTTGTGTG TGTGTGTGTG TGNNCGCCTG TGTGTGTGTT TTTGAGACAG 52620

GGTCTTACTC TGCTCAGGCT GGAGTGCAGT GGCGTGATTA TAGCTCACTA CAGCCTTGAC 52680

CTCCTGGGCT CCAGTGATCC TGCCAAAGTG TTGGGATTGC AGGCGTGAGC CACCTCACCC 52740

AGCCTTAAAT TATTTTTTTT TCAAGGATGT TTAACCTGAG GGTTAGAGGC TCTTTGGCAC 52800

GTGAGCTGCT GAAATGTGTG TGAAAGTGTT GTGCACGTGT ATGTTTCTCT TTTTTTCTGG 52860

GAAGTGGATC TGTAGTGATT CTTAGATGAG TCTATGAGAC AAGAAACTTT TATTTTTTTC 52920

ATTTATTTAG CGAATGTTTG TTAAGCGTAC TATGCCTTGG CCACTCTACA GGGTGCTGAT 52980

TGGACCAGTC TGTCTACCTA CCGTTGTAGA TGTTAGAAGC TATATTCTTT TCACATGCCT 53040

AATATAACTC TTTGTGTATG TATACATGCC CAGGCATGTT CCTTCCTCAG AACATTAAAT 53100

TCACCATTTT GGTCAACTCA AAGCAAGTAC ACCATGGGAC ACAGATCTGA AATAATGTCC 53160

AGATTTTTAC TTACTGAATG AGGTGTGTTG NAGTGTATAA GACTACATGA TGAGATGGCA 53220

AGTAATTGCC TGAAGAAATG ATGTAGTGAT TTTGTGTGTC TTATATTTAT TTACTTTTTG 53280

ATCCAGAAAT AAATTATATA GATACCACTA TTTTGTTTGG ATGGGGGAGA AAGGATGGGT 53340

GTGTATTCAG GAACTTATGT TACTTTTTTG CAACTAATAC CCCTTCTCAG TAGTACAAAG 53400

ATTTGATTTC TTTTTCTTTC TATTTCCTAC AGACTTCATC TGCAGAGAGA AAGAGACGAT 53460

TACCTGTGTG GTTTGCCAAA GGAAGTGATA CCAGCAAGAA ATTAATGGAC AAAACGAAAA 53520

GGGGAGGTCT TTTTAGTTAA GCTGGCAATT ACCAGAACAA TTATGTTTCT TGCTGTATTA 53580

TAAGAGGATA GCTATATTTT ATTTCTGAAG AGTAAGGAGT AGTATTTTGG CTTAAAAATC 53640

ATTCTAATTA CAAAGTTCAC TGTTTATTGA AGAACTGGCA TCTTAAATCA GCCTTCCGCA 53700

ATTCATGTAG TTTCTGGGTC TTCTGGGAGC CTACGTGAGT ACATCACCTA ACAGAATATT 53760

AAATTAGACT TCCTGTAAGA TTGCTTTAAG AAACTGTTAC TGTCCTGTTT TCTAATCTCT 53820

TTATTAAAAC AGTGTATTTG GAAAATGTTA TGTGCTCTGA TTTGATATAG ATAACAGATT 53880

AGTAGTTACA TGGTAATTAT GTGATATAAA ATATTCATAT ATTATCAAAA TTCTGTTTTG 53940

TAAATGTAAG AAAGCATAGT TATTTTACAA ATTGTTTTTA CTGTCTTTTG AAGAAGTTCT 54000

TAAATACGTT GTTAAATGGT ATTAGTTGAC CAGGGCAGTG AAAATGAAAC CGCATTTTGG 54060

GTGCCATTAA ATAGGGAAAA AACATGTAAA AAATGTAAAA TGGAGACCAA TTGCACTAGG 54120

CAAGTGTATA TTTTGTATTT TATATACAAT TTCTATTATT TTTCAAGTAA TAAAACAATG 54180

TTTTTCATAC TGAATATTAT ATATATATTT TTTAGCTTTC ATTTACTTAA TTATTTTAAG 54240

TACCTTTATT TTTCCAGGAT GTCAGAATTT GATTCTAATC TCTCTTATGT AGCACATGTG 54300

›Example 10 · 20 of 49

ACTTAATTTA AAACCTATAC TGTGACACAG AGTTGGGTAA ACGATGATTA TTTAACTTTA 54360

AGCAGTTCAC CATCCATTTC AAAGCCTTTG ATTGGCTTTT TTGTAAATAA AAATAACTTG 54420

TTAAGAAACA AATATATCTG TCATAGAAGA ACTAGAAAAT CCAGGGAAGT GAGAAAAATG 54480

AAAATAAAAA NTCATTCATA GTTTTACTAG TAGCTAATCA CAGTCAACCT CTTTTGTTGA 54540

TCCCACCAGA CTTTTTTATA TTCATTTGTT TTTAGGTAAA ATATAAAAGT CTCGTATATT 54600

CCCATTTTTC TGCATTGCAT TACCAGAAGG TAGTGGCGCC TATTAAATAT GTGATATGTT 54660

GTTGTCCAGC CATGGCTTCT GCATTTGCAT GCTTTTGTGT GTGCATCTGC AATACCCTGT 54720

GAATATCCTG TGTGATGGAG TGGCAAGTAC GCACAGACAC GTCTGCTGCA TGCCTAGGTA 54780

CGAGGCTGTC TCCAGGAGAA GCACTTGTTT GATTATTTGA GTTGCCAATT GAATTTGCTG 54840

CTTTTTTTCA TGGCTTGCCA TTTTCACTGA AAAGAATGAC TAATGAAAAA CGATGATTGG 54900

TTATTAGATT TGGATGTTTG GCAGACATTT TCTCAAAATT GAACTAAGTT GGCCTCTTCA 54960

CGGAAAACAA CTGGTATTTG TTGTGCCAAT GATAAAATTG GAGATTTCTA GCAAAATGTA 55020

TAATTTTGGA AAAGTTGTGT TCCTCCACTG GAAGCTTGAC AGCTTTCCTT AACATAAAGA 55080

CTTCTCTTTC TCTTCGCTTT CACTACTACT ACTACTAATT CTTCTTCTGA TTCTTCTTCT 55140

TCTCCTTCTT CCTTCTTCCT TCCTTCCTCC TCCTCCTCCT TCTTCTTCCT CTTCCTCTTC 55200

TTCTTTCTCT CTTTCCTTCC TTCCCTTCCC TTTCCCTTCC TTCCTTCCTT CCTTCCTGCC 55260

CGTCCGACCG CCCTGCCTTC CTTCCTTCCT TCCTCCCTCC CTCCCTCCCT CCCTCCTTTC 55320

TTTTTCTTTC TCTTTCTTTC TTTCTTTCTC TCTCTCTCTC TCTTTCTTTC TTTTTCTTTC 55380

TCTTTTTCTT TCTTTCAAGC AGTCCTCCCG CCTCAGTCCC CCAAAATAGT GGGATTATAG 55440

GTGTGAGCCA CCATGCACAG CCTTACATAA AGCCTTTTCT AATGAGATGG ATAGTAATTA 55500

ACAAATGTGA GTTTTTGATA TTATATAAAG ATTTTTTCTG TGTTTCGAAG ATCCGTATAA 55560

CTCAGTGAAT CAGTATGTTC TGGATGACTA ATATGTGATG TTAAGAAATC ATGACTGAGG 55620

CCGGGCGCGG TGGCTCACGC CTGTAATCCC AGCACTTTGG GAGGCCGAGG CGGGCGGATC 55680

ACGAGATCAG GAGATCGAGA CCACCCTGGC CAACATGGTG AAACCCCGTC TCTACTAAAA 55740

ATACAAAAAT TAGCTGGGTG TGTTGGTGCG TGCCTATAAT CCCAGCTACT CGGGAGGCTG 55800

AGGCAGGAGA ATCGCTTGAA CTCAGGAGGC GGAGATTGCA GTGAGCTGAG ACTGCGCCAC 55860

TGCACCCCAG CCTGGCGACA GAGCAAGACT CCGTCTCAAA AATAAAAAAA GAAATCATGA 55920

CTGGGTAAAA GATCTGTTCA GAGTACAAGA TGGACCAATG GATTTGATAT ATTTGAATAT 55980

AACAGAGTAT GAAAAAGTTT ATTGATATAG TTTCAGATTA CACACTGCAA CTAATCTTTA 56040

AGAAACTATT ACTTGTCCAC TTTTTGGTAA AATTTCAGAG AACAATGTCC ACCATTATCT 56100

GAACAGGCTA TTAAAATACT CTTCTCTTTT CCAACTACGT GCCTGTGCAA AGTCAGATTT 56160

TTTTCATATA CTTCAGCCAA AACAGCATAT CAAAATGGAT TGAATGCAGA AGTAGATCTG 56220

AGAATACAGC CACTTTTGTT AAGCCAGACA ATGAGATTTG CAAAATGTAA ACAATGCTGC 56280

TGTTCTCAGT TTTTAAAAAT ATGTTTTTTA AAAGTATTTA TGTTAATGTG TACTTGGTTT 56340

ACTACTGCTA TTTTTAAATA AAACAAGAAA CATTTTTAAA TGTCTGTTTT AATTTCTAAA 56400

GTGGTAGTGA TAGATATAAC CCATATTAAT AAAAGCTCTT TGGGGTCCTC AGTGATTTTT 56460

TTTTAAGAGT ATGGAAGGGT TCTCAGACCT AAGAGATTGA GAAATGCTGA TGTAATGTTT 56520

TATTATAAAG GTGTACCATG AATTATGTAC CTTACTTCAT ATTGTTGGAC ATTAAAGTTG 56580

CTTTCAGTTT TTTTGTTTTA AACAGCACTG CTTTGACCTT TTTTAAAAAA TGAGTCAGGG 56640

TCTTGCTGTG TTGCCCAGGT TGGAGTGCAG TGGCTATTCA CAGACATGAT CATAGCATGC 56700

TATAGCCTTG AATTCCTGGG CTCATGTGAT ACTTCTGCTT CAGCCTCCTG AGTAGCTGGG 56760

ACTATAGGCG TGCACCACTA TGCCCAGCTG CTTTGAATAT TCTTGAAATG AAATATGGTA 56820

TAGTCTCATA CCATATCATA GCCAGAGGGG GAGAGAGAGA ATTTTGTTGT TGTTGTTATG 56880

TTATCTGTAG TGGACTTTAT GCCTTCCCAG CATAAATTCT CTCTTTCCCC ATTTTTCGTG 56940

ACCCTTGATT TTTGTTGGGG TTCGTTCCAA GGAGAATAAT TTCCATCTGG ATATTGGATT 57000

GGCACCTGTG ACCTCTTCTG AGCTAGACCC TAGTAACAGC GTTTGGATCT GGGGTAGGTG 57060

TGTGGCCAAC TGAGCTGCTG GTTCATGCCT TTCCTGAAAT GAGCCCTACC TCTGAATATT 57120

TCAGAAACAT GGGACATTAA CTTCCCTTTA CTTACGTTAA ACCCCTTTGA ATGAGGAGTT 57180

GTTTTTCACT TCCAGTTGTG TTCAGTTGTC ACAGAAGCAC AGCGATGTGA TTGGTGGAAG 57240

GACCCGTCAA CAGACCCAGA AGATGTAAAG TGTTTTTAAT CTCAAAGGAT GTGGAATCTC 57300

AGAGATAGTT ACACCGAGTA GAGGATGAAG CGGCTCCTGG ATGGAGGCAG AGGCTTCCTG 57360

GATCTTCAAG TTCTGTATGG GTTGTTGTAT GAGGTTGGTG CAAAAGTGAG GCAGGAGAAT 57420

AGGGTCTGGA GGCAAGGAAA CTAAGGCCGA TTCACACTGA CTTCCTAGAA CTAAATCAAA 57480

AGGAAAACCC CAATTTTCCA GACCTAAATA ACAAAAGTAC CAGATGGCTC CTCCCTTTCA 57540

ACTGCCCCTC CCCCACACCT TTCTGCGTGA CACATGGAAA ATTGAAAGTA TCTCTGGTTG 57600

CTTCTGCGTA GGAATGTAAC TTTGTAACCA ATCAGACGGA TCGCAGGCCA AGTCGCCTGC 57660

ATAGAAATGT AACTTTGTAA CTTCACTTTA GCCTCTGATT GGTTGCTTTC CACAACCAAT 57720

CAGATGCTTG CATAGGGTGT ACCTGTTGTG ACTTCACAAA GTGGTGGAAG TGGTGGAAGT 57780

GGTGGAAGGG TGGAAGGGCT ATTTAAATTT TTATTCATCC TCTGATTGGT TGTTTCACTT 57840

AAGCCTCTAA TTGGTTCTTG AGTCCTGGAG CCTGTGAAGG GTACTTTATT TTCAGTAAAT 57900

GCATGCTTTT TTTGCTTCAT TCTTTCCTTG CTTTGTGCAT TTTGTTCAGT TCTTAGTTCA 57960

AGACACCAAG AGCCTGGACA CCCTCCACTG GTAACAAAAG TAACTGGTGT TTTTGCCATT 58020

AGAAGTAATG GCACAGAACA AGTACATGAG AGCGATTTCT TATGGAAAAT TAAATGGCGA 58080

ATAAGTCGTG TGCTCAGGTA AGGGAGCTGG GAACCGGTAG AGGAAGGTCT CCAACCCACA 58140

CCCGTGGGAT CTCTGAGTCT TTGAAAGTCC GTCCTCACCC TTTGTGAAGA ATGGGAGCAC 58200

GGCTGGACTC GTCACCGGGG GTTTTGGGGG GCTGAACTTG TCATTTGAGG GTGTAGGGAG 58260

GTTGGATGAA TCGCAGGGGT GCAGGGAGGG GGCCCACTGG AGCTCCACCA GGACCCCAGC 58320

ACCCTAGATC CAAACCTGGT CATGCTTCCC ATGCTCAGAG GCAAATCTCC CTCCCCTTGG 58380

GGGGCGGAGT CAGACGAGAC CCCCTCTCCA TCCTTTTCCA GGTCCGGTGG GGGCGGGACT 58440

TTAAAGGTAA AAACAGCAAT TACTTTTGCA CCAACTTATC TTCTAAGTTT CGCTCCCTAC 58500

CACCTGAGTG TGTTTGGAGG CTCTGGCTCA TTGTACCTGC CTGATCACCA GGTGCAAGTA 58560

GCTGGGCCAG AAGGACCTCG GCACGTTACG GAATATTTAC TACAGGAACA GGTGAGCTGA 58620

AGGCGAATTC CCCAGGTGTA GCCTGTGACC ATAGATTCAG ACAAAGCCCT GACTGTTGCC 58680

TGGAATTCAA AAAAGCTGTA GCCCTACCAG ATAGAATAAG AAAAGAATAT AGGATTCTTC 58740

CTATTCAAAT AGGTTGCATA TAATTAAGAG CATGAACGAT CCAATGGAAT GAACTCAAAG 58800

TAGTTTTTGA GTGTAATAGA CTTGAAGTGT CTTATGGAAA AGAATTGCAA AACCACAGAA 58860

ACAGTGAAGA AGGTTAGTTA TAGCCTTGAT GGGGTAGCTG ACTTCAGCAG TCTCAGCTAT 58920

CTGAAAAGTT ATTTACCAGA TTTTGGTTGG GAACATAATC CCTAAATCAT TTGAGATAAT 58980

GTACTTGTTT CCTTACTGGG TAAATGTGTT TAAACCTTGA GNAAAATGTA GACATAAGTA 59040

GNAATATANG AATAAATTAA ACCTTTGGTA GTTATGTTTT AGGATTAAGG ACTAATAAGT 59100

ACATATTTGA TATTTAAGCA TTTGTAATGC TTGAGATAAT TTATCCTACT CAAGTAACAG 59160

ATTACTCTTG TGACTCCAAT GTAAAATATA TCATTGAAAA ATTAGTATCT GCTTGTGATT 59220

TTTAAGTAGA AACCCTGCCA TTTGAAAGGT ATTTGCCTTT ATTATTGGAG ATATTTCATA 59280

TGAATGTTTA ACTTTGTTAT TGCATAGAAG TATTTAAACA GATTTCACTT GCAAGAGAAA 59340

GATATCTAAT AGGTTACTCT TAATCAGTAC TAAATTACTA CAATTACTAT ATTCTATTAA 59400

›Example 10 · 21 of 49

TATCGATTCA TTAAAACCCA GAGCTTTAAT TATGTCTCAG AAAATTAATT AAACTTTAGC 59460

CTCATAATCA GCTTTATTTT CTAACTCAAT GTTTAAAAAT TGACAAGTAT GTATTATACT 59520

TATTTATGTC TTCATTCAGT AAACATTTGC ATTTGTAGCA TGCAAGACAA CATGCTAGAC 59580

ACACGAAAGA TGGAATAAAT GGAAGAAAAT GCAACACAGA TCTCATGCTT AAGAGGGACA 59640

GATTTACTCT GAAGATTCAA TGAAAAAACA TCCACAAACA ACTTTTCTAC AAGAAACAAA 59700

ACATTTTAAA GAAAACATTT ACTTCAGCCG GGCGCGGTGG CTTACGCCTG TAATCCCAGC 59760

ACTTTGGGAG GGCGAGGTGG GTGCATCACG AGGTCAGAAG TTCGAAACCA GACTGGCCAG 59820

TATGGTGAAA CTGTGTCTCT ACTAAAAATA CAAAAATTAG CCTGGCGTGG TGGTGTGTGC 59880

CTGTGATCCC AGCTACTCAG GAGGCTGAGG CAGGAGAATC GCTTGAACCT GGGAGGCAGA 59940

GGTTGCAGTG AGCTGAGATC AGGCCATTGT GCTCCAGCCT GGGCAACAGA GCGAGACTCC 60000

GACTCAAAAA AAAAAAAAAG AAAAAAAAAA AGAAAACATT TACTTCACAT AATAAGATAT 60060

GAGAAAAAAT GGACTCTCTG AATGAAAAAA AGAGGAGATC ATGTGAAAGA TTTGCGCTTT 60120

TTTTTTTTTT AAAGTTATGG ACTGAAACAC TCCTAATCAT TAACATTTGT TATTTTAGGG 60180

GAGTGGAATT GGAAAGGTGG AAAGGGCTAT TTACATTTTT ATAATCTCCA TGTCTTTTAA 60240

ATCAATATAT ATTGCATTTA TTCTTTTAGT TAAAATTTTA AGAACTCTAT AAAAAATAGA 60300

GACAGGGACT CCCTTTGTTA CCCAGGCTGG TCTCAAACTC CTGGGATTAA GTGATCCTCC 60360

CACCTCAATT AGAAGGGTGG AAGGGCCAGC TGTTTAAGTT TCTATAATCT CTGTTAAATC 60420

AAATGTATAT TGCATTTATT ATTTTAAATT TTAAAAACTT TTTTAAAAAT AGAGATGGGA 60480

TCTTCCTATG TTGTCCAGGC TGGTTGTGAG CTCCTAGGAT CAAGTGATTC TCCCGCCTTG 60540

ACCTTTCAAA GAGCTGGGAT TACAGGCATG AGCCACCATG CCCAGCCTAT TTATTTGTTT 60600

ATTTATTTTT AGAGGCAGGG TCTCACTCTC ACTAGACTGA AGTGCAGTGG TGTGATCATA 60660

GCTCACTGCA GTCTCAAACT CCTGGACTCA AGCAATCAAC TAGCCTCAGC CTCTGAGTAC 60720

TGAGATGACA GGCATGTGCC TTCATACCCA GCTAATATTT TTGTAGAGAT GGGGTCTTCC 60780

TGTGTTGCCC GGAAGAGTCT CAAACTCTTG GCCTCAGCCT CCCAAAGCAC TGGGATTGCA 60840

GGCATGAGCC ACAACACATG GCCCTGCTTT TAAAAAATAT ATAGTGGGCC AGGCTTTCTG 60900

GGATGATGGG CAACCATTAC ATTTGCTTTC TCTCCATTCT GAATGTCAGC CTCCATACAC 60960

CTCTCTTGAG CCATCTCTTG ATGCCCAGGA CTGGCAGGCA AGCAGGATGT TAGGGTGCTG 61020

GCTGGAGGGC TGGAAAGCCC CAGGGCAAGG ATATGAACGT GAAGGATTTT AAGGAGATTC 61080

TTGGACCTCA AGGGAACTTT TGGTCCTGGT TTCCTAGAGT ATGTTAGATC TTCTTGGCCC 61140

CCAAAGAATC AAGGAAAAGC TGAATAGGTG GACCGAATCC TTTCCAGCAC TGAGGCTGGG 61200

AGAACTCTAT GACACCAGTG GGTGCTCATC CTGGTGCTGC CATGGACCTG ACTACCTACT 61260

TCCGCTAAAC TCTCCAGCAG CTGAGCCTTC AAGAGAAGAC GTCCTCCACC TTTTCCATGA 61320

GATGAAGAAT CCTTGGGGCC AGGGGATGTG CTCACTAGCT CACACCTGTC TCCATCCTCT 61380

AGACCATGCT TGCAGTACAC AGGACCCCAG AATGCCTGGC CCAAACACTC GTGAGCCTCC 61440

AGGGGCTGCA GGGGCTTCTG GCCTTGTTTC CCCATCTGAT GAGTTCGTTT CTTGGTCTGA 61500

AAGATTGTGA CAGTTACTAC GAGACTGAAT GAAGGGGGAT GAATGCAGAA ATGAAAACTT 61560

AAGACAAAAG TAACTTTTAA TGAGAGGGGC CGAGGGAAGA AGAAGAGGGC TCCCTGCTTC 61620

TAATGAGCAA AGGCAGCCAC CCTGAGCTTC TACAGCCCTT CGTATTTATT GAGTAGAAAG 61680

AGCAGGGAGG AGGAGGTAAT GATTGGTCAG CTGCTGGATT GATCACAGGT TCATATTATT 61740

GCTAACAGGC TTCAGATGTG CCTGATCACA AGAAACACTT GCGCCTGGGC ATGACTGCCC 61800

TCAGCATTCC TTCTGGGCGG CAGATGCAGT TTGTCAGTTT GCTAACAACC TGCTTTCATG 61860

AGAACAGTTT GCTGCTTACT TACACAGCCA CCAGTGATTT ACTGAGTTGA TCACGACCCT 61920

CACTCTTTCG GCCTCCAACA AAAGACGATC AAAGAATGGT TGTTTGCAGA GGTTATGGAC 61980

AAGACTTGAT GTCCAGGCCG AGTGTCCGTA TGCACAGGAG CCTCTTGGTG GTGCAGAGTG 62040

AAGCCAGAGG AGGAGGAGTG GGTTGTGTCC ATGGGCTGAT TCTCCCTGCA CCAACAGGAC 62100

AGAATCCTAA GGAATCCGAG CATTTGAAAT TCAAATCTGG TCTTACAGGT TGTTATGTAT 62160

TTGTCTAGGT AGGAGGCTAG AATGTATTGA AATGGGGTTA GCCTGACATA TTTATATATT 62220

TCATATTTAG GCTTCCATTT GTTCCTTTGT CTTGGGTCCC AAAAATATAT TAGAGGTGGG 62280

CCTGTCTGTT CTCTTGGACA CGAGGACCTC AACGAGTTTC CACTGTTCTC TGAATGTTTC 62340

CTTCCTGGTT TTCTGTGTAT ACAATAATTC CTAGTTTTCT GTTATTTACA ATTTTACTTC 62400

CACTTTTTAA AGACAAAAAT GTATGTTTTT TTAGTCAATA TTGATATAGT GGACCAATAT 62460

ATTTTACCGT TATTTTTGCT TACTGTTTTT GTTTTTTTGC CTTCCTCATC TTCTCACTAA 62520

GTTTGTCTGA CTACAGCCAC ACACCATTCA TTCAATACCA ACTCTTTTTT ATTTTTATTT 62580

TTTGGAGAGA GGGTCTCACT CTGTCACCCA GGCTGGAGTG CAGTGGCATG ATCTTGGTTC 62640

ACTGCAGTCT CAAACTCTTG GACTCAAATG TTCTTCCTGC CTCAGCCTCC TGAGTAGCTG 62700

GGACCACAGG TGCACACGAC CATGCCTGGC TAATTAAAAA CAAAACAATT TTTTTTTTTT 62760

TAGAGACGGG GTCTCACTAT GTTGCCTAGG CTGGTTTCAA ACTCCTGGGG TCAAGTGATC 62820

CAATACCAAC TCAACACGTG GTGAGACCCA GTGGTCTAGA CAAACAGCCA CATAGCAATA 62880

TGTTTTTCTC CATGATTCAT ATCCATGTTC GTTTGTTACA AAATAACAGG CATGAACATT 62940

TTCTTCAGAG AGGGAGATCC CCACTTATCC ATTAATGACT CATTTGGTGT CCATTCCAAA 63000

CTATTAAACT GCAAAAGCAG ACATGAGAAA AGAAACTTAA GTCAATGTTT TTATCACATG 63060

TTGGTGCCAG CCTCCCATAG TGGTGCTAAA TTTATGNAAA TTGCAACAAA ACAAAAACCC 63120

AAACAACCCA ACAACGAAAA GCTATTTAGT GAACACCGTG ACTAACAAGC TTATTAGAAC 63180

TGCTTATCAG AGCTATGTGT GGATTTTGTA GGGGGAAAGA TTTTCTTCCC TCGTAGACAT 63240

TTTGCAAAAT AAAAGTAAAA TATTACCTTT ATGTACGTGG TAGATAGAAT TCCACAAGCT 63300

TCAAATTCAA CGACTCAAAA ATGTTGCTTT TACTTTCCAT ATCTCAGAAG TCACTTTTCT 63360

TTTATTTATT TTTTAGAGAT AGGGTCTCGC TCTGTTGCCC AAGCTGGAGT TGCAGTGGCA 63420

CAATCATAGC TCACTGCAGC CTTGAACTCC TGGGCTCAAG CAGTCCTCTT ATCTCAGCAT 63480

CCTGAGTAGC TGGGACTACA GGCGCATACC ACCACTCCTA GCTGATTTTT AAATTCTGTG 63540

TAGACATAGG ATCTTGCTGT ACTGCCCAGG CTAGTCTTGA ACTCTTGGCC TCAAGTGATC 63600

CTCCCACCTT GGCCTCCTAA AGTGCCGGGA TTGCAGGTGT GAGCCACCAT ACCTGCCCAG 63660

AAATCTCTTA TTTTAAACCC CAATTCCTCC TGATAGTAAA AAAAAAAAAA AAAAAAAAAT 63720

GTCATCTTGG TGTATTTTGG GTAGGCTGGA TCACTTCAAG TTTCCCCCTC CTCCTGAAGC 63780

TCCGACAGAG GCCTGCAAGC CCTGCTGGGA TCTGTCCTCA GTCCCTCTCG GGCTCATCTT 63840

CTACCATCTT GCTGTCACTC CATCTCCCTG TCCTTCCCTT TGCTTCACCC ATACCAGACC 63900

CTGTACTGTT TCTGGAAGAC ACCAGGCATG CTGTGTCTTA GGGGAGAATG TGATTTCACC 63960

AACTAGTGCC GCCCAAGTAA CATGCATTTG CCCTGACTGC TCTTTTCACC TGCTGTGCTG 64020

CTCCCCCAGA TAACCACAGG CAAACCCCGC CAACTCCTAG TTTATTGAAC TATACCATGA 64080

GTAACTTACT TAAAATCTCC ATACCTTGTC CCATTCTCTC TTACCTGTTC CAATACTTAT 64140

TTATGATGTT GATAGATGAT CTCCCTCTAC TAGACTGGAA GCTCCTTGAC AGCGGGGATT 64200

CTTGTCTGTT TTGTTCACTG CTGTGTCTTT AGCACCTGGA GAAATGCCTG GCACACAGCA 64260

GGAACTCAGT AAATAACTGC TGAATAAATA AACATGAATA AATCAATGAA TGGGGATGCC 64320

TAAGTGCTTC GGGATTCTGG TCAAAGCTTT GGCAACTAGG GACGCACAGG GACCCTCATC 64380

ATCTCTGCCT CCTAGGCAGG TATCCACTGA GATCCGCAAT CCCATCTGGT CCTTGGACCA 64440

GTTACCCTTC ATGTTGGCCT CTGTTAAGAT GTCCAGGTTG TATCTGGTCT CCCACACAGC 64500

›Example 10 · 22 of 49

ATCCCTTTAT TACTACCCCT GGACCTCAGC AGTCAGCCAC ACATTCAGTA AAGGCCACAG 64560

CTCTGCCATC TCCTAGCTAG GGGACTTTGG ACAAATTACT TAGACACTCT GAGCCTCGTT 64620

TGTAACATGC AGAGACGTTG CTGGGATTAG ACACAATGCC TGTAGACCAT TTAACAATTG 64680

CTGTCACACA TGGTTGGTAT TCACTCAGCT GTCGCTATGG AATTAGCAGA CAGAAAAGGC 64740

ACAGCGTCAG TGGCTGGGTG TCCAGAGAGA AGCAGCCTGT CTCTCTAGAT AATACTTGGC 64800

AAAATCACAG CAGTCCGGTG TGTGGCCCTT TACTGACCTT GATTAAAAAT CGGGTGTCAG 64860

CACCCCAAGT GGATCCTTCT TACAGGTGCA GATTCAGACT CATTATCCAA GTTGACAGAG 64920

ACAGAAGTAA ATATTCAACA AATATTTATT GAGCACTTAC TATGTGCCAG GCACTGTTGT 64980

TGTAGGTGCT GGAATACAGC AATGAACAAA AAAAGTGAAA CATTCTTCCT TAGATGGTGG 65040

TAAAGCGATA GGAGGACACA GCAGGGAAGG GGTTTGGACT ATTTCAATTT GGGACAGGAA 65100

ACGCCTTGCT GAGAGAGTGA GGGTTGAGCT CTGGAATTAG CCTGAGTTTG ACCACATGTA 65160

ACTGCAACTT TGAGCAAGTC GATCCACTGT AAGTCTCTTT TATTAACACC ATTGTGTGTA 65220

AGAGGAAATA GAAACTCAGC TAAAGTCGTT GGAGAATTGA ATGTGGTGCA GCATTTAGCA 65280

CAGCGCAGGA ATAATAAAAG CCAGCTGTTC TCATCCTTTG CCCATAGAAA AGCTATCCGG 65340

GAAGCCACAT TATAGTCTGA AGGCTGCCTA CTGGTTTGGT CAAAGAAAGG GCAGTTAGAT 65400

AATTTTCATG TTTAATTAAG GGCACGGGGC TAGATTTCTT GAGGTGCCAG AGTAATGCTT 65460

GCTTTTCATG AACAACGGAT ACAAGATATG GGCATTGCAG AACCTTTAAA GAACATAACT 65520

GGAATAATCA AATAACCGAA AGTTCATGAA ATATTCTGGC TCATGAATTA GTTATCTGGT 65580

AAATCACAGT CTGAAAGTCA CAGAATACAA ATTACTTTAA ATTTCCTCCA AAGCTTACTG 65640

AGTAAGGGGA GGGACATTTA AGATGCGGAG GAAGCGCTGA ACTTGCAAGA GGAACAAGGA 65700

GGACGGTGGC TGCTGGAACT CTGTAACCCT TAGAGAAGAT GTGGGTGGGA TTTGGCAAGC 65760

CCCCTAGACT CTCTTTGTTT TGGGTCTTAA TAGGGACAGT TTATTATTTT TAATGACTCG 65820

CGTGAATTGT ATACTGTTTT AAGCATCCAC CAAAAGCCTT TCGGCTTTTT CCCTAATTAG 65880

ACTCATTCTC ACACAGAGAG GAACTGAACT TTTTACCTCT TTGGTTCAAG AGCACCATCT 65940

ACTGGTCAGA TTTGGTAATT TCGGGTTTAT GGCACTGGAA AATCAAAGAG CATTTTGATT 66000

TGGTTGTGTT TGGTTTTGGT CCATTTATCA ATACAGGTTT TTTGGCGGAC AAAATAATGT 66060

GAAAATCAGG GGAATCAGGT GAGGGCATTG GATGTCTCTG TCACAGACGA TGGGGAGCTC 66120

AGCCGATTTT AAGCTTCTAA CCTCAGCTGG TCTGGAGAAG AGCAAACCTG ACAACCAGCA 66180

CGAAGAAAGT AGCTCTGCCT CTGTGGTGTG CTGGACATTC TGGTTACATA GATGGGAAGA 66240

CGAGGCCCTT TCCGACAAAT ATGCAAATCC CCCACATCTC CAAATTTGGT AGCTCTGGGG 66300

CTTAGGGCAG CTTCTGGAAA CAGAACTCAG ACCTAGCCTG CTGGAGCAGG AAGGGCTTCT 66360

GAGAAGATGA TATCTGGACC ATCTAAGGAG TGTAAATAAG AAATAGCCGC CAGGCATGGT 66420

NGCTCACGCC TGTAATCCCA GCACTTTGGG AGGCTGAGGC GGGCAAGTCG CTTGACAAAG 66480

TCAGGAGTTT GAGTCCAGTC GGGGCAACAT GATGAAACCC CATCTCTACA AAAAATACAA 66540

AAATTAGCTG GGTATGGTGG TGCATGCCTG TAGTCCCAGC TACTCTGGAG GCTGAGGTGG 66600

GAGGATCACT TGAGCCTGAG AGGTTGAGGC TGCAGTGAGT CGTGATGGCT GCACTCCAGC 66660

CCGGGCAACA GAGTGAGACC CTATCTTAAA AAAGAAAGAA AAAAGGAAGA GGTCAGGAGT 66720

TTGAGACCAG CATGGCCAAC ATGATGAAAC CCCATCTCTA CTAAAAATAA AAAAAAAATC 66780

AGCTGGGCGT GGTGCATGCG CCTGTAATCC CAGCTACTGG GGAGGTTGAA ACTGGAGGAT 66840

TCCTTGAACC CGGGAGGCGG ACGTTGCAGT GAGCCGAGAC CACACCACTG CACTCCAGCC 66900

TGGGCGATAG AGCGAGACTC CACCTCAAAA AAAAGAAAAA AGAAAAAGAA AAGAAAAGAA 66960

ATAGCCAGAT GGAGAACAGG GGAAAGGCCA GAAGAGCAGG GGCGTAAAAG GCGTGGAATG 67020

GCATGCGGGG GAGTAACAAG GTTTTTTTTT TTTAAACGGA GTCTCACTCT GTTGCCCAGT 67080

TTGGAGTACA GTGGCGCGAT CTTGGCTCGC TGCAACCTCT ACCTCCCGGG TTCTAGCGAT 67140

TCTCCTGCCT CAGCCTCCTG AGTAGCTGGG ACTACAGGCG TGTGCCACCA CACCTGGCTA 67200

ATTTCTGTAT TTTTAGTAGA GATGGGGTTT CATCATGTTG GCCAGGCTGG TCTCGAACTC 67260

CTGACCTCAA GTGATCTGCC CGCCTCAGCC TCCGAAAGTG CTAGGATTAC AGGCGTGAGC 67320

ACCGTGCCCA GCTAGTAACA AGGTATTGAC TGAACCAGAG TGGGGTGTGT CAAGATCGGG 67380

AATCAGCAAG CAGCACAGGG GGTGTCCTGG GTGGGGATCT GGGGCTCAGG TCTTCCTGCT 67440

ATCCTGCTAC CCACCTGCAC ACTTGTTCGT TTTCTTTCCA CTCATTTTTC TCCCTTGCCC 67500

AGACTTCAGG TCTACCAGCT ACACTTCTTG ATTTCTTTGG CCTTCAAAAT TCGGTTCAAT 67560

AAGGAAAGTT TTAGCATTAT TTTCATATAG GTCCTTGACA TTTCTTGCTA AGGTTATCAT 67620

TAGATTTTTT TTTAATGGTG TAATAGTTCA GGCCTTCACT CAAATGTCAT CTCTCTAGAG 67680

AAGCCTTCCT TAACTACCAT ACCAAAAACG GTTCCAGCGC CGCTACCGTC TATCCCAGCC 67740

TATCCTCTCA CGTCCTGTGG TCCTGAGGTT CTGTGATAAT GTTCTATAAT TCTGTGCTGT 67800

CCAATATGGT AGCCACGAGC CACATGTATT CATATCGTCG TTATTGAGCA CTATATAATG 67860

TGGCTAGTGC AATTGACACA CTACAATTTT AGTTGAATGC AATTTAAATT AATTTACATT 67920

GAAATAGCCA CATGTTTGGC TCACACCTGT AATCCCAGCA CTTTGGGAGG CTGAGGCGGG 67980

TGGATCACCT GAGGTCAAGA GTTCGGGACC AGCCTGGCCA ACATGGTGAA ACCCCATCTC 68040

TACTAAAAAT ACAAAAATTA GCCGGGTGTG GTGGCACGCG CCTGCAATCC CAGCTACTCG 68100

GGAGGCTGAG GCAGGAGAAT CACTTGAACC TGGAGGGTGG AGGTTGCAGT GAGCCAAGAT 68160

TGCACCACTT CACTCCAACC TGGGCAAAAG AGTGACACTC TGTCCAAAAA AAAGAGAAAT 68220

AGCCATATGT GGCTGGTGGC TATTGTATTG GACAGCACAG CTCTGTTTCT CCCACTAGAA 68280

TGTAATTTGA TGAGGGTGGG GACTTGGACT TATTCACAGC TGAATACCTA GAATGGAACA 68340

TAACTGCTAT GTTTTGAATG TTTGTGTCCC TTCCAAAATG TATGTTGAAA CTTAATCCCC 68400

TATATAAGAG TTGAAGAACC TTTTAGAAGG TAATTAGGCC ATGAGGGCAG AGTCCTCATG 68460

GATGGGNATT AGGGTCTTAT AACAGGACTT GAGTCCTCTA TAANGGAACG GAGAGTTCAC 68520

CTTTNCCTTC CCTTCTGCCN ATGTGNAGGA CACAGCGTGT GTCCCCTCTG AAGGACACAG 68580

CGACAAGCCT CCATTTTGGA AGCAGAGAGC AGCCCTCACC AGACACTGAA CCTACTGGCG 68640

CCTTGATCTT GGACCTCCAG CCTCCAGAAC TATGAGAAAT AAACTACTGT TGTTTGTAAA 68700

TTGCCCAGTC TGTGGCATTT TGTTATGAAA ACAGCAAAAA CAGACTAAGA CAAATCAGTT 68760

CTGGCACATA CTAGTAACTC AGTGATTCTT TGTAGAGTGA GCAAACGTGT GAATGAATGA 68820

ATGAATACAT TGTCATGCGC AGCTTTCGTG GGTCGTGAGT ACAAATGAGA AAATACGATC 68880

ATGGTGCCAT TGCAATGGCT TGAAACCCCA GCACTTACTG GCAGGAAGTC TGTCATTTTT 68940

TGCAATTCTC CTTCCCAAGT GTTTCCAGAC TCCCGAGAAG TGCACATGTA TATTTAGGAA 69000

TCAGTTCTCA TCTGCTAGAA CATGGGAAGG GAGTTAGTTG ATAGCAGTTC AGCTGCTTCA 69060

AATGCAGTCC TAGCTGACCC TGGAGGATCC AGGTACCTAT GGGTGCCATC ACGGCCACCT 69120

TTGCACTATC CTGTGAGAAA CTCTCTCCCA TCCTTGGTGA TGTCCTCCTG TGGTAACCTC 69180

AGTGAGAGAA CTCCATTGAT TCCCTAAACC AGAGGTCCCC AACCTTTTTG GCACCAGGGA 69240

CTGGTTTTGT GGGAGACAAT TTTTCCATGG ACCATGGGTG GGGAGGGGGG GATGGTTTTG 69300

GAATAATTCA AGTGCATTAT AATACGTTTA TTGTGTACCT TGTTATTATT ATTACATTGT 69360

AGTATAGAAT AATTATACAA CACACGATAA TGTCTAATCA GTGGGAGCCC TGAGCTTGTT 69420

TTCCTGCAAC TAGACAGTCC CATCTGGGGG TGATGGGACA CAGTGGCAGA TCATCAGGCA 69480

TTAGATTCTC TTAAGGAACA TGCAACCTAG ATCCCTCGCA TACACAGTTC ACAATAGGGC 69540

TCATGCTCCT GTAAGAATCT AACGCTGCTG CTGATCTGAC AGGGGGCGGA GNTCAAGTGG 69600

›Example 10 · 23 of 49

TAATGTGATG GATGGGGAAC TGCTGTAAAT ACAGTTGAAG CCGCTCACCT CTTGCTTTGT 69660

GGCTGGGGCC TGGGTACCCC TGCCCTAGAC AGTAGACTTC TCAAGGGGAG GGGAAAGATT 69720

GGGCCAAGGA ACTGTGTCAG TCAAGAGGGC CCCCACTCAA CGGAAACAGA CCAGCCACTG 69780

GTCTCACAGT GCAAGTCAAG GAAGCTGGTC TCAGAGCTGT CCTCAGAGGG GACGCGTGAT 69840

AAGCAGATCA CACCCGGGAA GACTCGGCAT CAAGATGGAG AGGAGGGAAT GCGATGCGCC 69900

TGGTGGCAGC CGTAGGATCT CCTTCCAAGG CCGCACTGGA GGAGAGCTGC CTCCTAAGAA 69960

CAGGAAAGTG AATCAGAGTG AGGCTGTCAT TATAGTAAGA TAAAGAAAGA TGAGTGCTTG 70020

TTTGGGAATC TGGACAGAAT TAGCATCTGC TTGCTTTAGG ATAGTGGCTT CTTTTCTCTC 70080

TTGAACAAAA TACTCTCCTT AATAACTGCA GACCCAGGAT AACATGGAGT CATTGTTCAA 70140

ATTCACCCCG TTGCAGAATT CTCCAGTTAT CAGCATTTGT GTGTGTGTGC GTGTGTACCT 70200

ACATGTGCAC AGATGTATAC ACACACAGAT AAACACACTC CAGGCTTTGG GGAAATCGTA 70260

TTCGTAGATG CCTGTCTCTA CCTTTATTAT GTTAAAGAGA ATTCTGACTC TCAGGTCGTG 70320

GACTTCATTC ATTGTGTTGC TCACATGCAG GAAAAAAAAA AACCAGAATG CAATAAGGAT 70380

AATTCATTGA TTTGTGGGGA AAGAGAAAAT TCATTGTTTT GGGGGGAAAG AGAGAATGTA 70440

TTGATTTGTG GGGAAAGAGT CAATAAGTGA ATGTTTCCTG TTCTAGGACT GGCTTTGCCT 70500

TGTCAATAAT TGATTTTGTT GTTGAGAATA CATTTCAAAG CCTTTAAAGC AGTGTGCAGT 70560

TAAGGATGAT ATTTTTGCTT GAAATGACTA CTTTGCATCA TGTAGAAGGA ATAGTGTCTT 70620

TTAAAGGCAA CAGATGCAAG TCTAGGACCC CAGAGCTTTA GAAGGCTCTG GGCTTCGGGT 70680

ATGTGTCTGA TGTGTTGAGA GTTGCAGGGG ACGGGAGGGA TGTCCACTGT GGGCCAGTTT 70740

CTACCAGCCA CCGAGAAGCT GGAATTTGTT TATTCATTTA TAGAGCAACA GGAACTGGAA 70800

TCGAAATCTG TCAGTCCCTA TGTGCAGGGT GTAATTGAAT TGACTTCTCT GCTCTCAATT 70860

GGAACTTCCT TTGACCTGTA GTGAGAACAT TTTATGGCTC CCTCTAATCT AAAAAGGGTT 70920

TTTTTTTTTT TTTTAACTTT CCTTCCTATT CCCTTGTCTG CTAACCAACA GAGAACTCAG 70980

CCCACAGCCT CACAGACAGA ATGAGAGCAA TGCTTAATCC TTGTTCAGTG AATCTCATGG 71040

CCTCCTCTAG TCTTCAAACT TGGATTCCAA GTGCCTTGAA GAGCCAGACA CAGTGGCTCA 71100

TGCCTGTAAT CCCAACACTA TCGGAGGCTG AGGCAAGGGT GGATCACTTG AGATCAGGAG 71160

TTTAAGACCA GCCTGGCCCA CATGGCGAAA CCCTGATTCT ACAAAACATA CAAAAATTAG 71220

CCAGTCCTAG TGGTGCATGC CTGAAATCCC AGATACTCCA GAGGCTGAGG GAGGAGAATC 71280

ACTTGAACCT GGGAGGTGGA GGTTGCAGTG AGTGGAGATC GCACTACTGC ACTCTACTCT 71340

GTCTCAAATA ATAATAATAT ATATTTTTAA GTGCCTAGAA GAAAGAACTG CACTTCTGCA 71400

GAGAGCGCCT CCAAAGCTCA GGGTAAGTGA CATGCTGCTT ACCATCCTAG AATGGAACCA 71460

GGCCACCCAT CCCCAGGTGG GACAACTGCA CTCCCAGGAT AACCCCTGAG TTATGGGCAG 71520

ACTTGTGTCT CTCCCCAGTT CAGATCTTGA AGTCCTAGAC CCAGTGCCTC AGGATGTAAC 71580

TGTAGATTCT TTAAAGAGTG AATTAAGATG AGGCCATTAC TAAAAGCCTA GACCTGACCA 71640

CTATGCAATC TATGCATGTA ACAAAATTGC ACATGTATCC CATCTCTACA AATTAAAATA 71700

AATAAATAAA ACTACGTCAT TACAGTGGGT CCTAATCCAG TATGACTAGT GTTTTTGTGT 71760

TTGTTTTTGT TTTGAGATGG AGTCTCTGTC ACCTAGGCTG GAGTGCAGTG ACACGACCTC 71820

GGCTCACTGC AACCTCCACT TCCCAGGTTC AAGCAATTCT CCTGCCTCAG CCTCCCGAGC 71880

AGCTGGGATT ACAGGCACGT GCCACCACAT TCAGCTAATT GTTTTGTAAT TTTTTTTTGA 71940

AGTTTTTATT TTTTATTTAT TTATTTTTAA TCTTTTTTTA TTTTATTTTA TTTTTTTACT 72000

TTAAGTTTTA GGGTACATGT GCACAACGTG CAGGTTAGTT ACATATGTAT ACGTGTGCCA 72060

TGCTGGTGCG CTGCACCCAC TAACTCGTCA TCTAGCATTA GGTATATCTC CCAATGCTAT 72120

CCCTCCCCCC TCCCCCCAAC CCACAACAGT CCCCAGAGTG TGATGTTCCC CTTCCTGTGT 72180

CCATGTGTTC TCATTGTTCA ATTCCCACCT ATGAGTGAGA ATATGCGGTG TTTGGTTTTT 72240

TGTTCTTGCG ATAGTTTACT GAGAATGATG ATTTCCAAAT AGAGACAGGG TTTCATCGTG 72300

TTGCCCAGGC TGGTCTCGAA CTCCTGACCT CAAGTGAGTT GCCTGCCTTG GCCTCCCAAA 72360

GTGCTGGGAT TACAGGCGTG AGCCACCACT CCCCGCCTGG TGTTATTAGA AGAAGAGATT 72420

AGGACAGAGA CACAGACACA GAGGAAAGGC TGAGTGAGGA CACAGGGAGA AGACAGCCAT 72480

CTGCAAGCCA AGGAGAGAGG CCTCAGAAGA AACCAACCCT ACTGACATCC TGAGCTTGGG 72540

CTTCCAGCAT CTAGAAACTG TGAAAAAATA AATGTCTGCT GTCTAAGCCA CCCAGCCAGT 72600

GGTATTTCGT TGTGGTAGCC CTAACAGACT AATACATGCT GAGTCTCTCA TTGTTCAAAT 72660

CATCCTGTAA AACTGACTCA ACAGGCTTTT TTTGAGCAGG GTTTTCTATT CATGTACTCA 72720

TTAATTTTCC TTAAATTAAA AGTTGCAAAT ACAATATACA AAATTAAAAG TTCAATTAGA 72780

AAAATGAGTT TCTATAATCA GCCTACTCAG AATTAACCAT GGTTTCAAAT AGGGGTTTTG 72840

CTGGTGTTTT TTGTTTTGTT TTGTTTTGAG AGAAAGTTTT GCTCTTGTCT CTCAGGCTGG 72900

AGTGCAATGA CGTGATCTCA TCTCACTGCA ACCTCCACCT CCGGGTTCAA GTGATTCTCC 72960

CGCCTCAGCC TCCCAAGCAG CTGGGATTAC AGGCAAGCGC CACCATGCCC AGCTAATTTT 73020

GTATTTTTAG TAGAGACGGG GTGATCTGCC CTCCTTGGCC TCCCAAAGTG CTGGGATTAC 73080

AGGCGTGAGC CACTGCGCCC GTTAGCTGTT TTGTTTTGAA ATCAACTTTG AAAAATGTTT 73140

TGATATCTCA TCATGTCCCC AATGCCATTT GTAATGGTCA CACAGCATTC TGTTGTATGA 73200

TGTACCATGC TTTATCTAAC CTGTGTCCTA TTTTTGGATA GTTCGAATTT TCCTATTTCT 73260

TTTCACTATT AGAAGCAAGG CTGCAATGGA CATCCTTTTA AATACTTTTT AAAAACAAAA 73320

ACCTTGGTAC AAGTACCTGT ATATAGACTT GCAGGGTCAA AACTTCCCAT TTGATGGCTA 73380

TTGATATGTA CTAACAAATT GTCCTCCAGA AAGTGGTCTT TTCCTCACCC TCATCAGTTC 73440

TTGGTGTTAC CACCTTTTTG CATTTTGCCA AGCTGATAGG TAAAAAAGTG TCTCTTACTA 73500

TTGTATGTAT TGAATTAAAT TTATTTATTT ATTTATTTAG ACAGGGTCTG GTTCTGTCCC 73560

CCAGGTAGGA GTGCAGTGGT GCAATCATAG CTCACTGCAG GCTTCAACTC CTGGGCTCCA 73620

GCAATCCTCC TGCCTCAGCT TCCTAAGTAG CTGGGACTAT AGGTGGGCCC AGCTAATTAA 73680

ATTTTTTTTT TTTTTTTTTT TTTAAGATAC AAGGTCTCAC TACTTCGCCC AAGCTGGTCT 73740

TGAACTCCTG AGCTCAAGAC ATCCTCCCAC CTCAGCCTCC TGAGTTGCTG GGATTACAGG 73800

CAGGAGCCAC TGTGCCTGCT TATTATATAT TTCAAAATAA CGAAAAGAGT GGAATTGCAA 73860

GTTCCTCACA CAAAGAAATG ACAAATGCTT GAGATAATGA TTATCATAAT TATCCTGATT 73920

TGATCACTAC AACTTGTATG CTTATATCAA AATATCACAT ATTTATATTT TTAAAAATTA 73980

TATTTATATT TATGTGATAT TTTGATATAT TTTGTAATGA TCATTTTACA TATGAACATA 74040

TTTATACATA TATACAAACC AAATAAACCA TACATATTTA TACATATGCA CCTATGTACA 74100

AACCAAAGAA ATTGGGATAT AGCTATCCCA GTTCTATTAA AAAATTGAGA TTTTTTTCTT 74160

CTCTATTGAT ATTTCCTACT TTTTTTTTGT TTTGAAAAAT AATTTATCCT TGAGTCAGTT 74220

GTGATGATTT ATACCTGTAT AGAGATTACT AGTTTGATCA AAATCATTTC ATTTATTGTT 74280

AAAAATTGTA TAATGATATT ATCTCCTAAC TGAAAATTTT CCTTTATCTC TGTGATTATA 74340

TTCCATTTCT CATTCATCAT ATTTTCATTT CATTCCAGTT TTCCTTGGTT AGACTTTCCT 74400

ATGATTTGTG TCTTTTACTG TTCTTTTCAA AGAACAGCCT TGGTATTTAT TTATCAATTC 74460

TATTTCTTTT TAATTTCACA ATTAATTGTT TTCTGTTTTT ACCATGACTA ATTCCCACCA 74520

CTGCTTTCAT AGATTAATTT TGTGTTCTTT TTCTAATTTC TTCAATTAAT TTATTTTCAT 74580

TTTTTAAAAA CTTAATAATA AAAGTTCTTA AAGTCCTAAA TCTTTTCCTG AGTACTGTGG 74640

GATTCTTTCC ATGTGCTTCT GCATGTAGTA TGACTATTGC AATTGGTATA GATGGTATTA 74700

›Example 10 · 24 of 49

CAGTTCTTAC TCCTTCTTAC ATCCAGGGAT TACTAAGGAG ACTGATTTTA AATTTGCAAG 74760

AAGTTTGACT TCTAAAAGTG CCAGGCTCCT TTTTGATGTC AAGTCTCACC TATTTCTTCT 74820

GTTTTTCTCT AGTAACTGAG CTCAGGTTTT GTTGAAGGCA GCAAACTACT GGCTAAAACT 74880

GCTCAATGTT TTCCAGCTAA AATTGCTCAA GTATTTCCTG CAGCTAGTTA GGGCAAGTTA 74940

CCTGGCTCTG TCTAGAGAGA TGGAGGTGCA GGTCCTTGGA GACAGAGTAC CCTCTGAACA 75000

AAAAGGCAAA GACTTACCAG CAGAAAACCC ATTTGCCTTT TCCCTTTCCT CCTCACTGAC 75060

ATGCAAGGGT TATGTCTGGA GGTACGAGAA AAGGAAAGCA TAAGGATAAA ATCTAACAGG 75120

CTAAGAATGA CAGGGCAGAA AGATAGAAAG GATCTGTGTC CCCGATGGCA TCGTTGTACC 75180

AGCAAGACTG ATGATCATGA TGTAAGTCAA ATGAATGCCC AGCTGCTGCT GGCTGTGTTT 75240

TTTGTTATTT GCGGCTGAAT GCATTGCTAA TGTAAACATT ACCTTGCAGC CAGAGAATAC 75300

GGCTTGCCAA AAGTCTAGTT TTGTATGTTA ATCATGATAC ACCAGCCAGA CAGAGTGGCC 75360

CTCAGCTGTA ATCCCAGCAC TTGGGGAGGC CAAGGCAGGC GGATCACTTG AGGTTAGGAG 75420

TTCGAGACCA GCCTGACCAA CATGACAAAC CCCCGTCTCT ACTAAAAATG CAAAAATTAG 75480

CTGGGCATGG TGGCTCCTGC CTGTAGTTCC AGCTACACGG GAGGCTGAGG CAGGAGAATC 75540

GCCTGAATGC AGGAGGAGGA GGTTGCAGTG AGCCAAGATG GTGCCATTGC ACTCCAGCCT 75600

GGGCGACAGA GTGAGACTCT GTCTCAAAAA ATAAAAATAA TAATAATAAT GATATGCCCA 75660

CTGCTATAGC ACCTAGACTG CAAAATGTAC ATCACAACAG TCCGATTCTC TGTTCTCTTT 75720

GTTCAGGGGT AAGCATGGAG CTTAATTTTG ATCTATGAGT CAACGTGGGA AGTCCGTTAG 75780

GTTAGAAGTG CTTCTGGTCA AGGTTTCTTT GCTTCTAAAA GAGGAATGTG AGGAAAAAGT 75840

CCCTGTCTTG GTGTGGATTT TGGTGTGGGG GGATGTATAT AAAGCCTGTA GCTATTGAAG 75900

CCATCTGGCA AACTTGAAGG GAGCAGCTGA CTCTGAGCTG GTAGAATATA GAAATGGAAA 75960

GGATTTAGAT CTTGATGTGG TTGAGAGGCT GCCCTCCCTT GGGACTTCTT TTTTGTGTGT 76020

GAGTTAACAA GTTTTCCTTA TTGTTAAGTT GCTTTAGTGG GTTTGCTATT ACTTGTAGTC 76080

AAAACATTTA TTATGGCATC ATCTACTTTA TTCTATCCTT CTGCTTTCCT TATTACAAGT 76140

ATATTTACAA GCTCATTGTC ATTCATGTCA TCATTTTAAT CAGCACCAAC AACAGCATCA 76200

CCAGTAACAT TTATTGAGTG TTTTTAAGTG CCAGGCCCTG TTGTTGTCAT TTAAATCTTA 76260

CACCAATCCC TACTGCTCAG ATACTATTCT TTTTAAAAAT TATTTTTTTT TTAGGCACAG 76320

GATCTTGCTC TGTTGCCCAG GCTGGAGTGC AGTGGCATAA TCATAGCTCA CTGCAGCCTC 76380

AAACTCCTGG GCTCCAGTGA TCTTCCTGCT TCAGTTTCCC AAAGTGCTGG GATTACAGGT 76440

GTGACCACTA CCCCCTGTCC TATTATTATT GATTCAGATT TACAGATGAG GAAAATAAGG 76500

CTTAGGAAGG CTACATAATT TCCTAGATTG CTTATTTAGT AAGCGGCAGA GCCAGGATTC 76560

AAACCCAGAC CTGAGGGACT CCTAGACTAG TCCATGCCAC TGTGATATGG CCTTTCACAT 76620

CTCTTCTTTC ATCCGTCATC ATGATATCTT TCTCCTCTGA GTTCTGGGGA AGTTTCTCAA 76680

GTTGGACTGC CAATTTTCTG CAGGATTTTC CTGTGATATA TAACTCCTTC ATTTACTGCT 76740

TCCATTTTAT TTCATATCAC CTACAATTTC CCTTATGTCT AAAACCAATT GCTCCTATAT 76800

CTAAGATGCA ACGTCCTTCT GAATTATAGT GTTAATGCAA TAGGGTATTT TGAAGGTTTC 76860

TGTATGTTTT CTGTAGAAAA GTTATCTCAA AGGGGGATAT ATACTTCCAT TTCCCAGTGG 76920

TCTACTTCTT TTAAGCCACA AATAGGGCAC TTTCTCTTGT TAGTTTAATC CTACGGGTAT 76980

ATAATTTTCA GTATTTCTAG TGTTAGAATT TGAGATTCAG AGAACTATGA GTCTCTGTTT 77040

TAATCTTTCA GTCCTAGGAA AAGGAGAAAT AGGGCTGCCT ATCTTTTCTG TGGTTTTATT 77100

TTGCCATTTA ATTTCTAATT GACTGTGAGA TGTATCAAGA GATCTGTAGC TCAAGGCAGT 77160

TGAATGTCCC AGAGCTTCAC AGCTGAGCCA AGTGACTTCT TTTCCATGTT TATTGTGGCA 77220

GCCAAGGTCA GCAGATGCCA TGCCTCTTGC TCTGAGTGCC TGGACCACCC CCATTAAGAG 77280

CCTCCCACAG CAACAACTCC ACTTGACCCA CGATAAGTGA GGTTGGCACT GTGTCTCTCT 77340

CTTTGTACAT TTTGTTTTCT AAGTTGCTTG TAGGGCCAAG CTTTGAGTCC TTGTTACCAT 77400

CAGCTTAAGC TCCGGCCTCT CTGAATTGGA GGATTTTGTT TGTGTTTGAT TAGAGCCTGT 77460

TGGCAGAAGC AAGTGCCAAA GTCAGACATA AAACAGAAAA CTCTAATGTG GTGTCAAGTC 77520

TTTTCCAGAT GTTACTGATC CTCTTTCTTT TCCTTCTTTT TTTTTTCTTT TTTGTTATTT 77580

TTGATCCCCT TCCTTTTTGC TTCCCTTAGG TTGACCTTTG CTGTCCTACG GGCAGTACAA 77640

AGATTGGGTC TTTCTGTCTC TGCCTCTCCT GCCCTCGGAC TCCTACCATG GGTCTTTTCT 77700

TTTTTTATAG AGATAGGGGT CTCACTTTGT TTATCGTGTT TTTTTTTTTG TTTGTTTTTT 77760

GAGGTGGAGT CTTACTCTGT CACCAGGCTG CAGTGCAGTG GCGTGATCTT GGCTCACTGC 77820

AACCTCCGCC TCCTGGGTTC AAGCGATTCT CCTGCCTCGG CCTCCTGAGT AGCTGGGACT 77880

ACAGGTGTGT GCCACTATGC CCAGTTAATT GTTGTATTTT TACTAGAGAC AAGGTTTCAC 77940

CATGTTGGCC AGGATGGTCT CAATCTCTTG ACCTTGTGAT CCACCCGCCT CAGCTTCCCA 78000

AAGTTCTGGG ATTACAGGTG TGAGCCACAG CGCTCAGCCT GAACTTTTAC TTTTAAGACA 78060

ATTGTAGATT CAAATCCTGT GTCCTCTCTT ACACAGTTTC CTCCAATGGG GGCATTTTAC 78120

AAATATAATA ACCAGGATAT TGACATTGAT ACATTTGATA CAGTCAAGTT ACATTTTCAT 78180

CACCACAAAG ATCCTGGTGT TACTCTTTTA TAGCCATACC TGCCTCCTTC TCCCCTCCCC 78240

CATCCCTCAC GCCGGCAACC ACTAATCTGT TCTCCATTTC TACAATTTTG TCGTTTCAAA 78300

AATGTTATGT AAACAGAATC ATACAGTTTC TCATCTTTAA GATTCGTTCT TTCCTGTTTT 78360

TTTTTTCTTT TTTTTCTTTT CTTTGTTTTT TTGAGATGGA GTCTCACTGT GCCACCCAGG 78420

CTGGAGTGCA CTGGTGTGAT CTCGGCTCAC TGCAACCTCC GCCTCCAAGT TGTGGGTTGA 78480

AGCGATTCTC CTGCCTCAGC CTCCCAAGTA GCTGGGATTA CAGGTGCCTG CCACCACGCT 78540

CGGCTAATTT TTTTTTTGTA TTTTTAGTAC AGACAAGGTT TCACCATGTT GGCCAAGCTG 78600

GTCTCGAGCT CCTGACCTCA GGTGATCTGC CTCGGCCTCC CAACTTGCTG GGATTACAGG 78660

CATGAGCCAC CGCACCCGGC TGAGATTGGC TCTTTCACTC AGCATAATTC CCTGGAGACT 78720

TCATCCAAGT TGTTGCATGT ATCAATAGCT TGTTTCTTTT CATTGCCACC TAGTTTTCAA 78780

TGGTATGAAT GCCGCATTGC TTGTTTCATC AGTCACCTGG TGGAAAACAT CAGGGTTGTT 78840

CCCAGTTTTT AACTATTATG AATAAAGCTG CTATGAACAT TTGTGTACAG GTTTTTGTGT 78900

GAACATATTA TCATTTCTCT GAGATGAATC AATGCCAAAG NAATGCAATG GTATGTTTAG 78960

TTTTATAAGA AACTGCCAAA CTGTTTTCCA GAGTGGCTAT ATGANTTTTG TATTCCTACT 79020

AGCAGTGTAT GAATAATCTA GTTTCTTTAC ATCCTCACCA GCATTTCATG TTCTCAGTAT 79080

TTTTTTTATT TTAGTTAATC CGATATGTAT GTAGTGCAAT ATCACTGTGG TCTTAATTTT 79140

TAGTTCACCA GTGCTAATGA TGTTGAATAT CTTTCATGTA CTTATTTGCC ATCTGTATAT 79200

CCACTTGGTG AAATACTTCA TGTCTTTAAA GAAGACCCAG GATTTCTAAA AAACTGTTGA 79260

GTTTTGAGAA TTTAAGAAAT ATATTCTAGA TACTGGTACT TTGTTGGATA CATGGTTTGT 79320

AAATATGTTC TCCTAGTTTG TAGCTTGTCT TTTCATATGT GTTAAAGCTT ATCTCCCATT 79380

TTATTATTTG TTTTCTGTTT ACTTTGTTTC TTATTCCTCT ATTCTCACTT TGGGTGGATT 79440

ATTTAAATAT TTTTTAAGGT TTCATCTTGA TTTATTTGTA GCATTTTGGG TACATCTCTT 79500

TGTACACTTT TCTTAGTGGT TGCCCTGGGT GTTACCATAT ACATATGTCA AGAGTCACAT 79560

TCTGCTGGTG TCAGTGTTTT TCCAGTTGAA GGCAAGTGTG GAAAACTTAC CTCCATTTAG 79620

ATTCCTTTAC TCTTCCCATT TTTAAAACAT GTGTCTCAAG TATTCCCTCT ACATTCATTG 79680

ATCAGCACAC TAGAGAGTGT TATTTTGGCT TTAACCTTCA AATATAATTT AAGACACTCA 79740

GGAGAATAGG ATCATCTATT ATGTTTACCC CTGTCTTTGC CTGTTTTGAT GTTCTTCATT 79800

›Example 10 · 25 of 49

CTTTTCTAAA GTTTCAAGCA TTCTTCTGTT ATCATTTCCT TTCTGTTTAA AGAACTTCCT 79860

TTAGTCGTTC TTTAAGGACA GATTTACTAG CAACAGATTC TCAGTTTTCC TTCATCTGAG 79920

AATGTCTTTA TTTCCCCTGC ATTCCTGAAG GATATTTTCA CCTGATATGG AATTTGTGAG 79980

TGATAGTTCT TTTTCCTCTA AGCACTTGAA AAATGTTATG CCACTTTCTG CTGTCTTTTA 80040

TGGTTTCCGA AGAGAAATCC ACTTTCATTC AAACTGTCAT TTCCCTGTAA GTAATGGATG 80100

TTTTCTGTCT AGTTGCCTTC AAGACTTTGT CTTTAGTTTT TACAAGTTTA ATTATGATAT 80160

GTCTTGGTGT GAATTTCTTT GAGTTTATCC TGCTTATGAT AGTTCACACA GCTTTTTGAA 80220

ACTGTAGGTT TATGTCTTCC ACCAAATTTT ACTGAATTTC TTCAGTTCTA TGGTCTTGCT 80280

CCTCTTCCTG AAGTATTCCA ATGATACCGT GTTCTCTTTT GTTACGGTCC CACTGGTCTT 80340

TGAGACTCTC TGTTCATTTT ATTTCGGTCT TTCTTTTCTC TGTTGTTCAG ATTGGGTAAA 80400

TTCCATTGAT CTACCTTCAA GCCCACTGAT TCTGTCCTCT ATCATCTCTA TTATTGAGCC 80460

CAACCACACA GTTTTAATTT TGATTATTGT ATTTCTCAGT TCTATAATTT CCATTTGGTT 80520

ATTTTTCAAT GACTTCCATT TTTGCTGAAA TTTTCACTTG TTTCAAGAGA ATTTGTAATT 80580

ACTTGTTGAA GCACTTTTAT AATATCTGTT TAAAATACTT GTCATATAAT TCCAGTAACT 80640

AATTCATCTT GGTGTTGACA TCTGTTTATT GCTCACTTAA AAATAAAAAA TAAAAAACAC 80700

CTAGACTTTA TTTTTTATAG CAGTTTAAGG TTCACAGCAA AATTGAGAAG AAAGTAAAGA 80760

GTGTGCCCAG AAAAATAGTA CCCCTATGCA GAACCTCCCT GATATTGTTT GGCTGTGTCC 80820

CCCACCAAAT CTCATCTTGA ATGGTAGCTC CCACAATTCC CACGTGTTGT GGGAGGGATC 80880

CAGTGGGAGG TAATTGGATA ATGGGGGCGA ATCTTTCCCA TGCTGTTCTC ATGATAGTGA 80940

ATAAGTCTCA TGAGATCTGA TGGTTTTATA AAGAGGGGTT CCCCTGCACA AGTCCTCTCT 81000

TGCCTGGCGC CAGGTAAGAA GTCCCTTTGC TCTTCCTTCA TCTTCCATTA TGATTGCGAG 81060

GTCTCCCCAG CCATGTGGAA CTGTAAGTCC ATTAAACCTC CTTTTCTGTA TAAAGTAACC 81120

AGTCTCAGGT ATGTCTTTAT TAGCAGTGTG AGAATGGACT AATACACTCC CTATCAACAT 81180

CCCCTACCAG ATTGGTATGT TTGTTGTAAT CGATGAACCT ATGTCAACAC AGCGTTATTT 81240

CCCAAGCTCC ATAGCTTATA TGAGGATTCG CTCTTGGTGT TTACATTCTG TGAGTATTGA 81300

CAAATGTATG ATGAAATGTA TTGACCATTA TAGTGTCATA CAGAATACAG GATAGTTTCA 81360

CTGTCTTAAA AAATCTTCTG TGCTCCCCTT ATTCATCCCT TCCTTCTGTG TAAGCCCTGG 81420

CAACCACCGA GCTTTTCACT GCCTCCATTG TTTTGCTTTT TCCAGGATGT CATAGAGATG 81480

GACTCATACA GTAGGTAGCC TTTTGAAATT GACTTCTTTC ACTTAGTAAT ATGATTCCTC 81540

CATGTCTTTT CATGGCTTGA TAGCTAATTT CTTTATAGTG CTGAGTAGTA TTCCATTCAC 81600

TTATAATTCC TTGAATTCAT TGTTTGGAAT ATTTTGCAGA TGATATGCTA TTCCCTAACT 81660

TTATGCATCT TCACTCACAG GATTGTTTTT TTCTCACCAA TGCTTATTTA TATAAAAGCC 81720

ATATCAACAA AATTTTACAC ATCAAAAATT TTCAGACTTC TGGTTGCTCC AAAGAAGGAA 81780

TGACCCCATT CTTCTCAGGT CCTCTTCCTC ATGACTAAAA AACTCTGAAC AAAGCACAGA 81840

AAGTTGCGGA AGGCTCTGAA AGGTGAAAGG AGGTGGACTG CCTAGGGACC TCAGGACTTG 81900

GAAAACAACT CAGTGGGGAA TTCCGTGGAT TTCCTTATCA CCTCCCTTAT ATCCTGGACA 81960

CGGAGCTGCA GAAGACTCCA ACCTACAGTC ACCAATGCGC ATAGAAGAAA AAAGCTCCAA 82020

GAAAAGCCTT TTCCTCCTGG CCAGATGACT GGACAAGGGT GGCCTGACAA CAGAAAACCC 82080

ACAACAAGGA ATTACAGGTA ACTCCAGAGA GGATCAGCTT GAGTGGTTAA AACAAGTACA 82140

TGGAAAACAA AAAGAAGCAT TTTTCTTTTT TTGTAAAAGA GCTTGTACTG TAATAACTTT 82200

GATTTTGTTT TTTGTTTTTT GTTTTTTGTT TTTTTTTTGA GACTGAGTCT CACTCTATTG 82260

CCCAGGCTAG AGTGCTGTGG CGCAATCTTG GCTTACTGCA ACTTTTGCCT CCTGGGTTCA 82320

AGTGATTCTC ATGTCTCAGC TTCCTGAGTA GTTGGGATTA CAGGCATGCA CCACCACACC 82380

AACTAATTTT TGTATTTTTA GTAGAGATGG GGTTTGACCA TGTTGGCCAG ACTGGTCTTG 82440

AACTCCTGAC CTCAAATGAT CTGCCCACCT TGGCCTCCCA AAGTGCTGAG ATTACAAGCC 82500

TGAGCCACCG CACCTGGCCA ACTTGGACTT ATTTTTATAA TAAGTAGATA TTGTTCACTG 82560

TAGATATTGA ATCAATTTTT ATTTAATCTT GATTTTTTTT CTTGAGCTGC ATTAGAAATT 82620

CATTACAATA TTTCAATTTA TAAATCTTAT TAAAAATTAC TACTACCTAG ATCTCATTGT 82680

TTTCTTTTTT CTTTTTTGAG ACATGGTCTT GCTCTGTCAA GCAGGAGTGC AGTGGGACAA 82740

TCATAACTCA CTGTAGCCTC CAACTCCTGG GCTCAAACGA TCCTGCTACC TCAGCCTCCT 82800

GAGTAGGTGG GACTATAGGT GCACGCCACC CATGTGTGGC TAATTTTCTT TATTTTTTTT 82860

TGTAGAGACA AGGTCTCACT GTGTTGCCCA AGCTGGTCTT GAATTCCTGG CTTCAATCAA 82920

TCCTCCCGCC TCAGCCTCCC AAGGTGTTGG GATTTCAGAC GTGAGCCACT GCACACCTGG 82980

CCCCATTTTT TTTCCTTGAA TAAAGTGTAC TGGTAAATTT TAGGCTCATG AGGGTATATA 83040

TGCATTATTT TCTTCAAATC AAGCCTGAAT CAAAGAAACT TCTGCTTTAG TTTTAGTGAT 83100

ATTTGTCCCA AATGTTTAAA GACTGTATCA TTCTGATGAA TTGGATATTC CCATTGAGAG 83160

ATATTCAATA GGCCTTGATT GAAATGTTCT TCATTTTCTT TTTAAATTCT ATTTACAGTA 83220

GTCTGCATGT GTTAGAACTT TCAGAAAGGG AGAGATTTCT GTCTGGGCTG TCCCCACCAG 83280

CCAGAAGGGT CTGAGAGGCA CTGACTTGCC CTGGGGTGAT ATTTCTGCAG GACTTTGCTC 83340

CTCTGTAGGA AGACAGCCTA GAACAGAGGT GAAGGATGCC TCGGGCCTGC CTAGACCAAC 83400

AGCCATTCCC TGGTGATGCT GTAGTGTGAA GACCCTTGTC TTTCCCAACA CCTGTGATAG 83460

CTTTCAAATT ATTCTTTTCA GACAAACTTT ATGCCTGTTT CTTTATCTCT ATTTTGCATC 83520

CTAACAGAAA AAGCCAATCA CCTAGAAGGG AAAGTCAGAC TGGTCCCTGC TGCTTTCCCC 83580

ACATCTCCAC TGCCCCCAAT ATTGAATGCC GTGACAATGG AATGAAATTC CAATGTCCAT 83640

GAAATTCTGA GGGGAGACAT TTTGACTCAA GATTATATAC TCAGTGAAGA TGTCCTTTAT 83700

TTATTTATTA AATTAATTTT TTTTGAGATG GAGTCTCTCT CTGTCTCCCA GTTTGGAGTG 83760

CAGTGGTGCG ATCTCGGCTC ACTGCAACCT CTGCCTCCTG GGTTAAAGTG ATTCTCCTGC 83820

TGCAGCCTCC TGAATAGCTG GGACTATAGG TACTCACCAC CACACCTAGC TAATTTTTTT 83880

TTTTTTTTTT TTTTTTTTGG TAAAGATGGG GTTTCACCAT GTTGGCCCGT CTGGTCTTGA 83940

ACTCCAGACC TCAGGTGATC TGCCCGCTTT GGCCTCCCAA AGTGCTGGGA TTACAGGCGT 84000

GAGCCACCTT GTCTGGCCAA AGACGTCCTT TAACTAAAGA CTTCTGGTGT ATGTTACCTT 84060

AAAAATATAA ATATAAAAGC ATGAAGAAAA TACAACCTCC ATGGAATTTT TTTGCCAATG 84120

AATCTAGAAA AATAAGAATT GATTCAAAAT AATGAATAGG GAAGCTGTAA TAAAATGACT 84180

TGAGGGTTCA TTGAGTCCAT TTAAATATAT ATCTCTTACT AAAATCACTA AGGGTCATAA 84240

TTAGACAATG AAGTAAGTGC CATAAATCTA AACAATGTAA ATAACAATAT ATCTAAAAAA 84300

AAAAAACTAA GGAGTTTGGA GAGAGGATAC GGGAGGATGT GTTCTTTCAT AGTAGGGAAT 84360

TAGTTAATAT TCTTTAAAAT GGAAACATGT AAGAAAAAAG ACCCTAATGA CTGAAAACTA 84420

AGTTTTCCTC AATCTTTTTT TCATATCCTT TGAAGGCTAT TTTAAGAAAT AATATCTAAA 84480

GAACATCGAT TTGATGTTCA CAATTCCAGT TGATTTTCCT TCTGTGAAAT TCAAATGAAA 84540

TTAAATAAAT ATGTTTTGTT AAAAATGGTG TCATCCCATT TAAGTAAATG TCCTTTCTTT 84600

TACCTATTTA TCCATCTATA ATCTGTATCT ATTCATCCAT CAATGGATAC ATGTGCACAG 84660

ATAAATGGCC CCTTTGGTGA AGGGCTGAGA GGGTATTGTT TTCTAACCCC AACCTGTGAC 84720

GGCTTCCATG AGGCCAATGG AATCATTTTG AAATGTGTTT ACCACAGCAG GGAGACACAG 84780

AAGACTGGGG TCTCACACCT GTGTGGGAAC TCCAGAGGGT GAGAAAAGGG CCAATGAACT 84840

GCTCCGGTGA CACAGCAGGG AGGGTGGCTG CCGTGCTGGG TGCGGCCTGC CTTCCTAGAG 84900

›Example 10 · 26 of 49

AATGTCAGGG AAAGGGATGT GGGGTCATTT CCTGTGGACA CATTTAAGCC AAGTAGGGGA 84960

GAGGTCTGGT ATGGGGTCCT CTTGGGGCCT GTTGGACAGG GTTGACCAGC AGAGAGAGGA 85020

TGCCCAAGGA TTGAAGGAGG AGTGGGTAAG AGGTTCTCTA GGTCATGGGA ACTTCTGAAT 85080

TTCCCATGGA AAGCACCACC ATAATCTGTG TGCAATGAAC AGCCAGACCC ACGTGGGAAT 85140

TCTAGGCCAG CAAGAATCCC TTACTTGCTC ACTGGCTGCC ACGTGGCTCT GACCATGGAG 85200

AGGTCTGGAA CTGTAGCTTC CCAGTGGGGG AGAAGTAGGC TGGGAGAGAG AAGGGGACAG 85260

AGGAACCACA CCCTCCTTCC CCACCTCCAA ACAGAAGCCA GTAAAAATTG AGGGATGGAG 85320

AAAAATATAA GGCTAAATTA AGTTTTGGAA CTTTGGCATG ATCAAGGCTC ACTGCAGCCT 85380

CAACCTCCTG GGCTCAAACA ATCCTCCCTT CTCAGCCTCC TGAGTAGCTG GGACTACAGG 85440

CACATACAAC CATGCTCACC TTTTTTTTTT TTTTTTTTTT GTAGAGATGG GGTATTGCTA 85500

TGTTGCTCAG GGCTGGTCTC AAACTCCTGG GCTCAAGCAA TTCTCCTGCC TCAGCCTCCA 85560

AAAGTGCTGG GATTACAGGT GTAAGCCATT GGCCCTGCCA AGTTTAAGAA CTTTTACAGT 85620

TATAAGAGAC TAGATATTTT AATTATTATT ATTATTTTTT AGACAGAGTC TTACTCCGTA 85680

TCCAGGCTGG AGTGCGGTGG CACAATCTTG GCTCACTGTA ACCTCCACCT TCTAGGTTTA 85740

AGCGATTCTC CTGTCTCGGC CTCCTGAGTA GCCAGAATTA GTAGAGACGG GGATTCGCCA 85800

TGTTGATCAG GCTGGTCTCG AACTCCTGAC CTCAAGTAAT CCACCTGCCT TAGCCTCCCA 85860

AAGTGCTGGG ATTACAGTAG ATATTTTAAT TTTTTTGCAT GGAGGCTATT TTTACTACTA 85920

AAAGTGAATG AAGTATATTT TGTATCTTCC AGGAGTTTGG AAAGTCAAGT CTATTTGCAC 85980

CCAGCCACGT GCCTGCCATG GTGCCCGCGG CCTCTCAATT TTTGACCTTT GTTTATGCTG 86040

CTCTGTCTAC CCAGAATGCT CTCCATCGAG GGAAACCTAC TCTCTCTTCA AGGCCAAATT 86100

CCAGCATCAC CTCCGCCATG AAGCCTTCAT AGATCTACTC AANGTAGAAA CTTCTTAACC 86160

CCTCTAAACT GTCTTAGCAT CTTGGTTGTA GTATTGGTTT AGAATAGCAC AAATTCTACC 86220

CAAAATCTCA CTAAGTCTAT TCTAAGCAAA TCTTGGATAA TTTGCTAACA CTAAAATTAA 86280

ACCTGTTCTC TTTTGGTTTT TTGCTAACAA TGAAACAAAC TTGGTCTTAC TCTTTTGCTC 86340

AAGCTGGAGT ACAGTGGTGT AATCATGTCT CACTGCAGCC AGGAATTCCC GGACTCAAGG 86400

GATCGTCCTA CCTCAGCCTC CTGAGTAGCC GGGACTACAG GTGTGCATAA CCGTGCCTGG 86460

CCAGTTTTAA AATTTTTATT TAGGGACAGA GTTTTGCTAT GTTGTCCAGG CTGGTCTTGA 86520

ACTATTGACC TCAAGTGATC CTCCCACCTT GGCCTTTCAA AGTGCTGGGA TTAGAGGTGT 86580

GAGCTGCCAC ACCCAGCCCC GTTCTCTCTT TTGCATCTAT ATTAGTCTCT GTGCTCTTGG 86640

GAAAAGTGGA CCAATATCAT TTCAAAACTT GATGAAAAAG AAAATTAAAA TCTCATCCTC 86700

GGGAACTGAA ATCACAAACC ACCCAGCAAG GTCCACACCT CTAGGAGACT GGCATTTAGA 86760

AGACAGGACC ACAGTTGAAG CAACGGTTCT TTCTTTACCC TCCCTGCCTG TGACAGACTG 86820

CATGTGCTGA TTATCCCTGC GTTTTCTGCA GAGCTTGCCT TCCTGGTGAT ACAGTACTTT 86880

ATTTTATTCT GAGGGCCCCT TCCTGCCAGG GGATATCTGT CAGGGGATAC ATAAAACTGC 86940

ACAAAATGGA ACAAGTTATA GGTCATATAA AATTTCAGGA CATTGTTGAG AAGGAGAAGT 87000

TGCTAAATTG GAGACACCAT GATGTGAAAT CCCAGGGTCC CAGAATATTG ATGGAACTAG 87060

TATGTTTTTC TTATGTAATA TTTTATGGTG TCTGGGAAAT GGAGTTGCCT AAGTGAACTC 87120

ATTTTTTATG TCTAGGGGAA TAGCAACATA ACTATCATCT AACACTAAAT AAAGAGGAGC 87180

AAAATGTGCT ACATTTAGAA AGTGATGGTA TTATCCCCAG CTGAGGCAGA CTTAGTGATG 87240

GTGTTAGAAA TAAAGTATGG TAGGAGGCTG AGGCAGGTGG ATTGCATGAG CTCAGGAGTT 87300

TGAGACCAGA CTGGGCAACA TGGCGGAAAC CCCATCTCTA CAAAAATCCA 87350

25 base pairs

nucleic acid

single

linear

80

CATTGGGAGA TAAATGCTCA GTAGA 25

22 base pairs

nucleic acid

single

linear

81

AGATGTACTT TGGCCATTCC AG 22

22 base pairs

nucleic acid

single

linear

82

GCCATGACAG CAACATTATC TC 22

23 base pairs

nucleic acid

single

linear

83

CTTACTGCTA CTGCAAGTTC TTC 23

22 base pairs

nucleic acid

single

linear

84

TCGATCAAAA CCAGTACAGG TG 22

23 base pairs

nucleic acid

single

linear

85

GCAGATGTAG GAGACAAATC ATC 23

24 base pairs

nucleic acid

single

linear

86

TCATCCAAAA TCTCTAAATT TCGG 24

22 base pairs

nucleic acid

single

linear

87

CTGAGGACCA GAAACTGTAT GC 22

22 base pairs

nucleic acid

single

linear

88

GCTGATTTGG TGTCTAGCCT GG 22

20 base pairs

nucleic acid

single

linear

89

TGCCTGGGTT GCAGGCCTGC 20

22 base pairs

nucleic acid

single

linear

90

TTGGAAACAA CTGCACAGCA GC 22

23 base pairs

nucleic acid

single

linear

91

GATCCAGTGA ATTCTAAGAA GGG 23

20 base pairs

nucleic acid

single

linear

92

AGGGCCTCCA CGCATGACGC 20

23 base pairs

nucleic acid

single

linear

93

AGTCTGTTTT TCCAGAATCT CCC 23

22 base pairs

nucleic acid

single

linear

94

CCTATGCTTG GACCTAGGTG TC 22

25 base pairs

nucleic acid

single

linear

95

GAAGTTTACA AGTAACAACT GACTC 25

26 base pairs

nucleic acid

single

linear

96

ACTATAAATT GAATGCTTCA GTGAAC 26

24 base pairs

nucleic acid

single

linear

97

GAACACACCT CACCTGTAAA ACTC 24

21 base pairs

nucleic acid

single

linear

98

GGTAAACCAC CATACCTGGC C 21

23 base pairs

nucleic acid

single

linear

99

GTACATATCC TGGTCATTTA GCC 23

25 base pairs

nucleic acid

single

linear

100

ATTCAGATAG AAAGTACATT CTGTG 25

26 base pairs

nucleic acid

single

linear

101

GTTAAGAAAT ACTCAAGGTC AATGTG 26

25 base pairs

nucleic acid

single

linear

102

GGTTGTATTT TGGTATAACA TTTCC 25

24 base pairs

nucleic acid

single

linear

103

ATATTTTGGT AGAGTTTCTG CCAC 24

24 base pairs

nucleic acid

single

linear

104

CTCTTCGATT TTTCTGAAGA TGGG 24

23 base pairs

nucleic acid

single

linear

105

CCCTAATAGT CAGGAGTGTT CAG 23

25 base pairs

nucleic acid

single

linear

106

GGAAAGAAAA TGAAAATTTG ATCCC 25

26 base pairs

nucleic acid

single

linear

107

CAGCCTTAAT GAATAGTATT CTTCAC 26

25 base pairs

nucleic acid

single

linear

108

ATTGATCTTT TAAGTGAAGG TCAGC 25

23 base pairs

nucleic acid

single

linear

109

CTGCAACAGA GACTGTATGT CCC 23

23 base pairs

nucleic acid

single

linear

110

GCTTTCGACA AAATTGTAGG CCC 23

23 base pairs

nucleic acid

single

linear

111

CCAAACCATC CAAAACTGGA TCC 23

22 base pairs

nucleic acid

single

linear

112

TAACCCATGG TAGCTGTCAC TG 22

22 base pairs

nucleic acid

single

linear

113

CTGTTGCTGT TAAGCAGACA GG 22

24 base pairs

nucleic acid

single

linear

114

TTGAATGGGA CATTGGTCAA ATGG 24

25 base pairs

nucleic acid

single

linear

115

GTAGTTGCAT TTGTATTTTG AGAGT 25

26 base pairs

nucleic acid

single

linear

116

GTAAAAAGAA ATGAAAGCAT CAAAGG 26

24 base pairs

nucleic acid

single

linear

117

TCACCCACAG AAGAAAAAAA GAGG 24

26 base pairs

nucleic acid

single

linear

118

CAAAAAAGAA AATTGCAAAG AACAGG 26

23 base pairs

nucleic acid

single

linear

119

CAGCAACATG TAATTCACCC ACG 23

23 base pairs

nucleic acid

single

linear

120

GAAGAGACTG GAATTGGGTT TGG 23

25 base pairs

nucleic acid

single

linear

121

ATAGAGTATC ATGGGATAAG ATAGG 25

24 base pairs

nucleic acid

single

linear

122

TTCTCCTTTG GAGATGTAGA TGAG 24

25 base pairs

nucleic acid

single

linear

123

TCTTCAGCTT CTTTACCACT CCCCA 25

23 base pairs

nucleic acid

single

linear

124

CATGGTGTTT GACAACAGGA TGG 23

26 base pairs

nucleic acid

single

linear

125

›Example 10 · 27 of 49

GTTAAATATG CATTAGAAGG AAATCG 26

23 base pairs

nucleic acid

single

linear

126

ATAAAACCAA ACGGGTCTGA AGC 23

26 base pairs

nucleic acid

single

linear

127

AAAAGAAGTA TTCAATAAAG ATCTGG 26

23 base pairs

nucleic acid

single

linear

128

AATTCCACTT TGTGCCAGGG ACT 23

23 base pairs

nucleic acid

single

linear

129

ACTTGGGATA CTGGAAATAG CCT 23

23 base pairs

nucleic acid

single

linear

130

TTTTTATCTT GATGGGGTGT GGG 23

24 base pairs

nucleic acid

single

linear

131

AAATTCAGCA CACATGTAAC AGCA 24

24 base pairs

nucleic acid

single

linear

132

CTGAAGTCAA ATAATGAAGT CCCA 24

25 base pairs

nucleic acid

single

linear

133

GTTTGCTTTC TCATATCTAA ACACA 25

23 base pairs

nucleic acid

single

linear

134

CTTGTGAGAG GCCTATAAAC TGG 23

22 base pairs

nucleic acid

single

linear

135

GGTAAACAGT GTAGGAGTCT GC 22

22 base pairs

nucleic acid

single

linear

136

GCTTGAAGGA TGAGGCTCTG AG 22

22 base pairs

nucleic acid

single

linear

137

TGTTCAGAAT GAGCACGATG GG 22

23 base pairs

nucleic acid

single

linear

138

CTTGTGAGAG GCCTATAAAC TGG 23

22 base pairs

nucleic acid

single

linear

139

GGTAAACAGT GTAGGAGTCT GC 22

25 base pairs

nucleic acid

single

linear

140

GCCATTTTCT CTTTAATTGG AAAGG 25

25 base pairs

nucleic acid

single

linear

141

ATCTTATTCA TCTTTCTGAG AATGG 25

23 base pairs

nucleic acid

single

linear

142

TGAAATAGCC CAACATCTGA CAG 23

25 base pairs

nucleic acid

single

linear

143

GATTAATTTG ACAGCTTGAT TAGGC 25

25 base pairs

nucleic acid

single

linear

144

TGAAATATAA ACTCAGACTC TTAGC 25

24 base pairs

nucleic acid

single

linear

145

GTACTGATTT GGAAAGACAT TCTC 24

22 base pairs

nucleic acid

single

linear

146

GATGTGACAG TGGAAGCTAT GG 22

24 base pairs

nucleic acid

single

linear

147

GGAAAAATGT GGTATCTGAA GCTC 24

23 base pairs

nucleic acid

single

linear

148

AAGTGAGCAA ATGTTGCTTC TGG 23

23 base pairs

nucleic acid

single

linear

149

TCATTAGGAA GCTGAACATC AGC 23

24 base pairs

nucleic acid

single

linear

150

GTTGGAGGAA ATTGATCCCA AGTC 24

24 base pairs

nucleic acid

single

linear

151

TGTTGCTTAT GGGTTTAACT TGTG 24

25 base pairs

nucleic acid

single

linear

152

TAAAGGATTA ATGCTGTTAA CAGTG 25

23 base pairs

nucleic acid

single

linear

153

TCACACTGAG CATTTACTAC CTG 23

24 base pairs

nucleic acid

single

linear

154

GCAAAGGAAA TGTAGCACAT AGAG 24

23 base pairs

nucleic acid

single

linear

155

AGGCTATAGG CATTTGAAAG AGG 23

21 base pairs

nucleic acid

single

linear

156

GTAGGCTCCC AGAAGACCCA G 21

23 base pairs

nucleic acid

single

linear

157

GAAAGGATGG GTGTGTATTC AGG 23

22 base pairs

nucleic acid

single

linear

158

ACAGGCCATA GTTTGCCAAC CC 22

25 base pairs

nucleic acid

single

linear

159

TGGTATTAGA ATTTCCCTTT CTTCC 25

26 base pairs

nucleic acid

single

linear

160

TGAAAGAGAA TATGGAAAGA GGCTTG 26

23 base pairs

nucleic acid

single

linear

161

CTTTATGAAG CCAATTTCTA CCC 23

22 base pairs

nucleic acid

single

linear

162

TCAAAATCAG TCGCCTCATC CC 22

23 base pairs

nucleic acid

single

linear

163

CAATGTATCA GTCAGGGTTC ACC 23

29 base pairs

nucleic acid

single

linear

164

GATATTGTTT TGTATTTACC CATGAAGAC 29

23 base pairs

nucleic acid

single

linear

165

TCCGCTGCTG TGCAGTTGTT TCC 23

25 base pairs

nucleic acid

single

linear

166

TCAGTAGATT TATAAGCAAT ATCAC 25

22 base pairs

nucleic acid

single

linear

167

CTGGCAAGGA TCAAACAGAG AG 22

23 base pairs

nucleic acid

single

linear

168

CTTTATGAAG CCAATTTCTA CCC 23

18 base pairs

nucleic acid

single

linear

169

TTCTCGGGGT AAAGTGTC 18

36 base pairs

nucleic acid

single

linear

170

TACCTCTCAG TTTTCTTTAA AGAAAGGTAT GTTGTT 36

36 base pairs

nucleic acid

single

linear

171

TAAACTCAAG GCATGTGTGA TATTAGGTAA GTGATT 36

36 base pairs

nucleic acid

single

linear

172

CTCACTTTAG CATGAGTCCA TGTCAGGTTG GTATCT 36

36 base pairs

nucleic acid

single

linear

173

AATGTTACAG TTTTTCCCAT AAAAAGGTAA AAGCAA 36

36 base pairs

nucleic acid

single

linear

174

TCATTTCTAG CTGAAATGAT GCTTATGTAC GTGCTT 36

36 base pairs

nucleic acid

single

linear

175

TTTTTTATAG GCTGGTTTAA ATAAAGGTAT GTTAAG 36

36 base pairs

nucleic acid

single

linear

176

TTCCCCCTAG AGGAAGAACC ACGGAGGTTA AATATT 36

36 base pairs

nucleic acid

single

linear

177

TTTTTTTTAG GGTTTCTACT ACTGAGGTAC TAAAAT 36

36 base pairs

nucleic acid

single

linear

178

TTTTTTAAAG CATTTATCTG CTTAAGGGTA TGTTTA 36

36 base pairs

nucleic acid

single

linear

179

TTTTTTAAAG CATTTATCTG CTTAAGGGTA TGTTTA 36

36 base pairs

nucleic acid

single

linear

180

AAACTTTCAG TCTTTAGATG ATAAGGGTAA GCACTG 36

36 base pairs

nucleic acid

single

linear

181

TTATTTCCAG ACTTTTTGTT TAAACCGTGA GTATAA 36

36 base pairs

nucleic acid

single

linear

182

CACCTTCAAG AGTTCAGTGG CAACTGGTAA GTTGTA 36

36 base pairs

nucleic acid

single

linear

183

TCATTTCAAG GATATGGACA GCTTAAGTAA GTCATG 36

36 base pairs

nucleic acid

single

linear

184

CTTCTTATAG AATGTCCAAT TAAATTGTGA GTAATT 36

36 base pairs

nucleic acid

single

linear

185

GTTTTTACAG AGGTAAATTG ATATTGGTAA GTGATA 36

36 base pairs

nucleic acid

single

linear

186

TTTTTTACAG GTATCACGTG CCAATGGTAA GCTTTG 36

36 base pairs

nucleic acid

single

linear

187

CATCATTCAG GTTCCAATAA AACAAGGTAA GGATTT 36

36 base pairs

nucleic acid

single

linear

188

TTTTCTTTAG TTCCCACTAA ATTCAGGTAT GAGGAT 36

36 base pairs

nucleic acid

single

linear

189

TTGTTCTCAG TGTGTCATTT AAATAGGTAA AAAAAA 36

36 base pairs

nucleic acid

single

linear

190

TAATCGACAG GCACCTTCAG GAGACAGTAT GTATTA 36

36 base pairs

nucleic acid

single

linear

191

TCTTGGGTAG AATCATCTAG GTCCAGGTAA AGATTT 36

36 base pairs

nucleic acid

single

linear

192

TTTTATTTAG ATTGGATCGA GGATCTGTAA GTATAT 36

36 base pairs

nucleic acid

single

linear

193

CTAATTTCAG AATTCTCACG AAAAAGGTAA ACAGTG 36

36 base pairs

nucleic acid

single

linear

194

CTTTTAATAG GGTAGAAACT GCCTAGGTTC ATTTTT 36

36 base pairs

nucleic acid

single

linear

195

TATTTTTTAG TTCGAAAAAG AAGAAGGTTT GTTTTA 36

36 base pairs

nucleic acid

single

linear

196

TTAAATGCAG TCTAACTTAA AAAAAGGTAC AGAGTT 36

36 base pairs

nucleic acid

single

linear

197

AATATTTTAG TATCATGGAG ACTCAGGTAA GGCTTT 36

36 base pairs

nucleic acid

single

linear

198

TTTTGTTCAG ATTGTGTTAA AATGAGGTAA ACTATC 36

36 base pairs

nucleic acid

single

linear

199

TTAAACACAG ACCAACTAGT GTTCAGGTAA AATACT 36

36 base pairs

nucleic acid

single

linear

200

AATTCTGTAG ACAGACCTTG CCTTTGGTAA GTGTGA 36

36 base pairs

nucleic acid

single

linear

201

CTTTCTCTAG AAGAGCATCA ACTCAGGTGA GAGGCA 36

36 base pairs

nucleic acid

single

linear

202

TCGTTTACAG ATATGAGTAT ACTGAGGTAT TAATTA 36

18 base pairs

nucleic acid

single

linear

203

TTTCCTACAG ACTTCATC 18

13 amino acids

amino acid

single

linear

204

Phe Pro Gly Ser Glu Glu Ile Cys Ser Ser Ser Lys Arg

1 5 10

GTATAAAGTT AGTAAATGTG AGGCCTCTCT CGATGCCTGG GTCCTGGGCT TTGGTTCTCA 60

GTCCTCCATA AATCATCCTG CTGGAGGAGA AGACCCTTAG ATCTGGCTCT TCTCAGGGG 120

›Example 10 · 28 of 49

ATTTTAAAGA CAAATGAAAA TAAA ATG GAA ACC ACT TCA CTA CAG CGG AAA 171

Met Glu Thr Thr Ser Leu Gln Arg Lys

1 5

TTT CCA GAA TGG ATG TCT ATG CAG AGT CAA AGA TGT GCT ACA GAA GAA 219

Phe Pro Glu Trp Met Ser Met Gln Ser Gln Arg Cys Ala Thr Glu Glu

10 15 20 25

AAG GCC TGC GTT CAG AAG AGT GTT CTT GAA GAT AAC CTC CCA TTC TTA 267

Lys Ala Cys Val Gln Lys Ser Val Leu Glu Asp Asn Leu Pro Phe Leu

30 35 40

GAA TTC CCT GGA TCC ATT GTT TAC AGT TAT GAA GCT AGT GAT TGC TCC 315

Glu Phe Pro Gly Ser Ile Val Tyr Ser Tyr Glu Ala Ser Asp Cys Ser

45 50 55

TTC CTG TCT GAA GAC ATT AGC ATG CGT CTG TCT GAT GGC GAT GTG GTG 363

Phe Leu Ser Glu Asp Ile Ser Met Arg Leu Ser Asp Gly Asp Val Val

60 65 70

GGA TTT GAC ATG GAA TGG CCG CCC ATA TAC AAG CCA GGG AAA AGA AGC 411

Gly Phe Asp Met Glu Trp Pro Pro Ile Tyr Lys Pro Gly Lys Arg Ser

75 80 85

AGA GTC GCA GTG ATC CAG TTG TGT GTG TCT GAG AGC AAA TGT TAC TTG 459

Arg Val Ala Val Ile Gln Leu Cys Val Ser Glu Ser Lys Cys Tyr Leu

90 95 100 105

TTT CAC ATT TCT TCC ATG TCA GTT TTC CCC CAG GGA TTA AAA ATG TTA 507

Phe His Ile Ser Ser Met Ser Val Phe Pro Gln Gly Leu Lys Met Leu

110 115 120

CTA GAA AAC AAA TCA ATT AAG AAG GCA GGG GTT GGG ATT GAA GGG GAC 555

Leu Glu Asn Lys Ser Ile Lys Lys Ala Gly Val Gly Ile Glu Gly Asp

125 130 135

CAG TGG AAA CTT CTG CGT GAT TTT GAC GTC AAG TTG GAG AGT TTT GTG 603

Gln Trp Lys Leu Leu Arg Asp Phe Asp Val Lys Leu Glu Ser Phe Val

140 145 150

GAG CTG ACG GAT GTT GCC AAT GAA AAG TTG AAG TGC GCA GAG ACC TGG 651

Glu Leu Thr Asp Val Ala Asn Glu Lys Leu Lys Cys Ala Glu Thr Trp

155 160 165

AGC CTC AAT GGT CTG GTT AAA CAC GTC TTA GGG AAA CAA CTT TTG AAA 699

Ser Leu Asn Gly Leu Val Lys His Val Leu Gly Lys Gln Leu Leu Lys

170 175 180 185

GAC AAG TCC ATC CGC TGC AGC AAT TGG AGT AAT TTC CCC CTC ACT GAG 747

Asp Lys Ser Ile Arg Cys Ser Asn Trp Ser Asn Phe Pro Leu Thr Glu

190 195 200

GAC CAG AAA CTG TAT GCA GCC ACT GAT GCT TAT GCT GGT CTT ATC ATC 795

Asp Gln Lys Leu Tyr Ala Ala Thr Asp Ala Tyr Ala Gly Leu Ile Ile

205 210 215

TAT CAA AAA TTA GGA AAT TTG GGT GAT ACT GCG CAA GTG TTT GCT CTA 843

Tyr Gln Lys Leu Gly Asn Leu Gly Asp Thr Ala Gln Val Phe Ala Leu

220 225 230

AAT AAA GCA GAG GAA AAC CTA CCT CTG GAG ATG AAG AAA CAG TTG AAT 891

Asn Lys Ala Glu Glu Asn Leu Pro Leu Glu Met Lys Lys Gln Leu Asn

235 240 245

TCA ATC TCC GAA GAA ATG AGG GAC CTA GCC AAT CGT TTT CCT GTC ACT 939

Ser Ile Ser Glu Glu Met Arg Asp Leu Ala Asn Arg Phe Pro Val Thr

250 255 260 265

TGC AGA AAT TTG GAA ACT CTC CAG AGG GTT CCT GTA ATA TTG AAG AGT 987

Cys Arg Asn Leu Glu Thr Leu Gln Arg Val Pro Val Ile Leu Lys Ser

270 275 280

ATT TCA GAA AAT CTC TGT TCA TTG AGA AAA GTG ATC TGT GGT CCT ACA 1035

Ile Ser Glu Asn Leu Cys Ser Leu Arg Lys Val Ile Cys Gly Pro Thr

285 290 295

AAC ACT GAG ACT AGA CTG AAG CCG GGC AGT AGT TTT AAT TTA CTG TCA 1083

Asn Thr Glu Thr Arg Leu Lys Pro Gly Ser Ser Phe Asn Leu Leu Ser

300 305 310

TCA GAG GAT TCA GCT GCT GCT GGA GAA AAA GAG AAA CAG ATT GGA AAA 1131

Ser Glu Asp Ser Ala Ala Ala Gly Glu Lys Glu Lys Gln Ile Gly Lys

315 320 325

CAT AGT ACT TTT GCT AAA ATT AAA GAA GAA CCA TGG GAC CCA GAA CTT 1179

His Ser Thr Phe Ala Lys Ile Lys Glu Glu Pro Trp Asp Pro Glu Leu

330 335 340 345

GAC AGT TTA GTG AAG CAA GAG GAG GTT GAT GTA TTT AGA AAT CAA GTG 1227

Asp Ser Leu Val Lys Gln Glu Glu Val Asp Val Phe Arg Asn Gln Val

350 355 360

AAG CAA GAA AAA GGT GAA TCT GAA AAT GAA ATA GAA GAC AAT CTG TTG 1275

Lys Gln Glu Lys Gly Glu Ser Glu Asn Glu Ile Glu Asp Asn Leu Leu

365 370 375

AGA GAA GAT ATG GAA AGA ACT TGT GTG ATT CCT AGT ATT TCA GAA AAT 1323

Arg Glu Asp Met Glu Arg Thr Cys Val Ile Pro Ser Ile Ser Glu Asn

380 385 390

GAA CTC CAA GAT TTG GAA CAG CAA GCT AAA GAA GAA AAA TAT AAT GAT 1371

Glu Leu Gln Asp Leu Glu Gln Gln Ala Lys Glu Glu Lys Tyr Asn Asp

395 400 405

GTT TCT CAC CAA CTT TCT GAG CAT TTA TCT CCC AAT GAT GAT GAG AAT 1419

Val Ser His Gln Leu Ser Glu His Leu Ser Pro Asn Asp Asp Glu Asn

410 415 420 425

GAC TCC TCC TAT ATA ATT GAA AGT GAT GAA GAT TTG GAA ATG GAG ATG 1467

Asp Ser Ser Tyr Ile Ile Glu Ser Asp Glu Asp Leu Glu Met Glu Met

430 435 440

CTG AAG TCT TTA GAA AAC CTA AAT AGT GAC GTG GTG GAA CCC ACT CAC 1515

Leu Lys Ser Leu Glu Asn Leu Asn Ser Asp Val Val Glu Pro Thr His

445 450 455

TCT ACA TGG TTG GAA ATG GGA ACC AAT GGG CGT CTT CCT CCT GAG GAG 1563

Ser Thr Trp Leu Glu Met Gly Thr Asn Gly Arg Leu Pro Pro Glu Glu

460 465 470

GAA GAT GGA CAC GGA AAT GAA GCC ATC AAA GAG GAG CAG GAA GAA GAG 1611

Glu Asp Gly His Gly Asn Glu Ala Ile Lys Glu Glu Gln Glu Glu Glu

475 480 485

GAC CAT TTA TTG CCG GAA CCC AAC GCA AAG CAA ATT AAT TGC CTC AAG 1659

Asp His Leu Leu Pro Glu Pro Asn Ala Lys Gln Ile Asn Cys Leu Lys

490 495 500 505

ACC TAT TTC GGA CAC AGC AGT TTT AAA CCG GTT CAG TGG AAA GTC ATC 1707

Thr Tyr Phe Gly His Ser Ser Phe Lys Pro Val Gln Trp Lys Val Ile

510 515 520

CAT TCT GTA TTA GAA GAG AGA AGA GAT AAT GTT GTT GTC ATG GCA ACT 1755

His Ser Val Leu Glu Glu Arg Arg Asp Asn Val Val Val Met Ala Thr

525 530 535

GGA TAT GGG AAG AGT CTG TGC TTC CAG TAT CCG CCT GTT TAT ACA GGC 1803

Gly Tyr Gly Lys Ser Leu Cys Phe Gln Tyr Pro Pro Val Tyr Thr Gly

540 545 550

AAG ATT GGC ATT GTC ATT TCA CCT CTC ATT TCC TTA ATG GAA GAC CAA 1851

Lys Ile Gly Ile Val Ile Ser Pro Leu Ile Ser Leu Met Glu Asp Gln

555 560 565

GTC CTC CAG CTT GAG CTG TCC AAT GTT CCA GCC TGT TTA CTT GGA TCT 1899

Val Leu Gln Leu Glu Leu Ser Asn Val Pro Ala Cys Leu Leu Gly Ser

570 575 580 585

GCA CAG TCA AAA AAT ATT CTA GGA GAT GTT AAA TTA GGC AAA TAT AGG 1947

Ala Gln Ser Lys Asn Ile Leu Gly Asp Val Lys Leu Gly Lys Tyr Arg

590 595 600

GTC ATC TAC ATA ACT CCA GAG TTC TGT TCT GGT AAC TTG GAT CTA CTC 1995

Val Ile Tyr Ile Thr Pro Glu Phe Cys Ser Gly Asn Leu Asp Leu Leu

605 610 615

CAG CAA CTT GAC TCT AGT ATT GGC ATC ACT CTC ATT GCT GTG GAT GAG 2043

Gln Gln Leu Asp Ser Ser Ile Gly Ile Thr Leu Ile Ala Val Asp Glu

620 625 630

GCT CAC TGC ATT TCA GAG TGG GGC CAT GAT TTC AGA AGT TCA TTC AGG 2091

Ala His Cys Ile Ser Glu Trp Gly His Asp Phe Arg Ser Ser Phe Arg

635 640 645

ATG CTG GGC TCT CTT AAA ACA GCG CTC CCA TTG GTT CCA GTC ATT GCA 2139

Met Leu Gly Ser Leu Lys Thr Ala Leu Pro Leu Val Pro Val Ile Ala

650 655 660 665

CTC TCC GCT ACT GCA AGC TCT TCC ATC CGG GAA GAC ATT ATA AGC TGC 2187

Leu Ser Ala Thr Ala Ser Ser Ser Ile Arg Glu Asp Ile Ile Ser Cys

›Example 10 · 29 of 49

670 675 680

TTA AAC CTG AAA GAC CCT CAG ATC ACC TGC ACT GGA TTT GAT CGG CCA 2235

Leu Asn Leu Lys Asp Pro Gln Ile Thr Cys Thr Gly Phe Asp Arg Pro

685 690 695

AAT CTG TAC TTA GAA GTT GGA CGG AAA ACA GGG AAC ATC CTT CAG GAT 2283

Asn Leu Tyr Leu Glu Val Gly Arg Lys Thr Gly Asn Ile Leu Gln Asp

700 705 710

CTA AAG CCG TTT CTC GTC CGA AAG GCA AGT TCT GCC TGG GAA TTT GAA 2331

Leu Lys Pro Phe Leu Val Arg Lys Ala Ser Ser Ala Trp Glu Phe Glu

715 720 725

GGT CCA ACC ATC ATC TAT TGT CCT TCG AGA AAA ATG ACA GAA CAA GTT 2379

Gly Pro Thr Ile Ile Tyr Cys Pro Ser Arg Lys Met Thr Glu Gln Val

730 735 740 745

ACT GCT GAA CTT GGG AAA CTG AAC TTA GCC TGC AGA ACA TAC CAC GCT 2427

Thr Ala Glu Leu Gly Lys Leu Asn Leu Ala Cys Arg Thr Tyr His Ala

750 755 760

GGC ATG AAA ATT AGC GAA AGG AAG GAC GTT CAT CAT AGG TTC CTG AGA 2475

Gly Met Lys Ile Ser Glu Arg Lys Asp Val His His Arg Phe Leu Arg

765 770 775

GAT GAA ATT CAG TGT GTT GTA GCT ACT GTA GCT TTT GGA ATG GGC ATT 2523

Asp Glu Ile Gln Cys Val Val Ala Thr Val Ala Phe Gly Met Gly Ile

780 785 790

AAT AAA GCT GAC ATT CGC AAA GTT ATT CAT TAT GGT GCG CCT AAG GAA 2571

Asn Lys Ala Asp Ile Arg Lys Val Ile His Tyr Gly Ala Pro Lys Glu

795 800 805

ATG GAA TCC TAT TAC CAG GAA ATT GGT AGA GCT GGC CGG GAT GGA CTT 2619

Met Glu Ser Tyr Tyr Gln Glu Ile Gly Arg Ala Gly Arg Asp Gly Leu

810 815 820 825

CAG AGT TCC TGT CAC TTG CTC TGG GCT CCA GCA GAC TTT AAC ACA TCC 2667

Gln Ser Ser Cys His Leu Leu Trp Ala Pro Ala Asp Phe Asn Thr Ser

830 835 840

AGG AAT CTC CTT ATT GAG ATT CAC GAT GAA AAG TTC CGG TTA TAT AAA 2715

Arg Asn Leu Leu Ile Glu Ile His Asp Glu Lys Phe Arg Leu Tyr Lys

845 850 855

TTA AAG ATG ATG GTA AAG ATG GAA AAA TAC CTT CAC TCC AGT CAG TGT 2763

Leu Lys Met Met Val Lys Met Glu Lys Tyr Leu His Ser Ser Gln Cys

860 865 870

AGG CGA CGA ATC ATC TTG TCC CAT TTT GAG GAC AAA TGT CTG CAG AAG 2811

Arg Arg Arg Ile Ile Leu Ser His Phe Glu Asp Lys Cys Leu Gln Lys

875 880 885

GCC TCC TTG GAC ATT ATG GGA ACT GAA AAA TGC TGT GAT AAT TGC AGG 2859

Ala Ser Leu Asp Ile Met Gly Thr Glu Lys Cys Cys Asp Asn Cys Arg

890 895 900 905

CCC AGG CTG AAT CAT TGC ATT ACT GCT AAC AAC TCA GAG GAC GCA TCC 2907

Pro Arg Leu Asn His Cys Ile Thr Ala Asn Asn Ser Glu Asp Ala Ser

910 915 920

CAA GAC TTT GGG CCA CAA GCA TTC CAG CTA CTG TCT GCT GTG GAC ATC 2955

Gln Asp Phe Gly Pro Gln Ala Phe Gln Leu Leu Ser Ala Val Asp Ile

925 930 935

CTG CAG GAG AAA TTT GGA ATT GGG ATT CCG ATC TTA TTT CTC CGA GGA 3003

Leu Gln Glu Lys Phe Gly Ile Gly Ile Pro Ile Leu Phe Leu Arg Gly

940 945 950

TCT AAT TCT CAG CGT CTT CCT GAT AAA TAT CGG GGT CAC AGG CTC TTT 3051

Ser Asn Ser Gln Arg Leu Pro Asp Lys Tyr Arg Gly His Arg Leu Phe

955 960 965

GGT GCT GGA AAG GAG CAA GCA GAA AGT TGG TGG AAG ACC CTT TCT CAC 3099

Gly Ala Gly Lys Glu Gln Ala Glu Ser Trp Trp Lys Thr Leu Ser His

970 975 980 985

CAT CTC ATA GCT GAA GGA TTC TTG GTA GAA GTT CCC AAG GAA AAC AAA 3147

His Leu Ile Ala Glu Gly Phe Leu Val Glu Val Pro Lys Glu Asn Lys

990 995 1000

TAT ATA AAG ACA TGT TCC CTC ACA AAA AAG GGT AGA AAG TGG CTT GGA 3195

Tyr Ile Lys Thr Cys Ser Leu Thr Lys Lys Gly Arg Lys Trp Leu Gly

1005 1010 1015

GAA GCC AGT TCG CAG TCT CCT CCG AGC CTT CTC CTT CAA GCT AAT GAA 3243

Glu Ala Ser Ser Gln Ser Pro Pro Ser Leu Leu Leu Gln Ala Asn Glu

1020 1025 1030

GAG ATG TTT CCA AGG AAA GTT CTG CTA CCA AGT TCT AAT CCT GTA TCT 3291

Glu Met Phe Pro Arg Lys Val Leu Leu Pro Ser Ser Asn Pro Val Ser

1035 1040 1045

CCA GAA ACG ACG CAA CAT TCC TCT AAT CAA AAC CCA GCT GGA TTA ACT 3339

Pro Glu Thr Thr Gln His Ser Ser Asn Gln Asn Pro Ala Gly Leu Thr

1050 1055 1060 1065

ACC AAG CAG TCT AAT TTG GAG AGA ACG CAT TCT TAC AAA GTG CCT GAG 3387

Thr Lys Gln Ser Asn Leu Glu Arg Thr His Ser Tyr Lys Val Pro Glu

1070 1075 1080

AAA GTT TCT TCT GGG ACT AAC ATT CCT AAA AAA AGT GCC GTG ATG CCG 3435

Lys Val Ser Ser Gly Thr Asn Ile Pro Lys Lys Ser Ala Val Met Pro

1085 1090 1095

TCA CCA GGA ACA TCT TCC AGC CCC TTA GAA CCT GCC ATC TCA GCC CAA 3483

Ser Pro Gly Thr Ser Ser Ser Pro Leu Glu Pro Ala Ile Ser Ala Gln

1100 1105 1110

GAG CTG GAC GCT CGG ACT GGG CTA TAT GCC AGG CTG GTG GAA GCA AGG 3531

Glu Leu Asp Ala Arg Thr Gly Leu Tyr Ala Arg Leu Val Glu Ala Arg

1115 1120 1125

CAG AAA CAC GCT AAT AAG ATG GAT GTA CCT CCA GCT ATT TTA GCA ACA 3579

Gln Lys His Ala Asn Lys Met Asp Val Pro Pro Ala Ile Leu Ala Thr

1130 1135 1140 1145

AAC AAG GTT CTG CTG GAC ATG GCT AAA ATG AGA CCG ACT ACT GTT GAA 3627

Asn Lys Val Leu Leu Asp Met Ala Lys Met Arg Pro Thr Thr Val Glu

1150 1155 1160

AAC ATG AAA CAG ATC GAC GGT GTC TCT GAA GGC AAA GCT GCT CTG TTG 3675

Asn Met Lys Gln Ile Asp Gly Val Ser Glu Gly Lys Ala Ala Leu Leu

1165 1170 1175

GCC CCT CTG TTG GAA GTC ATC AAA CAT TTC TGT CAA GTA ACT AGT GTT 3723

Ala Pro Leu Leu Glu Val Ile Lys His Phe Cys Gln Val Thr Ser Val

1180 1185 1190

CAG ACA GAC CTC CTT TCC AGT GCC AAA CCT CAC AAG GAA CAG GAG AAA 3771

Gln Thr Asp Leu Leu Ser Ser Ala Lys Pro His Lys Glu Gln Glu Lys

1195 1200 1205

AGT CAG GAG ATG GAA AAG AAA GAC TGC TCA CTC CCC CAG TCT GTG GCC 3819

Ser Gln Glu Met Glu Lys Lys Asp Cys Ser Leu Pro Gln Ser Val Ala

1210 1215 1220 1225

GTC ACA TAC ACT CTA TTC CAG GAA AAG AAA ATG CCC TTA CAC AGC ATA 3867

Val Thr Tyr Thr Leu Phe Gln Glu Lys Lys Met Pro Leu His Ser Ile

1230 1235 1240

GCT GAG AAC AGG CTC CTG CCT CTC ACA GCA GCC GGC ATG CAC TTA GCC 3915

Ala Glu Asn Arg Leu Leu Pro Leu Thr Ala Ala Gly Met His Leu Ala

1245 1250 1255

CAG GCG GTG AAA GCC GGC TAC CCC CTG GAT ATG GAG CGA GCT GGC CTG 3963

Gln Ala Val Lys Ala Gly Tyr Pro Leu Asp Met Glu Arg Ala Gly Leu

1260 1265 1270

ACC CCA GAG ACT TGG AAG ATT ATT ATG GAT GTC ATC CGA AAC CCT CCC 4011

Thr Pro Glu Thr Trp Lys Ile Ile Met Asp Val Ile Arg Asn Pro Pro

1275 1280 1285

ATC AAC TCA GAT ATG TAT AAA GTT AAA CTC ATC AGA ATG TTA GTT CCT 4059

Ile Asn Ser Asp Met Tyr Lys Val Lys Leu Ile Arg Met Leu Val Pro

1290 1295 1300 1305

GAA AAC TTA GAC ACG TAC CTC ATC CAC ATG GCG ATT GAG ATT CTT CAG 4107

Glu Asn Leu Asp Thr Tyr Leu Ile His Met Ala Ile Glu Ile Leu Gln

1310 1315 1320

AGT GGT TCC GAC AGC AGA ACC CAG CCT CCT TGT GAT TCC AGC AGG AAG 4155

Ser Gly Ser Asp Ser Arg Thr Gln Pro Pro Cys Asp Ser Ser Arg Lys

1325 1330 1335

AGG CGT TTC CCC AGC TCT GCA GAG AGT TGT GAG AGC TGT AAG GAG AGC 4203

›Example 10 · 30 of 49

Arg Arg Phe Pro Ser Ser Ala Glu Ser Cys Glu Ser Cys Lys Glu Ser

1340 1345 1350

AAA GAG GCG GTC ACC GAG ACC AAG GCA TCA TCT TCA GAG TCA AAG AGA 4251

Lys Glu Ala Val Thr Glu Thr Lys Ala Ser Ser Ser Glu Ser Lys Arg

1355 1360 1365

AAA TTA CCC GAG TGG TTT GCC AAA GGA AAT GTG CCC TCA GCT GAT ACC 4299

Lys Leu Pro Glu Trp Phe Ala Lys Gly Asn Val Pro Ser Ala Asp Thr

1370 1375 1380 1385

GGC AGC TCA TCA TCA ATG GCC AAG ACC AAA AAG AAA GGT CTC TTT AGT 4347

Gly Ser Ser Ser Ser Met Ala Lys Thr Lys Lys Lys Gly Leu Phe Ser

1390 1395 1400

TAANATGACN ACGATGGAAC AGTTTGTGTG TCCTACATCT TCATTCCTAT AAAGAATGAA 4407

NAGAAATATT TTAACCTCAA AATTATTTAA AGTCCAAAGT GAAGCTCACC TAAACGTCGA 4467

GCCATAGAGT CTTTAATTGN CCGTTGGCAG TTGAGCTACA GTATCTGAAC CTTCTGAGAC 4527

CCGGAGTGCA GCATAGACTG TGAAGTCGGC TTCCTTTCCG ATTGCCTTCC GAACCCGTTGT 4587

CACTGTCAGG TTGCAGTCTT TCTCTTCTTG CAGCAGTGTG TGTTGGAAAT GGAGGCTGTG 4647

TCGCTTTGAC ATATAGAACA GATCAGTANT TGCATAGGGA CAGATATGAA GATNCAGCCG 4707

GTCTTTGCTT TCTTATGCAG ATGCCTGTAT GACAGTATCA GTGCACCAGC CCAGCCAGGG 4767

AGACATCAGC TTCCATTTAA AAAGG 4792

1401 amino acids

amino acid

linear

protein

206

Met Glu Thr Thr Ser Leu Gln Arg Lys Phe Pro Glu Trp Met Ser Met

1 5 10 15

Gln Ser Gln Arg Cys Ala Thr Glu Glu Lys Ala Cys Val Gln Lys Ser

20 25 30

Val Leu Glu Asp Asn Leu Pro Phe Leu Glu Phe Pro Gly Ser Ile Val

35 40 45

Tyr Ser Tyr Glu Ala Ser Asp Cys Ser Phe Leu Ser Glu Asp Ile Ser

50 55 60

Met Arg Leu Ser Asp Gly Asp Val Val Gly Phe Asp Met Glu Trp Pro

65 70 75 80

Pro Ile Tyr Lys Pro Gly Lys Arg Ser Arg Val Ala Val Ile Gln Leu

85 90 95

Cys Val Ser Glu Ser Lys Cys Tyr Leu Phe His Ile Ser Ser Met Ser

100 105 110

Val Phe Pro Gln Gly Leu Lys Met Leu Leu Glu Asn Lys Ser Ile Lys

115 120 125

Lys Ala Gly Val Gly Ile Glu Gly Asp Gln Trp Lys Leu Leu Arg Asp

130 135 140

Phe Asp Val Lys Leu Glu Ser Phe Val Glu Leu Thr Asp Val Ala Asn

145 150 155 160

Glu Lys Leu Lys Cys Ala Glu Thr Trp Ser Leu Asn Gly Leu Val Lys

165 170 175

His Val Leu Gly Lys Gln Leu Leu Lys Asp Lys Ser Ile Arg Cys Ser

180 185 190

Asn Trp Ser Asn Phe Pro Leu Thr Glu Asp Gln Lys Leu Tyr Ala Ala

195 200 205

Thr Asp Ala Tyr Ala Gly Leu Ile Ile Tyr Gln Lys Leu Gly Asn Leu

210 215 220

Gly Asp Thr Ala Gln Val Phe Ala Leu Asn Lys Ala Glu Glu Asn Leu

225 230 235 240

Pro Leu Glu Met Lys Lys Gln Leu Asn Ser Ile Ser Glu Glu Met Arg

245 250 255

Asp Leu Ala Asn Arg Phe Pro Val Thr Cys Arg Asn Leu Glu Thr Leu

260 265 270

Gln Arg Val Pro Val Ile Leu Lys Ser Ile Ser Glu Asn Leu Cys Ser

275 280 285

Leu Arg Lys Val Ile Cys Gly Pro Thr Asn Thr Glu Thr Arg Leu Lys

290 295 300

Pro Gly Ser Ser Phe Asn Leu Leu Ser Ser Glu Asp Ser Ala Ala Ala

305 310 315 320

Gly Glu Lys Glu Lys Gln Ile Gly Lys His Ser Thr Phe Ala Lys Ile

325 330 335

Lys Glu Glu Pro Trp Asp Pro Glu Leu Asp Ser Leu Val Lys Gln Glu

340 345 350

Glu Val Asp Val Phe Arg Asn Gln Val Lys Gln Glu Lys Gly Glu Ser

355 360 365

Glu Asn Glu Ile Glu Asp Asn Leu Leu Arg Glu Asp Met Glu Arg Thr

370 375 380

Cys Val Ile Pro Ser Ile Ser Glu Asn Glu Leu Gln Asp Leu Glu Gln

385 390 395 400

Gln Ala Lys Glu Glu Lys Tyr Asn Asp Val Ser His Gln Leu Ser Glu

405 410 415

His Leu Ser Pro Asn Asp Asp Glu Asn Asp Ser Ser Tyr Ile Ile Glu

420 425 430

Ser Asp Glu Asp Leu Glu Met Glu Met Leu Lys Ser Leu Glu Asn Leu

435 440 445

Asn Ser Asp Val Val Glu Pro Thr His Ser Thr Trp Leu Glu Met Gly

450 455 460

Thr Asn Gly Arg Leu Pro Pro Glu Glu Glu Asp Gly His Gly Asn Glu

465 470 475 480

Ala Ile Lys Glu Glu Gln Glu Glu Glu Asp His Leu Leu Pro Glu Pro

485 490 495

Asn Ala Lys Gln Ile Asn Cys Leu Lys Thr Tyr Phe Gly His Ser Ser

500 505 510

Phe Lys Pro Val Gln Trp Lys Val Ile His Ser Val Leu Glu Glu Arg

515 520 525

Arg Asp Asn Val Val Val Met Ala Thr Gly Tyr Gly Lys Ser Leu Cys

530 535 540

Phe Gln Tyr Pro Pro Val Tyr Thr Gly Lys Ile Gly Ile Val Ile Ser

545 550 555 560

Pro Leu Ile Ser Leu Met Glu Asp Gln Val Leu Gln Leu Glu Leu Ser

565 570 575

Asn Val Pro Ala Cys Leu Leu Gly Ser Ala Gln Ser Lys Asn Ile Leu

580 585 590

Gly Asp Val Lys Leu Gly Lys Tyr Arg Val Ile Tyr Ile Thr Pro Glu

595 600 605

Phe Cys Ser Gly Asn Leu Asp Leu Leu Gln Gln Leu Asp Ser Ser Ile

610 615 620

Gly Ile Thr Leu Ile Ala Val Asp Glu Ala His Cys Ile Ser Glu Trp

625 630 635 640

Gly His Asp Phe Arg Ser Ser Phe Arg Met Leu Gly Ser Leu Lys Thr

645 650 655

Ala Leu Pro Leu Val Pro Val Ile Ala Leu Ser Ala Thr Ala Ser Ser

660 665 670

Ser Ile Arg Glu Asp Ile Ile Ser Cys Leu Asn Leu Lys Asp Pro Gln

675 680 685

Ile Thr Cys Thr Gly Phe Asp Arg Pro Asn Leu Tyr Leu Glu Val Gly

690 695 700

Arg Lys Thr Gly Asn Ile Leu Gln Asp Leu Lys Pro Phe Leu Val Arg

705 710 715 720

Lys Ala Ser Ser Ala Trp Glu Phe Glu Gly Pro Thr Ile Ile Tyr Cys

725 730 735

Pro Ser Arg Lys Met Thr Glu Gln Val Thr Ala Glu Leu Gly Lys Leu

740 745 750

Asn Leu Ala Cys Arg Thr Tyr His Ala Gly Met Lys Ile Ser Glu Arg

755 760 765

Lys Asp Val His His Arg Phe Leu Arg Asp Glu Ile Gln Cys Val Val

770 775 780

Ala Thr Val Ala Phe Gly Met Gly Ile Asn Lys Ala Asp Ile Arg Lys

785 790 795 800

Val Ile His Tyr Gly Ala Pro Lys Glu Met Glu Ser Tyr Tyr Gln Glu

805 810 815

Ile Gly Arg Ala Gly Arg Asp Gly Leu Gln Ser Ser Cys His Leu Leu

820 825 830

Trp Ala Pro Ala Asp Phe Asn Thr Ser Arg Asn Leu Leu Ile Glu Ile

835 840 845

His Asp Glu Lys Phe Arg Leu Tyr Lys Leu Lys Met Met Val Lys Met

850 855 860

Glu Lys Tyr Leu His Ser Ser Gln Cys Arg Arg Arg Ile Ile Leu Ser

865 870 875 880

His Phe Glu Asp Lys Cys Leu Gln Lys Ala Ser Leu Asp Ile Met Gly

885 890 895

Thr Glu Lys Cys Cys Asp Asn Cys Arg Pro Arg Leu Asn His Cys Ile

900 905 910

Thr Ala Asn Asn Ser Glu Asp Ala Ser Gln Asp Phe Gly Pro Gln Ala

915 920 925

Phe Gln Leu Leu Ser Ala Val Asp Ile Leu Gln Glu Lys Phe Gly Ile

930 935 940

Gly Ile Pro Ile Leu Phe Leu Arg Gly Ser Asn Ser Gln Arg Leu Pro

945 950 955 960

Asp Lys Tyr Arg Gly His Arg Leu Phe Gly Ala Gly Lys Glu Gln Ala

965 970 975

Glu Ser Trp Trp Lys Thr Leu Ser His His Leu Ile Ala Glu Gly Phe

980 985 990

Leu Val Glu Val Pro Lys Glu Asn Lys Tyr Ile Lys Thr Cys Ser Leu

995 1000 1005

Thr Lys Lys Gly Arg Lys Trp Leu Gly Glu Ala Ser Ser Gln Ser Pro

1010 1015 1020

Pro Ser Leu Leu Leu Gln Ala Asn Glu Glu Met Phe Pro Arg Lys Val

1025 1030 1035 1040

Leu Leu Pro Ser Ser Asn Pro Val Ser Pro Glu Thr Thr Gln His Ser

1045 1050 1055

›Example 10 · 31 of 49

Ser Asn Gln Asn Pro Ala Gly Leu Thr Thr Lys Gln Ser Asn Leu Glu

1060 1065 1070

Arg Thr His Ser Tyr Lys Val Pro Glu Lys Val Ser Ser Gly Thr Asn

1075 1080 1085

Ile Pro Lys Lys Ser Ala Val Met Pro Ser Pro Gly Thr Ser Ser Ser

1090 1095 1100

Pro Leu Glu Pro Ala Ile Ser Ala Gln Glu Leu Asp Ala Arg Thr Gly

1105 1110 1115 1120

Leu Tyr Ala Arg Leu Val Glu Ala Arg Gln Lys His Ala Asn Lys Met

1125 1130 1135

Asp Val Pro Pro Ala Ile Leu Ala Thr Asn Lys Val Leu Leu Asp Met

1140 1145 1150

Ala Lys Met Arg Pro Thr Thr Val Glu Asn Met Lys Gln Ile Asp Gly

1155 1160 1165

Val Ser Glu Gly Lys Ala Ala Leu Leu Ala Pro Leu Leu Glu Val Ile

1170 1175 1180

Lys His Phe Cys Gln Val Thr Ser Val Gln Thr Asp Leu Leu Ser Ser

1185 1190 1195 1200

Ala Lys Pro His Lys Glu Gln Glu Lys Ser Gln Glu Met Glu Lys Lys

1205 1210 1215

Asp Cys Ser Leu Pro Gln Ser Val Ala Val Thr Tyr Thr Leu Phe Gln

1220 1225 1230

Glu Lys Lys Met Pro Leu His Ser Ile Ala Glu Asn Arg Leu Leu Pro

1235 1240 1245

Leu Thr Ala Ala Gly Met His Leu Ala Gln Ala Val Lys Ala Gly Tyr

1250 1255 1260

Pro Leu Asp Met Glu Arg Ala Gly Leu Thr Pro Glu Thr Trp Lys Ile

1265 1270 1275 1280

Ile Met Asp Val Ile Arg Asn Pro Pro Ile Asn Ser Asp Met Tyr Lys

1285 1290 1295

Val Lys Leu Ile Arg Met Leu Val Pro Glu Asn Leu Asp Thr Tyr Leu

1300 1305 1310

Ile His Met Ala Ile Glu Ile Leu Gln Ser Gly Ser Asp Ser Arg Thr

1315 1320 1325

Gln Pro Pro Cys Asp Ser Ser Arg Lys Arg Arg Phe Pro Ser Ser Ala

1330 1335 1340

Glu Ser Cys Glu Ser Cys Lys Glu Ser Lys Glu Ala Val Thr Glu Thr

1345 1350 1355 1360

Lys Ala Ser Ser Ser Glu Ser Lys Arg Lys Leu Pro Glu Trp Phe Ala

1365 1370 1375

Lys Gly Asn Val Pro Ser Ala Asp Thr Gly Ser Ser Ser Ser Met Ala

1380 1385 1390

Lys Thr Lys Lys Lys Gly Leu Phe Ser

1395 1400

29604 base pairs

nucleic acid

single

linear

207

TGAGGTTATT CTTTGAAGGG GACAGAATCC CATTTCACTT TTACTAGATA AGAATTTAGA 60

ACCTAACATC TGCCACCGTA GACTCTGAGT TATTAAATTG AGAGGAAATG GCCAAAGTGT 120

ATCCTGTAAT GAAATAATCC TCATATGAAA TTGTTCTTAT ATGACATTGG AAGACCTGTC 180

TTGCTCTGTC TTTTCAGTTT TGGATACATT TTCTTGACAC AAACCGGTAT CAGAGCCAGA 240

CTCTTTTCTG CTCTAACATC TTGCTTCTGT ACGTTATAAT CCTCAGTCCT CAAGCGGTCT 300

CTAACATCTT GCTTCTGTAC GTTATAATCC TCAGTCCTCA AGCGGTCTTC GGCGACGTCA 360

GCTACTCTTT TTTTGTACAG AGTGATGGTT ATAAAGTCTT CTTGTTGAAA ATCACTGTGA 420

ACTTAGTAGC TATAGTAAAA TTTTCATAAA GATCCGTAGA AATTAAAATT ATAGCATAAA 480

TATACAACTA GCTTTTTCTA ACATTTTGTT ATCAGATTTC AGAATAATCA TACATTTTTT 540

ACATTTTTAC TAAAAAATGA GTATTTACAT ATTTGACCAA AATAAAATTG AACCATTTTA 600

GATAATTATT GAAACAATTT CCACATTAAG CAGTATAACT GCCAATTAGT TAATTGCTGA 660

ATGATTACAT ATTAGTTATT AATATTGTCT AGCAACAACT TTATCTTATA CTCAAAATGA 720

TTATATTGGC CATTTAACTT AATTAAGTTT CTCGCTTTTT TAATGCTTTT AGAAAAGATT 780

GGGATGCCTT ATTTAGTTTA GCCCTCAAGC AATTAGGTGA GGCAATTACC ATGGTAACAG 840

AAGGTATTCA TTTCCTTACC TTAGCTAAAG GTTTTGGGAA CAAAGAAACC TCTCAGCTCA 900

TCCATTGAAA CCCAACTTTC TCCTGAGCCT GGCATTAAGT GTTTGTTCTC TAAAAGAGGA 960

CTTAATTTTA AGTGGGGAAA ACATGCCCCT GAGCTGAGTC TCTTTGTCAT AGGGCGATTA 1020

AAAAGCTACC TCTTCTTAAT AGGAAGTGTG GTCTTAACTT TTATATTTCA CATTTTATAT 1080

TGAGAATTTC TACACTCATA TAATGTTTTG ATCAAACTTT CCCTTTAAAT CCTTGCCTTC 1140

CCTATCCTCT TTCTTCCTTT GTTTCCTTCT TTGTTTGTTT CTCTCTCTCT CTCTCTCTAC 1200

CTCTCTCTCT CTCTCTCTCT CTCTTTCTTT CTTTCCTTCA AATGCCCTGA ACGTCCTTCC 1260

GCTGCTTCTC GCTGCATGAG TACAGGATCA CCTGAGATAC CTACCTAGCT GTCAGGAATG 1320

ACATCCTGAA GAAGACAGAC CCTTGCTTCC CCAGTGGCTG GCTATCTGTT GCCAATACTG 1380

TAGGCTTCAT GAGCTTCCCC TCAGTGCACG CTGAGATTTG GCTGGCTTGA TTTTTTTGCA 1440

TGCAGACATA GCCTCTGAGA TGGACAATAA TCCTGCCAAC AGTCTTCCTG CCCCTCTTCT 1500

GCAATGATTC CCAAGCCTTG TGACATGGGA GTCACATTTA GAGCTGGTCA GTTTTTGTTC 1560

TTTTTTCTTT TGTTTTGAAT TAAACTCGAA ATCTCATTGG TATGCTCTCT TTTGACAAAA 1620

GGATACCAGA CCACCTCTCC TAACGGTCTA ATTGCTGTCA AATAAAATCA CTTAAGGTGT 1680

ATTTTTCAAC ACATAATTTA TAGTTTTTGA CAGGTAATTT ATTAATATTT ATTTGGCTAG 1740

TTCTACCATT CCCAAGCAGA AAGTCTACTT ACTAAATTAG CTATCATGAG GCAAATTTTG 1800

TAACTAATTT ATCAAAAATT CTGGTCATGG TGGTGCATAT CTATAATCCT ATCACCCAGG 1860

ATTGTGGTTC AAGGCCAATC TCAAAGGAAA CTTTGTCTCA AAACAAACAA ACAAACAAAC 1920

AAACAAATTA ACATGAAACA GAACACATTA AAAAAACCCA GGGTTTTTAC CAGAAATTTA 1980

ATTATTAAAT ATATCTTGGA AATTAAAACC AGACAACAAC AACAACAACA TCAACCCACC 2040

CTGAGTATGC TGTTAAAAAT ACCAGTACTA GAGGCCTGGA GACATTGCTC ATGCTTGAGA 2100

CTATTAAGCA TTCTTACAGA AGAATGGGTT CTGTTTCTTG CAACCTCATG GTGGCTCACA 2160

GCTCCCAGTA TATGGACATC TGAGACTGGA AATGATAGGA AGAATTAAGG CTTTACACAA 2220

ATATCTGTCT AAAAACACGC ATGCGCCAGG CTGTCTATAT ACAGCGACTC CTGAATATTC 2280

ACACTTGCAT TTAATTTGAA TTCTGCATTG TGATGCCATA TAAACTGTTA AGTGCAGTGG 2340

AATTCAGGAA CTTGTGGTAC TTTCTGTTTA GTTTAAGATT AAAAGTGCAG TTACTATGTA 2400

GTGGGTAAAG GTGCTTGCTT TGCAAGCCTG ACAGCCTGGC TCAGGGTTCA GCCTCTGTGT 2460

GATGTAGGAG AGAAGCACAC CAGAGCATCA GTAACACTGT CAGGCATTGG TGCCTCTCAT 2520

GAGCTGGATC CCAAGTTGGG CCTGTCATTC CTGTTCCCCA GGCTCTTCTC CATATTTTTC 2580

CCTGCAGTTC CTTTAGACAG GAACAATTCT GAGTCAGAGT TTTTGACTGT GGGATGACAA 2640

CCCCATCCCT CCACTTGGTG CCCTGTCTTT CTATTGGAGG TGGACTCTAC AAGTTCCCTC 2700

TCCCCACTTT TGAGCATTTC GTCTAAGGTC CCTTGCTTTG AGTCCTGAGA GTCTCTCACC 2760

TCCGAGGTCT CTGGTACTTT CTAGAGGGTC CCCCCATTTG AGGGCAACTG ACAGTGCATT 2820

GAGCTTACCA AATATTTTGT AAACTTCTTG TTGTTCAGAT TTAATTACAT CTTTAAAGAG 2880

TTTTGTCCCT AGCTATCGTT CTCGCCGGCA AGAACACACG CGGACAACCG GATTCTTCTG 2940

CGGCAAGCTT TATTGCTTCT TAAGGAGGGA AGACCCAGAC CCTGGAAAAT GGTGCTGCTT 3000

ATATAGCCCT CAGCGTGGCG TTTCAGCACC TGATGTGGCA TGTCACCTCC TGATTTGTTG 3060

CTCGCCCATC ACTTCATTAC TATGCCCCGA GATGGGCAGT GACTAGGCGT GAGTTCACTC 3120

TTGCACTTGC GCACAAGGCT TGTTTATTAG GCACAGCGGA AGCCAGCGCC ATCTTATAAT 3180

GGTGATTACT CGCGGCACGG CTCTCCACAG AGTTTACCAG AAAATGTATT CATAAAATGA 3240

GTGTTATATT ACTTTCCTGT TATATTTATT CCCAATAATA TTGTTTATTT TATTGTATAG 3300

CTTTTTGCTA TTGTAAATAT AATTTTGACT CTGCCCTAAT TTCTGAGGAT GCATTGTCAT 3360

ATCAGAAAAA GTTTTATTAT AGTTTCTATT GTGTTTCTAT AGTTTTTATT ATAGTTTCTA 3420

GTTCAAACCA TATTACTGTT TTCTTTATCA ATTGAAAAAG AGCTACTTTT TAAATTATAG 3480

GCTCCTTGGT TCTCTGGTTA TAAACAATGG TATGCAAAAT AAAACCATTT ACCACTGTGT 3540

CTCTTAAAAA GAAAGTAGGA GATAACTGAC TTCACAAAGT TGCTCTGTGA TCCCCCACGC 3600

ATGTGTCATG GTGGGAGCTT GCTGGCATTC AAACATAAAC ATATCACAAA CGCACACACA 3660

TGCACACATA CTCTCTCTCT CTCACACATG CACACACACA CAATTTGTTA TTTCACTATT 3720

›Example 10 · 32 of 49

GAAGTCTTGA GAGACCAAAA GAAGGTTTTA CACTAAAAGG AACATTTTTA ATTATCCCCT 3780

CTGTTTCCTT TTTGAAGACT TGTAATATAA TTACATTATA GTTAAAACTG TAGCAATCAC 3840

AGATCACAGG GAAGATGCCC TGATAGCCCA GAAGTAGTAG CATGAAACAA TGTTTAATTA 3900

ATGCTGTCTG ACTCTCAAAT AATAACTAAT AGTACTAACA GAGCAGATGA GAGCTTTTAA 3960

TAGTATTTTG AAAATATTTT ATATAAAATT TAGTCATATT CAAAGCTGTC TATATGATTG 4020

GAAGGAATTA ACATGTCTCC TCTTTAAGGA AACAGAGACT CTCTTAGCTT TAAGGGCTTT 4080

GTGCCCTTGG TAATCCATGT AAGGGGCCTG AACTGCTGCA CAGCAGTTGG TTGTAAAGAA 4140

GTTTTTAGAC TGCCAAGCGA GACACTCCTC CTGCTGTTTG CTACCACTTG ATTAGAAAAT 4200

AGTTTGTGTG GTGGTTGTTA AATAAAATTC AAGTCATGAT CAAAAGTAAG CATAAAGTCC 4260

AATATATAGT AACCTTAATA ATGGGGGGAG GAGAGTGAGT ACTTGTCGAG TGTTCAAGAA 4320

GTCTCAGGTT CCGTCCACAG TCCCACATAC ACCAGGCACA GGGGCACAGA CCTGTCATCT 4380

CATCTCAGTA CGCGGGCAAG AAAATCAGGA GTTCAAAGCC ATCCTTGGCT ACATAGCA 4440

TTTGAGGCCA GCGTAGACGT CATGACATTC TGTCTCAATA AAACAAGCAA CAACAAGA 4500

ACTCCCCAAA CAACAACCTT CCCTCAAGTC CAAAGAAGAC TGAGACATGC GAGATGCA 4560

GTAAACTAAG GTCATCAGGA GTGTGAGGGG CTTAGAGAGG ATGGGTGGGG GGGACTAC 4620

TGTATGAAGC TGTCACAAAG ATGCACACTA GACAAGGGAA AATGTCTTTA AAATGCAG 4680

ATATAATCTT ATTTATTATT GTGTGTGAGT GTGGGTAGAC ACATGCCATG GCATGCAT 4740

CAACTTTGTG GAGTTGCTTC TCTTTTTCTA CCTTTCCATG GATTCTGAGT CTCCAATT 4800

GGTCACCACA CCTGTGGAGT TAATACCCTT ATCTGCTGGG CTGTCTCATC AGCGCCAA 4860

AACTTGTTTT TAATACTGCC TGTGAATGAG ATGAATGGCA CTACTGAAAA ACTGTAAA 4920

AATATAAATT ATGCTGATCC CTGCTTAGCC TCAAATGAAT GAGACCCAAA CTATAATT 4980

TTTATTGGGC TCTGCTCAAT TACCTCGGGA TGACCCCAAA TCTATTCTCT AATGCTAG 5040

TGGCTACTTC CCCAACTGTG CTCCCCAAAT ACTTGCCGTC TGAATCTTCC TGGGTGAT 5100

CTGCTCTAGC AGCCTGGTGT CCCAGGAAGG CATTTCACTC AGGCAGTGCT GCTGGTCC 5160

CAGGACTAAT GGAGATCTCC TCTTTTCTAT GTCTTCTTCC CCATTCCCAC CCCACCCT 5220

TAATTGGTTG TTGCCAGTTT TACTTAACTA ATAGTTTTAA ATTGGATAAG TTTGCACA 5280

AAAGGTGGGT TGTAACTAGG GATTTGCTTG TCTTGGCGCA ACCAGATCAT GGAGTACA 5340

ATTTAACATA TGGATACAAG TAGCACCAGA CCAACCCACA ATAAAAAACA GACAAAAA 5400

AAAAAAAAAA AAAAAACCAG CAAAAAAAAC CCCCATAGAC AGTCTTTAAA TGATAAGA 5460

GGAAAAGTTG TAGGTGGTAA TAGATGGTTA GACAGGATAA TTTCAGGGAA GATTTAAG 5520

ATTTAAAAAA AATCTATTTA TATATGCATG CAATTGTGTG TGAGTGTGTG TGTGCGCA 5580

TGATTGTATG AGTATGTGAT GGCCAGTGCT CTTGGAGGTC AGGGTGTCAG ATCTGGTA 5640

TGGAGTCTCA ACTTGGGTAG AAACTTTTAA CCTCTGAGCC ATCTTTCTAG CCCCAAGA 5700

CTGGTTTTGT AAATAAATTT ACCTTTAAAT TCTCTTCCTG GGGGGTATCT AGATCCAA 5760

TTGTACGTAA GCAGATATTT CAAATTAAAA TGATGCTGGT GTCACACAGC TGCCGATT 5820

TTACTGAGAT TTACGTTTGC TTCAACATTG TGCTGAACTA CATGCATAGC TTTTGTAA 5880

GGTTATTTGC TGAAACTAGC TTTCTGGTAT TTCACCAGTA ATATACTCTG GGCACAGA 5940

AAACTTGTTT TCTGACTCAA TATAAATATA TTGCGTGTGT GTGTGTGTGT GTGTGTGT 6000

GTGTGTGTGT GTGTGTGTGC ATGTTATAAA ATCCTGTCTT CTGCTCATGA CATAGCTG 6060

TCATTAACTC ACAGCAGTTT GTATTTGCCT GCATGAGACC TATATAAGAT CAAGCCAG 6120

TGAATCCCAG CATGCAAAGG GGAGATGCTA TCTGGGACCC ACCCTTCATG GGAGATAC 6180

GAATTGGTGG CTCCTGGGGG AGGGAAGAGT AATTTTTCTT TGGGAGTGTG GCCATTGT 6240

TCTTGTCCAT GTTCCAGTGG ATAGCCCTAC ACTCATACAC AGAAGCAACA GTAACTGG 6300

TTAGTGGGTT ATAAAAAATA TTAGAAATGG AATTTGTATA CAACCGAGCC GTATCACT 6360

TGATCATATA CCCAAAGGAC TTTACCATAC AATAGAAGTA TTTGCTTAGC CATGTTTA 6420

GCTAATCTTT TCATAATAGT GAGTATGTGA ATAAGTGGAT GAGTGGATAG AGAGTCTG 6480

ACTAGGTAGG AGACCATGAA CGGGAACAGT AGGTGTTGAG AAGGGGCAGG AGCAGAAA 6540

AAAAGGTCAC ATTGGGCATT GTCTTAGTTA GGCTTACTAT CGTTGTGACA AAACACAA 6600

TAAAATCTCC AAAAGCAACT TGGGGAGGAA AAGATTAGAA TTTACGACTC TTGAGTTC 6660

ACTCCATCAC TGTGGGAAGT CAGAGCAGGA ACTCTAGGCA GGAACTGAAG GAGAGGCC 6720

GGAGGAACAC TGCTTACTGG CTTTCTCTTC ATGGCTTGCT CAGCCTGTTT TCTTAGAC 6780

CAAGAACAAC CTGCCCTGGG GTGACATCAC TTACTGTAGA CCAGGCCCTC CCACATTA 6840

CATGTGTCAA GAAAATGTCC CACATGCTTT CTTTAAGGCC AATCTTATAG AGCTGTGG 6900

AGCCACATGT GCCGTTGCAG AGTGGCACCG GCTACTGCTG GCTACCACGC ATAAGTTT 6960

ACAAACAACC AATGTGTACA TATGCAGTAA AGCTTTTTGC CAAGTCACTG CCTGGCCC 7020

GCATGTTAAT GAGGTACTGA GAATATAACC AATCAGATGT GAGACATGCA AATGAGGT 7080

GATAATGAGG TTCTGTGAGG TACTGAGAGA GAGTAGCCAA TCAGATGAGG AACATGCA 7140

TGAGGCATAG TGCATAACCA ATCCGTGTGT GAGACACGCC TCTCCTAGGC CTATATAA 7200

AGCACCAGTT CTGGGCTCAG GGTCTCTTTG CCTCTGCAAT CAAGCTCTCC CAGAAGGA 7260

CTGTTGCAGC GTCGTTCTTG CTGGTCAAGT CGGGCGAGCA CAAAATAGAG CCTTTTTT 7320

TTTTTAAATT GAGAGTCCCT CCTCCCAAAT GACTCCCGCT TGTGTCAGGT GGACAGTA 7380

CTAGCCAGGA CAGATGACCC CCTTGTCAAC TTGGCACACC AGTACTTATT ATGAAAAC 7440

AACCTTTCCC TTTTTGTTCA TTTTTAAGGT CTCATATTAA TATTATAATA TAAGCTAT 7500

ATAACTTTAA AAGTTTCATA TTCTTTAAAA ATTCAAAAAA TTTACAAGTT AAGTCTCT 7560

AAAATATCCA AAATTTCTCT AAAATTACCA AGTTTCTTTG AAATATCCAA GGCCTCAT 7620

ATGGATGTTT CTGTAAAATT AAAATAAATT ACTTTCTTAT TCCAAGAGAG AAGAAGCA 7680

GCACAGCCAC AGAAAATTCT GAGTGCACAT TAATAACTAA GTAAGATAAT GCCCCATA 7740

GTTGTCTTCT GTCGGCCTGT CTTACAGAGG CAATTTCTCA ATTATGCTTC CCTTTTCT 7800

GACAACACAT ACTTGTGTCA CATTGGCAAA AATCTAGCCA ACAAAGGCTT GAAAGCAG 7860

GGCTACTGGG GATGGCAGGG CTCAAGGACT GGGGACTTGG TGATTAGGGA GAAATAGG 7920

ATAGGAAGAG AAACCGCAAA AACAAAAATT TCTTGTAAAA ATGCTACAAT GAAACCTA 7980

CATCTGTATA TAATAAAAAG TGAATAGAAC AGATTGTACA TCTGTAATTT GCTATCAT 8040

TTTGACTTCT GTTAGTGGTT TTGAAATCTT GGCAAAAAGC AACTTAACCA TTAACAGT 8100

TAAATTGCTT TAGGGTTTAT AAAACCTGCA TTTTCACATG AGATTGTCTT ATTACATT 8160

AGTTGGGTGG ATCTGGGAAG AGTTACACTA TGTATGCAAT TCTCAAAGAA CCGAGGAA 8220

GAAGATAAAA TTTCTTTATA TTATTTAATA GTGCTGAGTG TAGTAGGCTG TTCCTCCA 8280

TTAAATGCGT GCTCTGATTT CTTCATGGTA ACAGAGGTTT CATCAGGAGA CTCTTCCA 8340

ACATATTTAA AACTTTACTC CCCACAAGAC ATTTGGGTAA CAGGAACTTT CCGGANGT 8400

GAGGAGTTTA TTACTTGGCT TTAGTATAAA TCATGTAGGA GCATGGATGC ATTTCATT 8460

TGAAAAAATA ATATATTTGG AGTCTCATAC TTGAAGTCTG GGTTATATTC CAGAGAGC 8520

TCAAAACTAG TAACAGCTTA AGAGAAAGAT CATCCAAGAA ACCCTTTCTT TTTAGGGA 8580

TGTCTCTTAC TCAGCCAAGA GCACAGTGAA AGGGCTTAGT ATTGGACAGC TATTATAT 8640

TCAAAACTAG GTCTTTATTT TATTTTACGA ATAAATCCAG TAGTTGCTCT GAGTCAGC 8700

ATACCTTATG AGAGATGATA ATTATACAGA AAATCAAAGA TGCTGAAAAT GTAATACC 8760

ACATACTGAG GGATCCTGTT CATTAAGGAG ATAAAAATTA TTCTTTTGAA GGAGCAAA 8820

TATACACATA ACATATTAGA ATTTTGAAAC AGCCACAATC ATAGAACTTA ATTTGTTA 8880

AAAGGAAGAA GTAATGTATA GTTAATAAGT GGTTTAAGCC TTGTCCTTGA GGCTAGAT 8940

TATAACTCAT ACTAAATATG TATGTTTGTT TCAGGCTAGG TATCATATCC TACACGAA 9000

›Example 10 · 33 of 49

ATGTATGTAT GTTTCAGGTT AGATGCTATA TCCTACACTA ATTATATATG TTTGTTTC 9060

TTTCAGTCCT ATCTATGGAG CTGTCTCTGA GCTTTCTATC AAATATTTGT CATATTTA 9120

CATAGATATT GTTTATTGGA ATTTGCAAAC AGGGCATTTT AAAGACAAAT GAAAATAA 9180

TGGAAACCAC TTCACTACAG CGGAAATTTC CAGAATGGAT GTCTATGCAG AGTCAAAG 9240

GTGCTACAGA AGAAAAGGTA ATTGTTCATT GATTATTTGT CTAAATGGGC AATCTTGT 9300

GAGTTTGACT ATGCAGTGAG TCACATCATT GCTTGTGAGC TTTGGGTCAT TGTTGAGG 9360

AAACTTTCTG TTGTGTGAAT GAACCAGAAC TAAGTTGTTC AAAGGTAAAT GAGACTCA 9420

TTTATACATG TTTTATAAAA TGAGATTCCC TAGAGTATAT TCTTTCTTTT TATAGTTA 9480

ATTCTTAGTT GAAGTTATTG GTTTGTTCAA ATTCAAGTAA TAATTTATAC AATATTAA 9540

TTGGCATTTT TTGGTTAAAA TAGTTTGAGT CCTTAGAGGC TTAAGATCTG ATAATTAG 9600

ACCAACATTT TTTTGTTTTC TTTTTCAATA TTTTATTAGA TATTTTCTTC ATTTACGT 9660

CAAATGCTAT CCCGAAAGTC CCTTATACTC CCTCACTCCA CCCACTCCCC TACCCACC 9720

CTCCCACTTC TTGGCCCTGG CGTTTCCCTG TACTGGGGCA TATAAAGTTT GCAAGACC 9780

GGGGCCTCTC TTCCCAATGA TGGCTGACTA GGACATCTTC TGCTACATAT GCATCTAG 9840

ACATGAGCTC TGGGGGGTAC TGGTTAGTTC ATATTGTTGT TCTACCTATA GGGTTGCA 9900

TCCCCCCAGC TCCTTGGGTA CTTTCTCTAG CTCCTCCATT GGGGGCCCTG TGATCCAT 9960

TATAGATGAC TGTGAGCATC CACGTCTGTG TTTGCCAGGC ACTGGCATAG CCTCACA 10020

GACAGCTATA TCAGGGTCCT TTCAGCAAAA TCTTGCTGGC ATGTGCAATA GTGTCTG 10080

TTGGTAGCCA CCAACATTTT AAGGTTACAT TATTGCATCT AGCATGCTAA TATAATT 10140

AGGAAAAAAC AAGTAAATTA AGTGACTTCA CAAAAGAAAG ATTGGATGTT TGAAAAT 10200

ATTGTGTGGA AAAATAACTT TATGTTTACC CTTGTTAATC TGACCTTATG AATTCTT 10260

CTATAATATA AAATGTAGTG CTATAAATTT CTTCAGTGAA CTTTATTATT TCAGTTA 10320

CTACAACTTA CTGTGATATT TATTTGTGCC TGTTTTGAAT TTTGCTCAAC TCAAGGC 10380

CGTTCAGAAG AGTGTTCTTG AAGATAATCT CCCATTCTTA GAATTCCCTG GATCCAT 10440

TTACAGTTAT GAAGCTAGTG ATTGCTCCTT CCTGTCTGAA GACATTAGGT AAGGGAT 10500

AAGTTCTTAC CATTAAGTTT GTACCCGTAA GAAATAGCGA TATTTATGAG TGCCTAG 10560

TACAATGGAA GTATATCTCA GAAGTATATT TACATACATC ATATCACAGT TGTATTC 10620

TTTTTAAAAT ATAAAATAAA CTCACTAAAT TAAATTAGTA AGGTTCCTAT TTGTTAA 10680

GTAACCTTTT CTACTTTATT AGATACTTTT TTTTTCTTTT AGTGCTTTAG ATGTAAA 10740

AGGTAAAACT ATTGAAGACA ACTGTTTACC AATTTAGGAA AAAATGGAAA ATGTTAT 10800

ATGTCGAACT ATTTTCATAT CTTAAAACAT CAATGTATTA AGTAATGTTT ATGATTC 10860

GTTTTATTTT TTTTAATTTA TTTTTAGCTT TTAAAATTGT GTTAGGATGC CTCCTCT 10920

TGTATGTTTG TATACCACAT GGTTACGGTG TCCACAGAGG CCAGGAGAGG GCTTTGG 10980

CCCTTGAACT GGAGTTGTGA GCGATCTTAT GGGTGCCGGG AATCAAGCCT AGGTTCT 11040

GAAGAGCAGC CAGTGCATTC AGCTGCTGAA CCATTTTAAA AGATAGTGAT AGTTCCT 11100

AATGGTCCAT GAAAAGAGCT TTAGCAATGA CTGTTGGTAC TTTAAGAGTT GCCTGTC 11160

GTTTTTCTAA GGCTATAACA AAATCCATGG CCTGAGTAAA TTATAAAAAA ATACATA 11220

GTAAATTCAT AAATAAATTT ATTCCTTACA GTTTTGGAGG CTATAGAGCC CCCAGAG 11280

GGGATTGGCA TTTGTAAGGG GACCATTTTT TTTTTTAAAT TGGATATTTT CTTTATT 11340

ATTTCAAATG TTATCATCTT TTCTGGTTTC CTTCCCTCCT GGAAACCCCC TATCACA 11400

TCCGTCTCTC TGCTTCTGTA AGAGTGTTCC TCTACCCACC CACCCACCCA CCCACCC 11460

CCCACCTTCC TGCCCTTGAT TCACCTACAC TGATGCATCT ATTGAGCCTT CATAGGA 11520

CGGACATCTC CTCCCACTGA TGAATGACAA GGCCATCCTC TGCAACATAT GCAGCTG 11580

CTATGTGTAC TCCTTGGTTG ATGGCTTAGT CCCTAGTTTT CTGGGGGTGG GGGAGGT 11640

ATCTGGTTGG TTTATGTTGT TGTTCTTCCT ATGGGATTTC AAACCCTTTC AACTCTT 11700

GTCCCTTCTC TAACTCCTCT ATTAAGGACC CTGCGCTCAG TCCAATGGTT GGCTGTT 11760

ATCCACCTCT GTATTTGTAA GGCTCTGGCA GGGCCTCTCA GGAGCAGGCT CCTTTCA 11820

TGCACTTCTT GGCATCCACA ATAGTGTCTG GGTTTGGTAA CTGTATATGG AATGAAT 11880

CAGGTGAGAC AGTTTCTGGG TGGTCTTTCC TTCAGTCTCT GCTCTTCACT TTATCTC 11940

ATTTGCTCCT GTGAGTATTT TGTTCTCCTT CTAAGAAGGA CCGAAGCACC CCCACTT 12000

TCTTCTTTCT TATTGACCTT CATGTAGTCT GTGAATTGTA TCCTGGTCAT TTGGAGC 12060

TGGGCTAATA TCCACTTATC AATGAGTGTA TAATATTTGT GTTCTTCTGC GATTGGG 12120

CCTCACTCAG GATGATATTT TCTGTCCATT TGCCTAAGAA TTTCATGAAT TCATCAT 12180

TAATAGCTGA GTAGTAAGTA CTCCATTGTG TAAATGTACC ACATTTTCTG TATCTAT 12240

TCTTTTGAAG GACATCTGGC TTCCTTCCAG CTCCTGGCTA TTATAAATAA ATATATA 12300

ATAGTGGAGC ATGTGTTCTT ATTACATATT GGAACAGAAA GAGCAATTTG CAAATTC 12360

TGGAATAACA AAAAAAAAAA AAAAAAAAAC CCAGGATAGC GAAAACTATT CTCAACA 12420

GAAGAACTTC TGGGGGAATC ACCATCCTGA CCTCAAGTTG TATTACAGAG CAATAGT 12480

AAAGACTGCT TGGTAATGGT TCAGAGACAG GCAGGAAGAT CAATGGAATA GAATTGA 12540

CCCAGAAATG AACCCACACT CATATGGTCA CTTAATCTTT GACAAAGGAG CTAAAAC 12600

CCAGTGGAAA AATGACAGCA TTTTTAACAA ATGGTGTTAG TTTAACTGGT AGTCAGC 12660

TAGAAGAATG CAAATCGACC CATTTTTTTC TTTTCTTTTC TTTATTTACA TTTCAAA 12720

TATTCCCTTT CCTGGTTTCC CCTCTAACCC CCCCCCCCCC CCACACACAC ACACACA 12780

ACCAACCCAC TGGCTTCCTC TTCCTGGCCC TGGCATTCCT CTATACTGGG GCATAGA 12840

TTCAAAAGAC CAAGGGCCTC TCCTCCCATT GATGACCAAC TAGGCCATCC TCAGCTA 12900

ATGTAGCTGA AGCCATGAGT GTGCTCTTTG GTTAGTGGTT TAGTCTCTGA GAGCTCT 12960

GGTACTGGTT AGTTCATATT GTTGTTCCTC CAATGGGGCT GCAAACCTCT GCTACTC 13020

GGTTACTTTC TCTAACTCCT TCACTGGGGA TCCTGTGCTC AGTCCAATGG ATGGCTG 13080

GCATCCATTT CTGTATTTGA AGTTGACCCA TTCTTACCTC CTTGTACAAA GCTCAAG 13140

AAGTGGATCA AGGACCTTCA CATAAAACCA GATACACTGA AACTTATAGA GAAGAAA 13200

GGGAAGAGCC CCAAACATAT GGGCACAGGG GAAAAATTCC TGAACAGAAC ACCAATG 13260

TATGCTGTAA GATAAAGAAT CAACAAATGG GACCTCATAA AATTGCAAAG CTTCTGT 13320

GCAAAGCACA TTGTCAATAA GAAAAAAAGG CCACCAACAG ATTGGGAAAA GATCTTT 13380

AATCCTACAT CTGATAGAGG GCTAATATCC AATATATTCA AAGAACTCAA GAAGTTA 13440

TTCAGAGAAC CAAATAACCC TATTAAAAAT GGGGTTCAGA GCTGTCTTAG TCAGGGT 13500

TATTCCTGCA CAAACATCAT GACCAAGAAG CAAGTTGGGG AGGAAAGGGT TTATTCG 13560

TACATTTCCA TATTGCTGTT GATCACCAAA GGATGCAGGA CTGGAACTCA AGCAGGT 13620

AAAGCAGGAG CTGATGCAGA GACCATGGAG GGATGTTCTT TACTGGCTTG CTTCCCC 13680

CTTGCTCAGC CTGCTCTCTT ATAGAACCCA AGACTACCAG CCCAGAGATG GTTCCAC 13740

CAAGGGGCCT TTCCCCCTTT ATCACTAATT GAGAAAATGC CTTAGAGTTG GATCTCA 13800

AGGCATTTCC TCAACTGAAG CTCCTTTCTC TGTGATAACC CCAGCTGTGT CAAGTTG 13860

CAAAACCAGC CAGTACAAGA GCTAAACAAA GAATTTTCAA CTGAGGAATA CTGAATG 13920

GAGAAGCACC TAAAGAAATG TTCAACATCC TTAATGATCA GGGAAATGCA AATCAAA 13980

ACCATGAGAT TCCACCTCAC ACCAGTCAGA ATGGCTAAGA TCAAAAACTC AGGTGAC 14040

AGATGCTGGC AAGGATGTGG AGAAAGAGGA ACACTCCTCC ATTGCTGGTG GGATTGC 14100

CTTGTACAAC CACTCTGGAA ATCAGTCTGG CGGTTCCTCA GAAAACTGAA CATAGTA 14160

ACTACCTGAG GACCCAGCTA TACCACTCCT GGGCATATAT CCAGAAGATG CTGCAAC 14220

TAAGGGAACT TTGTACTGCG TCTGTATCAG GGTAGAGGCT AAGATGGGTT GGGATTA 14280

CAGTTCTCTG GATACCTGTT CTGGGAGTGG AGCCCTGATG AGCCAAACAC TTGTGTT 14340

›Example 10 · 34 of 49

GCCCCACCTC CACGCCCTGC TCCATTAAGG ATTCCATTTT AACAGGGACT ATGAATA 14400

TATTCATGAC CCAGCACCTT GTGTAATTCG GGTTCTGGAG TAATGCAATC TAAGCCT 14460

GATGCAACTT ACACTGAGAA GTAGTAAATC AATTCAGATC ATTGAAATGA CTGCGTG 14520

CCTTTTGGTT TTTAACTATT TTCATGAAAA GCAGAAGTGA ATAAAGTTGT TCATCAG 14580

CCTCCTGGTG GTTGGTAAAT GTGATCTAGA AGTGGCATTT AGGTATCTTT ACTTCCA 14640

CATTTACTGG TTATGTGTGG GCTTCATTTT GCTGAACTAA AATTAGACTT ACAGAAT 14700

TAAATCTATT ACACACGGTT ATATATTGTC CTCACCATGT TACCTTTGTC TTCCTAC 14760

ATGACATGTG TTTTATTAGT CAGAGGGTTT TTTTTTTTTG GTTTGTTTGT TTATCTT 14820

TTTTTAAAGG AATAGAACTG GCAGAATGAA CGTATATATA TATCAAACAG GGATTTA 14880

GTGTGGCTTT GCAGACTGAG GTCTCTTGTC CAACAATGGC TGTGCCTCAT CAAAGCC 14940

AATCCTTTTT TCTCGTAGTT GTTCATTCGA GGAGCCTGGG TGTCTAAGTC AGTCTTC 15000

CTGCATGGGC TTCCTGAAGA AGGAATTTCT AACACCAGCT AAGTAGTGCC TTAGTAG 15060

GACAGACGAA CTTGCCAGCC AGACTGAGGA CAGGCTGACA AAAAGCCAAA GCTTCCC 15120

TCCGTGCCCC TTCAGAAGTG GGCCGCCATC AGAAAGCGTA ACCTAGATTT AGGATGC 15180

TCTCCTGTCA CATAATCTAA TCAAGAAAAG CCCTCATAGG TGAGCCCAGG GCTTATA 15240

TAGATGATTC CAAATGGAGT CAGGTTGCCA GCCAAGATCA GCTCAGCACA GTAAGTT 15300

GTGGTCTGAA TGAAGCTCTG TGTTCATTTT GAAGTGCAAG ACGGGCTTGG TTTGCTT 15360

ATTACTTTTC ATATGGCCAC TTTGGAGATC CTCGCATCAG GGGCTGGAAA CATGGCC 15420

CATTAAGAGC AGGAAGCGCT ATTGCAGAGG ACCCCAGTCT GGTTCCCAGT ACCCATA 15480

GTGGCTCACA GACCTCTGTT TTCTATGACT CCAGCTCCAG GGTGCTGAGT CCCTCTT 15540

CCCTCTACAG GCACCTGTGC TTATGTGCAC ATATGTACCC CTCTTCCCAT ACACACC 15600

TTAGAAAAAT AAAAATCTTA AAGAATATTT TTACACCAGG GCCAGTGACA TGGCTCA 15660

GGTAACAGGG CCTGCCACCA AGACTGGAGA TCTGAGTTCT AATCCCATTT CAACCTC 15720

GGCTCATGGT GGAAGCCAAG AGCTGATCCT GAATTCAACA TGCATGGGGC CACCAAA 15780

GAAAGAAAGA AAGAAAGCAA TTTAAAAAGA TGTTTACCCC ATGGGGTTTC AACAGTT 15840

TATGACATAC CTTTGTGTGC TGAAGTTTGT GCTGATCCTG CTTGGGGACC ATCGACC 15900

TTTTTTTTTT TTTTTAAATT TGTGGGTTTA ATAGTTTTTG TCCAATTTGA AAATCAT 15960

CAGTTTTTAT TTTTTTCAGT ACTGTGCTTT TCTGGGACTC TGATATACAT ACACTAG 16020

GCTGGATACT ATGTCTTAAC TTCTTTTCTC TTTTTGTTTA TGCTTTGGTT TGAATGT 16080

TTCTGCTGTG TCTTTAAGTT AATCACCTAT ATTTCTTCTG TAGTGGCTGA TCTACTG 16140

ATCCTCCCTG TGTATTTTTA ATTTTCATTG TGTTTTTCTC TTTTTTGTTA TTGAAAA 16200

TTTTTTTAAA AATACAACAC ATTTGGACTG TGGTTTCCCT TTCCACAACT CACCCCA 16260

CCTCTCCACC TCAACAGAAA AAGAAAGGGC CAGAGAAGAA GCACAGGAAA CACATAC 16320

TGCAGGCCAC ACACGTGTAC ACACAGGAAT CTCATAAGTA CACAAAATCA GAAACCA 16380

ATATAAAAAT TATATAAGCA AAAGACTTGC TAGATTAACA AAATAAAGGT TCATTCT 16440

TTGGCCATTT ACTGCTGGGC CTAGGGCCTG CTGGTGAGTG TGGTTTGTAT ACCCAGT 16500

TCTGGTGGAG AAACTAGTTT TTCCTTTGTG AGTGGTTATA AATAGGAGAT AATTTCT 16560

TGAGGGATAG GATCGGCGCT GGGACTTTAT CTGGTTAGAC CTGGGTAGAC CCTGTGT 16620

CTCCCACATG AAAGCTCTTC TGTGCTTTAT CAGCCCTGCT GTGTCTTGAA GGGCTTC 16680

CCTTGGTGTC TTCCATCCCA CTGGGTCTTA CAACCTCTCT GCCCCCTCTT TTGCAAA 16740

CCCTGAGCCA TGCGGGGAGG GGTCTGTCAT TGTTCCCATC TCCTGCAGGA GGCAGTG 16800

CTGACATTGG CTGGGCAAGA CACTGAGCCA TGAGCATAAA AAAACCCTGC CAATTTG 16860

TTCATTGTGT GCATGCTTTC CTTTAAATTC CTGAACATAT TTACAATTTA TAATAGT 16920

CGTTTGTCTT GTTTTGAGCA GGGGCTTATG TAGCCTAGGC TGGCCTTGAA TGTACTC 16980

CGCCAAGGCT GATCTTAGTT CCTGATCCTA TTGCCTATGC CACCAAGTGC TGGGATC 17040

GACTTGTGCC AGCAGGCCCT GCTGTGACCA TAATGCAAAT TTCAGTGATA TTTTAGC 17100

ATTTTTGCCT CTATTGAGTG ATCACCCCGC CAACTGATTA TGTTTATGTT TGATATG 17160

CAGGGCTGTT GAGGTTTTTT TTCTTTTTCT TTTTTTTTTT TTTTTTTTGG TCTGCTG 17220

TGATTTTACC TTGCTCAATA TATATATATA TATATATATA TATATATATT TTTTTTT 17280

TAGTTTGCTT TCTAAGAAAA GAGGTTTTGC CAGAGGGCTC ACCCAGAGAT GGGTTTT 17340

TTCGGAGGCT TGCTTTTAGA CCTCATTAGG CCGGCAATTG CTTTTCCTCC AAAGGTA 17400

TAGTTCTCTC AGGTGCGATC ATAAGGGAGG CTGCTGCATG TTCCTAGAGT TCAGCAA 17460

TGTCTGCTGG GACTTGGGAA CTTACGCTCT TACCTCTGTC TGTGTCCCCA CCTCAGG 17520

GTCCTTTCTC TGTTGTCTGT AAGGCATTCT AGGAGAACCA GGGACAACGA CAGAGAC 17580

CCTCTTGTTC AGAGAACAGT AAATTTAGAC GTGTTTGTAC AATTTATTGT TTCTTTT 17640

TGGAAAAAGA AGTACTTGTA AATTTTATCT TAGCCTGAGG TATTAGTTGA TATTCTT 17700

TGTTTGTAAT AAATTTTTAA TCAAAACTTG TGAACTAGGC ATAGAAACAA TAGTAAA 17760

AACCGTATCT TCTTATTTAA TTATATCAAA TCTTTATTAT TTAGTGTGTA TGTGTGT 17820

CTCATGTATG TAGATATATA CTTGGTCAGA GGACAACTTT CAGGAGTAGT TTTCTTC 17880

TATTTATGTC TAAAATTAAA TAGAAAATAA AAGCTCATGT ATACCCTTTT TAATTTA 17940

TCTTCCAACC CCCGTGCTAC TTTAAATAAC ATGTCATGAA TTTAGTATTT ATCATTT 18000

TATATTGTGT TATTTGCCAA CTTAGAAACT ATATGGTTTT CCTGAAGCTT GTCTTTT 18060

CTCAAGTTTT GAGAATTTTT CATTTTGATA TATGTAGTTC CATTATTTTA TATGCTA 18120

TATGTTTTGG CATGCCACAA TTTCTTTATT TTTTTGTTTT ATGGAAACAT AGTTTTT 18180

ATTCCCCCGT CTGCAAAAGG ATCAGGGTTG TAGTGAACAT TCTTTCTTTG CTGTGTT 18240

TAGTGTTTCT TGTCCATTTG GCACAGCCTA GAGTCGTCTG AGGCTAAGGA ACCCAAC 18300

GAGAATGCCC CATCAGATTG GTGTATAGGC AAGCGTGGGA ATAGGGTTTT CTTGACT 18360

GATTGATGTG GGAGGGACCA GCTCACCTTG GGCAATGTCA TCCCTTGGGA GTTGGTC 18420

CCTTGTATAA GAAAGCAAAC CTAGCAAGCC AGTTAGCAGT GTTTCTCCAT GGCCTCT 18480

TCCGCTCCTG CTTCTAGGGA CCTGCCTTGA GTTCCTGCCC TGACTTCCTT TTCTTCC 18540

ATTGCTTTTG GACATGGTGA TGATCACAGC AATAGATGGC AAACTAAGAC ATTAATC 18600

TGAGCTGTCT CACCTTTTAG AGTGGTTTGA ATAAGCATGG CCCTCAAAGG CTCATAT 18660

GAATGGCTAA TCACCGAGGA GTGGAACTCT TTGATAGGAT TGGAACAGTG GTTCTCA 18720

TGAGAGTCTT GATGTCTTTG GACATTAAGC GACCCTTTCA CAGATATCCT GAATATC 18780

TATTTACATC GTGATTCATA GCAGTAACAA AATTACAGTT ATGAAGTACC AATGAAA 18840

TTTTATGGTT GGCGTCATTA GGAAGGTTGA CAACCACTGG ATTAGAAGAA TTAGGAC 18900

TGACCTTGTT GGGGGAAGTG TGTCACTTGG GGTGGGCTTT GAGGCTTCAA AAGCCTA 18960

TTTGAACAGA CCTTTTGCAC AAGAACAGGC CTCTTGTTCT CTCTACTGCT GCTCAGG 19020

TAGCTCTCAG CTGCTGCCGC AGTGCCGTGC TTTACACCAT GATAATGGAC TAAGCCT 19080

AGCTGTAAGC CAGCCACCAA TTACATGCTT TCTTTTATGA GAGTTGCCAT GGTCATG 19140

TCTCTGCAGC AGTACAACAG TGACTAAGAC AGAAGGAAAC ATAGAAACAT TCACGCA 19200

AATCCACACA ATTTTTCCTT TGATAGCATG CGTCTGTCTG ATGGCGATGT GGTGGGA 19260

GACATGGAAT GGCCGCCCAT ATACAAGCCA GGGAAACGAA GCAGAGTCGC AGTGATC 19320

TTGTGTGTGT CTGAGAACAA ATGTTACTTG TTTCACATTT CTTCCATGTC AGGTTGG 19380

CTCTGCTTCA TTGTCATATG GCCATCAATA ATACCATATC AACTTTCTTC CTGCAAA 19440

AAGTTCTTTC ATTAGCAGGC CTTCTTTCAT GATCTTGTAT TTGTTTAAGT ATTTATA 19500

TTACTTGATT TTTATACCTT TTCCCTTGGT TAGAGAATAG AGAACTGAAG TTTAGAG 19560

TAAATGACTA GGAATAATAC CCTATTACTG TTACTACAGG TGGCGTTCGA ACTCATT 19620

TCTAGTCAAA TTTCAGTCTG GACTCTGCAT TAGCTAAGAA AAGAGATAGT TAAGGTG 19680

›Example 10 · 35 of 49

GTGATTCTAA ATTTAAGCTT AATATAAACA GTTTACCACA CATTCCGTGT GCATTAA 19740

AGTAAATCCA TTATATTAAA GAGTTTTATG GAAATAATAA TGAAATGTTT TAGTTTT 19800

CCAGGGATTA AAAATGTTAC TAGAAAACAA ATCAATTAAG AAGGCAGGGG TTGGGAT 19860

AGGGGACCAG TGGAAACTTC TGCGTGATTT TGACGTCAAG TTGGAGAGTT TTGTGGA 19920

GACGGATGTT GCCAATGAAA AGGTAGGCGT AATAAATGCA GTATTTTAAT AAACATG 19980

ACCTGAGTTT CATAGAATGT GCATTTTCAT CTAAATGTTA AGTTTCTTTT TTTTTCC 20040

TTTTATTAGG TATTTAGCTC ATTTACATTT CCAATGCTAT ACCAAAAGTC CCCCATA 20100

ACCCACCCCC ACTCCCCTGC CCACCCACTC CCCCTTTTTG GCCCTGGCGT TACCCTG 20160

TGGGGCATAT AAAGTTTGCA AGTCCAATGG GCCTCTCTTT CCAGTGATGG CCGACTA 20220

CATCTTTTGA TATATATGCA GCTAGAGTCA AGAGCTCCGG GGTACTGGTT AGTTCAT 20280

GTTGTTCCAC CTATAGGGTT GCAGATCCCT TTAGCTCCTT GGCTACTTTC TCTAGCT 20340

CCATTGGGAG CCCTATGATC CATCCATTAG CTGACTGTGA GCATCCACTT CTGTGTT 20400

TAGGCCCCGG CATAGTCTCA CAAGAGACAG CTACATCTGG GTCCTTTCAA TAAAATC 20460

CTAGTGTATG CAATGGTGTC AGCGTTTGGA TGCTGATTAT GGGGTGGATC CCTGGAT 20520

GCAGTCTCTA CATGGTCCAT CCTTTCATCT CAGCTCCAAA CTTTGTCTCT GTAACTC 20580

CCATGGGTGT TTTGTTCCCA AATCTAAGGA AGGGCATAGT GTTCACACTT CAGTCTT 20640

TCTTCTTGAG TTTCATGTGT TTAGCAAATT ATATCTTATA TCTTGGGTAT CCTAGGT 20700

GGGCTAATAT CCACTTATCA GTGAGTACAT ATTGTGTGAG TTTCTTTGTG AATGTGT 20760

CTCACTCAGG ATGATGCCCT CCAGGTCCAT CCATTTGGCT AGGAATTTCA TAAATTC 20820

CTTTTTAATA GCTGAGTAGT ACTCCATTGT GTAGATGTAC CACATTTTCT GTATCCA 20880

CTCTGTTGAG GGGCATCTAG GTTCTTTCCA GCTTCTGGCT ATTATAAATA AGGCTGC 20940

GAACATAGTG GAGCATGTGT CCTTCTTACC AGTTGGGGCA TCTTCTGGAT ATATGCC 21000

GAGAGGTATT GCTGGATCCT CCGGTAGTAA ATATGTCCAA TTTTCTGAGG AACCGCC 21060

CTGATTTCCA GAGTGGTTGT ACAAGCCTGC AATCCCACCA ACAATGGAGG AGTGTTC 21120

TTTCTCCACA TCCACGCCAG CATCTGCTGT CACCTGAATT TTTGATCTTA GCCATTC 21180

CTGGTGTGAG GTGGAATCTC AGGGTTGTTT TGATTTGCAT TTCCCTGATG ATTAAGG 21240

TTGAACATTT TTTCAGGTGT TTCTCTGCCA TTCGGTATTC CTCAGGTGAG AATTCTT 21300

TCAGTTCTGA GCCCCATTTT TTAATGGGGT TATTTGATTT TCTGAAGTCC ACCTTCT 21360

GTTCTTTATA TATGTTGGAT ATTAGTCCCC TATCTGATTT AGGATAGGTA AAGATCC 21420

CCCAATCTGT TGGTGGTCTT TTTGTCTTAT TGACGGTGTC TTTTGCCTTG CAGAAAC 21480

GGAGTTTCAT TAGGTCCCAT TTGTCAATTC TCGATCTTAC AGCACAAGCC ATTGCTG 21540

TGTTCAGGAA TTTTTCCCCT GTGCCCATAT CTTCAAGGCT TTTCCCCACT TTCTCCT 21600

TAAGTTTCAG TGTCTCTGGT TTTATGTGAA GATCCTTGAT CCACTTAGAT TTGACCT 21660

TACAAGGAGA TAAGTATGGA TCGATTCGCA TTCTTCTACA CGATAACAAC CAGTTGT 21720

AGCACCAATT GTTGAAAATG CTGTCTTTCT TCCACTGGAT GGTTTTAGCT CCCTTGT 21780

AGATCAAGTG ACCATAGGTG TGTGGGTTCA TTTCTGGGTC TTCAATTCTA TTCCATT 21840

CTACTTGTCT GTCTCTATAC CAGTACCATG CAGTTTTTAT CACAATTGCT CTGTAGT 21900

GCTTTAGGTC TGGCATGGTG ATTCCGCCAG AAGTTCTTTT ATCCTTGAGA AGACTTT 21960

CTATCCTAGG TTTTTTGTTA TTCCAGACAA ATTTGCAAAT TGCTCCTTCC AATTCGT 22020

AGAATTGAGT TGGAATTTTG ATGGGGATTG CATTGAATCT GTAGATTGCT TTTGGCA 22080

TAGCCATTTT TACAATGTTA ATCCTGCCAA TCCATGAGCA TGGGAGATCT TTCCATC 22140

TGAGATCTTC CTTAATTTCT TTCTTCAGAG ATTTGAAGTT TTTATCATAC AGATCTT 22200

CTTCCTTAGT TAGAGTCACG CCAAGATATT TTATATTATT TGTGACTATT GAGAAGG 22260

TTGTTTCCCT AATTTCTTTC TCAGCCTGTT TATTCTTTGT ATAGAGAAAG GCCATTG 22320

TGTTTGAGTT TATTTTATAT CCAGCTACTT CACCGAAGCT GTTTATCAGG TTTAGGA 22380

CTCTGGTAGA ATTTTTAGGG TCACTTATAT ATACTATCAT ATCATCTGCA AAAAGTG 22440

TTTTGACTTC CTCTTTTCCA ATTTGTATCC CCTTGATCTC CTTTTCTTGT CGAATTG 22500

TGGCTAATAC TTCAAGTACT ATGTTGAAAA GGTAGGGAGA AAGTGGGCAG CCTTGTC 22560

TCCCTGATTT TAGTGGGATT GCTTCCAGCT TCTCTCCATT TACTTTGATG TTGGCTA 22620

GTTTGCTGTA GATTGCTTTT ATCATGTTTA GGTATGGGCC TTGAATTCCT GATCTTT 22680

ACACTTTTAT CATGAATGGG TGTTGGATCT TGTCAAATGC TTTTTCTGCA TCTAACG 22740

TGATCATGTG GTTTTTGTCT TTGAGTTTGT TTATATAATG GATTACATTG ATGGATT 22800

GTATATTAAA CCATCCCTGC ATCCCTGGAA TAAAACCTAC TTGGTCAGGA TGGATGA 22860

CTTTAATGTG TTCTTGGATT CGGTTAGCGA GAATTTTATT GAGGATTTTT GCATCGA 22920

TCATAAGAGA AATTGGTCTG AAGTTCTCTA TCTTTGTTGG GTCTTTCTGT GGTTTAG 22980

TCAGAGTAAT AGTGGCTTCA TAAAATGAGT TGGGTAGAGT ACCTTCTACT TCTATTT 23040

GAAATAGTTT GTGCAGAAGT GGAATTAGAT CTTCTTTGAA GGTCTGATAG AACTCTG 23100

TAAACCCATC TGGTCCTGGG CTTTTTTTGG TTGGGAGACT ATTAATAACT GCTTCTA 23160

CTTTAGGTGA TATGGGACTG TTTAGATAGT CAACTTGATC CTGATTCAAC TTTGGTA 23220

GGTATCTTTC CAGAAATTTG TCCATTTCGT CCAGGTTTAC CAGTTTTGTT GAGTATA 23280

TTTTGTAGAA GGATCTGATG GTGTTTTGGA TTTCTTCAGG ATCTGTTGTT ATGTCTC 23340

TTTCATTTCT GATTTTGTTA ATTAGGATTT TGTCCCTGTG CCCTCTAGTG AGTCTAG 23400

AGGGTTTATC TATCTTGTTG ATTTTCTCAA AGAACCAGCT CCTCGTTTGG TTAATTC 23460

GAATAGTTCT TCTTGTTTCC ACTTGGTTGA TTTCACCCCT GAGTTTGATT ATTTCCT 23520

GTCTACTCCT CTTGGGTGAA TTTGCTTCCT TTTTTTCTAG AGCTTTTAGA TGTGTTG 23580

AGCTGCTAGT ATGTGCTCTC TCCCGTTTCT TCTTGGAGGC ACTCAGAGAT ATGAGTT 23640

CTCTTAGAAA TGCTTTCATT GTGTCCCATA GATTTGGGTA CGTTGTGGCT TCATTTT 23700

TAAACTCTAA AAAGTCTTTA ATTTCTTTCT TTATTCCTTC CTTGACCAAG GTATCAT 23760

GAAGAGTGTT ATTCAGTTTC CACGTGAATG TTGGCTTTCC ATTATTTATG TTGTTAT 23820

AGATCAGCCT TAGGCCATGG TGGTCTGATA GGATACATGG GACAATTTCA ATATTTT 23880

ATCTATTGAG GCCTGTTTTG TGACCAATTA TATGGTCAAT TTTGGAGAAG GTCCCGT 23940

GTGCTGAGAA GAAGGTATAT CCTTTTGTTT TAGGATAAAA TGTTCTGTAG ATATCTG 24000

GGTCCATTTG TTTCATAACT TCTGTTAGTT TCACTGTGTC CCTGTTTAGT TTCTGTT 24060

ACGATCTGTC CTTTGAAGAA AGTGGTGTGT TGAAGTCTCC CACTATTATT GTGTGAG 24120

CAATGTATGC TTTGAGCTTT ACTAAAGTGT CTCTAATGAA TGTGGCTGCC CTTGCAT 24180

GTGCGTAGAT ATTCAGAATT GAGTGTTCCT CTTGGAGGAT TTTACCTTTG ATGAGTA 24240

AGTGTCCCTC CTTGTCTTTT TTGATAACTT TGGGTTGGAA GTCGATTTTA TCCGATA 24300

AAATGGCTAC TCCAGCTTGT TTCTTCAGTC CATTTGCTTG GAAAATTGTT TTCCAGC 24360

TTACTCTGAG GTAGTGTCTG TCTTTTTCCC TGAGATGGGT TTCCTGTAAG CAGCAGA 24420

TTGGGTCCTG TTTGTGTAGC CAGTCTGTTA GTCTATGTCT TTTTATTGGG GAATTGA 24480

CATTGATATT AAGAGATATT AAGGAAAAGT AATTGTTGCT TCCTTTTATT TTTGTTG 24540

GAGTTGGCAT TCTGTTCTTG TGGCTTTCTT CTTTTTGGTT TGTTGAATGA TTACTTT 24600

GGTTGTTCTA GGGCGTGATT TCCGTTCTTG TATTGCTTCT TTTCTGTTAT TATCCTT 24660

AGGGCTGGAT TCGTGGAAAG ATATTGTGTG AATTTGTTTT TGTCGTGGAA TACTTTG 24720

TCTCCATCTA TGGTAATTGA GAGTTTGGCC TGGTATAGTA GCCTGGGCTG GCATTTG 24780

TCTCTTAGTT TCTGTATAAC ATCTGTCCAG GCTCTTCTGG CTTTCATAGT CTCTGGT 24840

AAGTCTGGTG TAATTCTGAT AGGCCTTCCT TTATATGTTA CTTGACCTTT CTCCCTT 24900

GCTTTTAATA TTCTATCTTT ATTTAGTGCA TTTGTTGTTC TGATTATTAT GTGTCGG 24960

GAATTTCTTT TCTGGTCCAG TCTATTTGGA GTTCTGTAGG CTTCTTGTAT GATCATG 25020

›Example 10 · 36 of 49

ATCTCTTTTT TTATGTTTGG GAAGTTTTCT TCTATTATTT TGTTGAAGAT ATTAGCT 25080

CCTTTAAGTT GAAAATCTTC ATTCTCATCA ATTCCTATTA TCCGTAGGTT TGGTCTT 25140

ATTGTGTCCT GGATTACCTG GATGTTTTGA GTTAGGATCC TTTTGCATTT TGTATTT 25200

TTGACTGTTG TGTCGATGTT CTCTATGGAA TCTTCTGCAC CTGAGATTCT CTCTTCC 25260

TCTTGTATTC TGTTGCTGAT GCTCGCATCT ATGGTTCCAG ATCTCTTTCC TAGGATT 25320

ATCTCCAGCG TTGCCTCGCT TTGGGTTTTC TTTATTGTGT CTACTTCCCC TTTTAGT 25380

AGTATGGTTT TGTTCATTTC CATCACCTGT TTGGATGTGT TTTCCTGTTT TTCTTTA 25440

ATTTCTACCT GTTTGGCTGT GTTTTCCTGC TTTTCTTTAA GGGCCTGTAA CTCTTTA 25500

GTGCTCTCCT GTAATTCTTT AAGTGACTTA TGAAAGTCCT TCTTGATGTC CTCTATC 25560

ATCATGAGAA ATGTTTTTAA ATCTGGGTCT AGATTTTCGG TTGTGTTGGG GTGCCCA 25620

CTAGGTGGGG TGGGAGTGCT GCGTTCTGAT GATGGTGAGT GGTCTTGATT TCTGTTA 25680

GGATTCTTAC GTTTGCCTTT CGCCATCTGG TAATCTCTGA AGCTAGCTGT TTTAGTT 25740

ACTGTTAAGA GCTTGTTCTT CAGGTGACTC TGTTAGCCTC TATAAGCAGA CCTGGAG 25800

AGCACTCTCC TTAGTTTCAG TGAGCAGAGT ATTCTCTGCA GGCAAGCTCT CTTCTTG 25860

GGCAGGTACC CAGATATCTG GTGTTCGAAC CAGACTCCTG GCAGAAGTTG TGTTCCA 25920

ACTAGAGGTC TTAGGATCTT GTGTGGAATC CTGTGTGGGC CCTTGCAGGT GTCAGGC 25980

TCTGCTGGCA AGGTAGCCCG GGGCTCGAGT CGAGTGGAAG GGACTTGTGC CCCAGAT 26040

GCCCGGGTAG CCTGCTTCCC TATGTACTGC AGTCTCAGGT TCCGCGCGAT TGGATTG 26100

CAGGCACTGT GTTCCACTCA TCAGAGGTCT TAGGATCCTG TGGGGGGTCC CGTGTGG 26160

CTTGCGGGTG TTGGGCAAAC TCTGCTGGCA AGGTAGCCCT GGGCTCGAGT CGAGCGG 26220

GGACTTGTGC CCCAGATCAG GCCAGGGTAG CCTGCTTCCC TATGTACTGC AGTCTCA 26280

TCCGCGCGAT TGGATTGGGG CAGGCGCTGT GTTCCACTCA CCAGAGGTCT TAGGATC 26340

TGGGGGGTCC CGTGTGGGCC CTTTCGGGTG TTGGGCAAGA CTCTGCTGGC AAGGTAG 26400

GGGGCTCGAG CTCTTTTTTT TTCTTTAAAA AAAAATTTTT TTTATTAGGT ATTTTCC 26460

TTTACATTTC CAATGCTATC CCAAAAGTCC CCCATACCCT CCCCCTGACT CCCCTAC 26520

CCCACTGCCA CTTCTTGGCC CTGGCGTTCC CCTGTACTGA GGCAGATAAA GTTTGCA 26580

CCAATGGGCC TCTCTTTCCA CTGATGGCCT GCTAGGCCAT CTTCTGCTAC ATATGCA 26640

AGAGACAAGA GCTCCAGGGG GTACTGGTTA GTTCATATTG TTGTTCCACT TATAGGG 26700

CAGATCCCTT TAGCTCCTTG GATACTTTCT CTAGCTCCTC CATTGGTGCC CTGTGAT 26760

TCCAATAGCT GACTGTGATC ATCCACTTCT GTGTTTGCTA GGCCCCGGCA TAGTCTC 26820

AGAGACAGCT ATATCAGGGT CCTTTCAGCA AAATCTTGCT AGTGTATGCA ATGGTAT 26880

TGTTTGGCGG CTGATTATGG GATGGATCCC CGGATATGGT AGTCTCTAGA TGGTCCA 26940

TATTGTCTCA GCTCCAAACT TTGTCTCTGT AACTTCTTCC ATGGGTGTTT TGTTCCC 27000

TCTAAGAAGG GGCAAACTGT CCACACTTTG GTCTTCATTC TTCTTGAGTT TCATGTG 27060

TGTATCTTGT ATCTTGGGTA TTCTAAGTTT CTGGGCTAAT ATCCACTTAT CAGTGAG 27120

ATATCATGTG AGTTCTTTTG TGATTGGGTT ACCTCACTCA GGATGATGCC CTCCAGG 27180

ATCCATTTGC CTAGGAATTT CATAAATTCA TTCTTTTTAA TAGGTGAGTA GTACTCT 27240

GTGTAAATGT ACCACATTTT CTGTATCCAT TCCTCTGTTG AGGGGCATCT GGGTTCT 27300

CATCTTCTGG CTATTATAAA TAAGGCTGCT ATGAACATGG TGGGGCATGT GTCTTTC 27360

CCAGTTGGAA CATCTTCTGG ATATATGCCC AGGAGAGGTA TGTCGGGATC CTCTGGT 27420

ACTATGTCCA TTTTTCTGAG GAACCGCCAG ACTGATTTCC AGAGTGGTTG TACAGCT 27480

AATCTGACCA GCAATGGAGG AGTGTTCCTC TTTCTCCACA TCCTCACCAG CATCTGC 27540

CACCTGAATT TTTGATCTTA GCCATTCTGA CTGGTGTGAG ATGGAATCTC AGGGTTG 27600

TGATTTGCAT TTCCCTGATG ATTAAGGATG CTGAACATTT TTTCAGGTGC TTCTCGG 27660

TTCGGTATTC CTCAGGTGAG AATTCTTTGT TTAGCTCTGA GCCCCATTTT TAATGGG 27720

ATCTGATTTT CTGGAGTCCA CCTTCTTCAG TTCTTTATAT ATATTAGATA TTAGTTC 27780

ATCTGATTTA GGATAGGTAA AGATCCTTTC CCAGTCTGTT GGTGGCCTTT TTGTCTT 27840

GACGGTGTCC TTTGCTTTAC AGAAGCTTTG CAATTTTATG AGGTTCCATT GGTCAAT 27900

AGATCTTACA GCACAAGCCA TTGCTCTTCT ATTCAGGAAT TTTTCCCCTG TGCCCAT 27960

TTCAAGGCTT TTCCCCACTT TCTCCTCTAT AAGTTTAAGT GTCTCTGGTT TTATGTG 28020

TTCCTTGATC CTATTAGATT TAACCTTAGA ACAAGGAGAT AGGAATGGAT TAATTCG 28080

TCTTCTATAT GTTAACCACC AGTTGTGCCA GCACCATTTG TTGAAAATGC TGTCATT 28140

CCACTGGATG GTTTTAGCTC CCTTGTCAAA GATCAAGTGA CCATAGGTGT GTGGGCT 28200

TTTTGGGTCT TCAATTCTAT TCTACTGGTC TACTTGTCTG TCACTATACC AGTACCA 28260

AGTTTTTATC ACAATTTAGG TCAGGCATGG TGATTCCACC AGAGGTTCTT TTATCCT 28320

GAAGAGTTTT TGCTAACCTA GGGTTTTTGT TATTCCAGAT GAATTTGCAG ATTGCTC 28380

TTCATTGAAG AATTGAGTTG AAATTTTGAT AGGGATTGCA TTGAATCTAT AGATTGC 28440

TGGGAAGATA GCCATTTTTA CTATATTGAT CCTGCCAATC CATGAGCATG GGAGATC 28500

CCATCTTCTG AGATCTTCTT TAATTTCTTT CTTCAGAGAC TTGAAGTTTT TTTTCAT 28560

GATCTTTCAC TTAGTTAGAG TCACACCAAG GTATTTTATA TTATTTGTGA CTATTGA 28620

GGGTGTTGTA TCCCTAATTT CTTTCTCAGC CTTTTTATTC TTTGTGTAGA GAAAGGC 28680

TGACTTGTTT GAGTTAATAT CCAGCCACTT CACCGAAGCT GTTTATCAGG TTTAGGA 28740

CTCTGGTGGA ATTTTTAGGG TCACTTATAT ATACTATCAT ATTATCATCT GCAAAAA 28800

ATATTTTGAC TTCTTCTTTC CAATTTGTAT CCCCTTGATC TCCTTTTCTT GTCGAAT 28860

TCTGGCTAGG ACTTCAAGTA CAATGTTGAA TAGGTAGGGA GAAAGTGGGC AGCCTTG 28920

AGTCCCTAAT TTTAGTGGGA TTGCTTCCAG CTTCTCACCA TTTACTTTGA TGTTGGC 28980

TGGTTTGCTG TAGATTGCTT TTATCATGTT TACGTATGGG TCTTGAATTC CTGATCT 29040

CAAGACTTTT ATCATGAATG GGTGTTGGAT TTTGTCAAAT GCTTTCTCCT CTTCTAA 29100

GATGATCATG TGGTTTTTGT CTTTGAGTTT GTTTATATAA TGGATTACGT TGCTGGA 29160

CCATATATTA AACCATCCCT GCATCCCTGA AATAAAATCT ACTTGGTAAG GATGGAT 29220

TGTTTTAATG TGTTCTTGGG TTCGGGTAGC GAGAATTTTA TTGCTTATTT TTGCATC 29280

ATTCATAAGG GAAATTGGTC TGAAGTTCTC TATCTTTGTT GGATCTTTCT TTGTTTT 29340

TATCAGAGTA TTGTGTCTTC ATAGAATGAA TTGGGTAGAG TACCTTCTGC TTCTATT 29400

TGGAATAGTT TGTGCAGAAC TGGAATTAGA TATTCTTTGA AGGTCTGATA GAACTCT 29460

TTAAACCCAT CTGTCCCTGG GCTTTTTTTG GTTGGCAGAC TATTAACGAC TGCTTCT 29520

TCTTTAGGGG ATATAGGATT GTTTAGATCA TTAACCTGAT CTTGATTTAA TTTTGGT 29580

TGGTATCTGT CTAGAAACTT GTCC 29604

16442 base pairs

nucleic acid

single

linear

208

TGTTCTTGTG GCTGTCTTTT TGGTTTGTTG AAGGATTACT TTCTTATTTT TTCTAGGGCG 60

TGGTTTCTAT CCTTGTATTG GGTTTTTTTT TTTTTTCTGT TATTATCCTT TGAAGGGCT 120

GATTCGTGGA GAGATAATGT GTGAATTTGG TATTGTCATG GAATACTTTG TTTTCTCCA 180

CTATGGCAAT TGAGAGTTTG GTTGGGTATA GTAGCCTGGG CTGGCGTTTG TGTTCTCTT 240

GGGTCTTTAT AACATCTGTC TAGGATCTTC TGGCTTTCAT AGTCTCTGGT GCAAAGGTC 300

GGTATAATTC TGATAGGCCT GCCTTTATAT GTTACTTGAC TTTTTTCCCT TACTGCTTT 360

AATATTCTAT CTTTATTTAG TGCACTTGTT GTTCTGATTA TTATGTGTGG GGAGGAATT 420

CTTTTCTGGT CCTGTCTATT TGGAGTTCTG TAGGCTTCTT GTATGTTCAT GTGCATCTC 480

TTAAGTTTGG GAAGGTTTCT TCTATTATTT TGTTGAAGAT ATTTGTTGGC CCTTTAAGT 540

GAAAATCTTC ATTTTCATCT ACTCCTATTA TCCGTANGTT TGGACTTCTC ATTGTGTCC 600

GAATTTCCTG GATGTTTTAA GTTAGGATCT TTTTGCATTT TGCATTTTCT TTGATTGTT 660

TGCCTATGTT CTCTATGGAA TCTTCTGCAC CTGAGATTCT CTCTTCCATG TCTTGTATT 720

›Example 10 · 37 of 49

TGCTGCTGAT GCTTGCATCT ATGGTTCCAG ATTTCTTTCC TAGGGTTTCT ATCTCTAGC 780

TTGCCTCATT TTGGGTTTTC TTTATTGTGT CTACTTCGCT TTTTAGGTCT ACTATGGTT 840

TGTTCATTTC CATCACCTAT TTGGATGTGT TTTCCTGTTT TTCTTTAAGG ACTTCTACC 900

GTTTGGTTAT TTTTTCGTGT TTTTCTTTAA GGACTTGTAA CTCTTTAGCA GTGTTCTCC 960

GTATTTCTTT GAGTTATTAA AGTCCTTCTT GATGTCCTCT ACTATCATCA TGAGATAT 1020

TTTTAAATCC GGGTCTAGCT TTTCGGGTGT GTTTGGGTGC CCAGGACTGG GTGAGGTG 1080

AATGCTGCAT TCTGATGATG GTGAGTGGTC TTGGCTTCTG TTACTAAGAT TCTTACGT 1140

GCCTCTCACC ATCCAGTAAT CTCTGGAGTC AGTTGTTATA GTTGTCTCTG GTTAGAGC 1200

GTTCCTCTTG TGATTCTGTT AGTGTCTATC AGCAGACCTG GGAGACTAGC CTTCTCCT 1260

GTTTCAGTAG TCAGAGCACT CTCTGCAGAT AAGCTCTCCT CTTGTAGGGA CGGTGCCC 1320

ATATCTGGCA TTTGAACCTG CCTCCTGGCA GATTTTGTGT TCCACTCACC AGAGGTCC 1380

AGATCTCGTG GAGAGTGTTC TGGGTACCTT GGGGGTGTCC GACAACTCCG TGTCCGAC 1440

TTCTAGTGCT GGGGCCGACT GGAAGGGACC TCTTTTTCTT TTATAAAGTA ATGAAAGC 1500

TGTGTTGATT TTGGTGGCAA AAGAGAAGTT CAAAGTGCAA TAATGAAACC CTCCATTT 1560

GAAACTCCAT CTCAGCGTCC AGTTGCCTGA ACTAACGCCC GTTCATCTTT CCTGCCAA 1620

TTAGTATTTT GTATATTGCA CACTTGAATG TTTATTGTAT CTAACGGATT TATTCCAA 1680

GCACGTCTTT GGAAAAGATG ACTACAGGGC AACTCTCAAT ATAGAATGTT GAGTGTCT 1740

TTGACCTTTA ACATCATCAC CTATGTTTCC ATCATTTTAT TGATGAGATG ATTACATC 1800

TATATTCAGC CACGTATTCA TTTGGTTTTG AGATCAAAAC CATTCTTGCC TATTCCGC 1860

CCTTCTAGGA ACAGCATCTT TAACGTTTCA GCCCTTTGAT ACCCACATTA TGGAACCT 1920

GAGTTAAATT CCTACTGTCC ACTATGAATG AGGTCTCAGA TGGGAGGCTT GTTTTTTT 1980

TGGTCCCTGG GGACAGCTGA CTATGACTGT GAATGTTTGC TCTGTCCCCC TTTCACTC 2040

TCCAGTTGAA GTGCGCAGAG ACCTGGAGCC TCAATGGTCT GGTTAAACAC GTCTTAGG 2100

AACAACTTTT GAAAGACAAG TCCATCCGCT GCAGCAATTG GAGTAATTTC CCCCTCAC 2160

AGGACCAGAA ACTGTATGCA GCCACTGATG CTTATGTATG TATTTAAAGA CCTTTAAT 2220

GACATCATTC TCATTTCTCG GACCAAATCA CTTTAGTAAA AATGTATTGG GGTTATGT 2280

TTAGCTGAAA TATTTTATTA TAGTTTGGCA TTAAAATTTG CTTAGGAATA CATCAAGT 2340

AATTCTTCAT GTTAATTAGA AAATACCAAT TAATAGGTTG TTTAGCAGTA GTTATTTC 2400

CTATTACGAT GTAAAGTGAT GTCCAATTCC TGTGTAAAAG AATGTGAACT TACTGAAA 2460

ATGAAAGGCT TTGAGCTTAG CAGGCACAAA TAGTTTGATG ATGTATTTTG TATATAAG 2520

ACTCAGAATC AGAAAAATCA CAGGCTTTCC ATATTTAAAC TAGCCTTATT CCCTACAT 2580

ATATTTAAAA TGTGGAAATT TAGATAAATT GCCTCCAAAT TTAGTTGCTG CTGTTCTT 2640

ATGTATTTTC ATATGTGTAA TCTGTACATA CTGGCATCTA GGCTTGTCTT TATATATA 2700

ACTGTGGTCT GTGTGTGCTT TACCTTAAGA AATGTTTCTT TTGTAAATTT CTTTGCCC 2760

GATCATACTT ATTGCTCATA TTTAAATAGT ATTTATTGAT AAATATCTTG TTAATTTT 2820

ACCTTACATT TATTTTTAAG ACATCGATAC TCTAACTTTT AGCCAGAAAA ACAAAGGA 2880

ACCAACTGTC TTAGTCAGGG TTTCTATTCC TGCACAAACA TCATGACCAA GAAGCAAG 2940

GGGGAGGAAA GGGTTTATTC AGCTTACACT TCCATACTGC TGTTCATCAC CAAGGAAG 3000

AGGGCTGGAA CTCAAGCAGG TCAGAAAGCA GGAGCTGATG CAGAAGCCAT GGAGGGAT 3060

TCTTTACTGG CTTGCTTCCC CTGGCTTGCT CAGCCTTCTC TCTTATAGAA CCCAAGAC 3120

CCAGCCCAGA GATGGTCCCA CCCACAAGGT GTCTTTCCCC CTTGATCACT AATTGAGA 3180

ATACCCCACA GCTGGATCGC ATGTAGGCAC TTCCTCAACT GAAGCTCCTT TCTCTGTG 3240

AACTCCAGCC TGTGTCAAGT TGACACAAAA CTAGCCAGTA CAGCAACAGA TGCTTTTT 3300

CAGGAGAACA GCTGGATGAG TTGGGATGTG CTGTTGTTCC TTTGGCTTCC TTTGCTTC 3360

TGCTTACTTG CTTTAAAAAA AATAACAGAC TCTCTTGCAG CTTATTCCAC TCTTGAAC 3420

TTCATGCAGC CGAGGCTGCC CTTAATGTCC AGATCCTCTT GCCCCTGTTT CCTTGCTA 3480

GAGATTACAG GCTGTAGTGT CTATATTCTT GACAGTTTGT ATGACTTGAT CAAGTCTG 3540

AAAAATACCC AGCATGCATT GTTGTTCATA CACTGACCAG CATTCTCAGT TGGTTTAA 3600

AAATCTCAAG AATTGGATAG GATCTGTCAC CAAAACAGAT GTTTCTTACT AGATGGTA 3660

TATTAGATTT TGTTTACAGA TCATTTCATT TGGATACCTA TTTACAATAC TGAAAATT 3720

TAAGTGAAAA TTTAAAGCTG TATTTTATAG CCTAGGCAGC TTTTGTTTCC CCATTGGG 3780

GTGCTTACAT GAAGACCCGA GTCTTTGCAT ACTGAAATAG TTTTACTTCA TTTTTGGA 3840

GTATTTTGGA AATCATTCTT GTAGATGTTG CTTGAGATAT CACATATATA TATTTATT 3900

GGTAATCTTT AACTTGCACT TTGTTTTTCT TTTGTCTTTT TATAGGCTGG TCTTATCA 3960

TATCAAAAAT TAGGAAATTT GGGTGATACT GTGCAAGTGT TTGCTCTAAA TAAAGGTA 4020

TTGTGGCCTA AAATAAAAGA TAAAAATATG AATTTGCTAT TTTGTGAGAT TCATTTAA 4080

AAGTCAAAGT ATTATGTATC TTTGCAAAGT ATTATGGTAC TTCTTAAATG TCTGAGCA 4140

GTTGCTGTAA AGGTGACATC CATCAGGATC AGAAATTAGA GTTGTAGATC TTCCCTTG 4200

AAAAGCAGGG ATTCCATTGC TAGTTTGATA GTGTTGCTGC TCTTCTTGTC CATGGAGT 4260

CCATGTTATT GTCCTTGATA ACATCAGTTA GCCAGCCAGC TGCCTCTTGG CTGGTAAC 4320

CCACATTCTT TCTACACTTG TTTAAAACGG ATTTGCCTCG ACTATTCCTG TGTATATG 4380

GCACTGTAGT GTTCTGCCTT TCTGTGTTCG GTTGCTGTTT TCTTCACTCA GCTTCATT 4440

CCTTGTCAGA TGCTTTGATC TGTTAGTGAT TACAGGCAGA GTCAGCCAGT AGGTGGAT 4500

GCACCAGCTT TTGTGCTGCA GAACCTCTGT GGTGGAGCCT TAGCCATCTG ACCTGTAA 4560

TGTCCCTTTC CCCATGCTTG TAATGTGGAC AATAGATAAG TGTCTATCTC ATGGATTG 4620

TGTGACCACT AAAGGGACAG ATGTTCAAAG TAAGATGGTC AGAGAAAATT GTTAAATA 4680

TTGAACAGTC CTATAATACA TGATCTGAAA TGCTTTGAAA TCGGAAACTT TTTGGTGA 4740

ACATGATTTA CGTATTCATT AGTATATTTC ATTGAAAATA TTTCCTGGAA GAAGCAAT 4800

TTGAGAAGCC TGAAATAGGA ACAGAAATTT GCCAGCCAAA GCCAGAGGGA AAGTGATA 4860

CAGGTACAAA GCCTCAGAGG GCAGCTCTCT GGAACTTATG CAGTGTAAGG AAACTGTT 4920

CTGTGACAGT GTAATGTAGG AGAAGCAGAA AAATGAGACA GGCCTCACTA AAGAGGTT 4980

ATGTAGCCTT CCAAAGAGCA AATTGAAGCT GTTATTGACG GTTCTAAATG TGGAAGTG 5040

ATGCGCTGGA TTGAAAACAA GCTAACAAAA CAAGCTGTAG AATAAAACAC ACTAACTA 5100

CGAGCCACAG AGAAAGAAAG TGGATCTTAG GATTACAAAA GAATGGTGGG AAAGGCTT 5160

TGGAGGCTAT GATGGTAAGC CAAGAAAGAG GAATTGGTAC CTTGAATTGG TTATTTGT 5220

CAAGGGTCGG CACAGTGGGT AGCGTCANCC TACATTTAAT GGAGGCAACA GAATCTGC 5280

TAATGACAGG CACACGCCAA GGATCCTCCT GGCTTTTGGC TGCACGACAG ATTAAAAT 5340

AGGGTAAAGA CTCACTTTAT ATAGACCAGG CTGGCCTAGA ACTCAGAGAC CTACCTGC 5400

CTGCCTCCTG AGTGCTGGGA TTAAAGGTGT GCACCACCAC CACTCAGCTG GAAGTAAA 5460

TTTATAGTTG TTTTTTTAGA CATGTTCAAG GAGAGTAACA TCTCAGGTAG CAAGAGGG 5520

GTAGCCTGTG GACACCTAGA TATGTAGGTT GTATCTCAGA AGACAGTTTG TCTGAGAT 5580

AATGTAAGCA CTAAGTGTCC TAAGAAACTG CTGGCGTCTA ATCTTTGTGT GGGGGAGG 5640

ACCCTATAGG AGTTGCCCTG GGTGTGGAAG GAGATGAGAA AGTGCTGGAC AATTCAAG 5700

CCAGTGTGCT GAAAGTCAAG GGAGGGCTAG GTTTGAGGGA GGAGGATGTT ATCAACTG 5760

TTGAATTCTG CTGAGATTTT GGCAAAGTGA AGGCTTGTAG GCAATCATCA GATTTGGC 5820

AATGGCCACT ATCATTTGTA ACCTTCTACA CCAGTGGTTC TCAACCTTCC TGTACTGT 5880

CCCTTTAATA CAGTTCCTCG TGCTGTGATG GCACCAACCA TGACATTATT TCCTTTGC 5940

CTTCTTGACT GTAATTTTGC CACCGTTATG AATTGTGATG TAACTATCTG ATATACAG 6000

TGTTTGATTT GTAAACCCTG TGAAAGAGCC ATTTGATCAA TCATTGTTCT GTGCTCTA 6060

›Example 10 · 38 of 49

TCTGGTGTCC TGGGTGTTGA CAAAAGAGTA TTGCAATCAG AGGGTGAACT TCTAGAGC 6120

ACAGGGTCCA GAGGCTTTGG TAGTATAAAA ATATTATAGG CATAGCAAGA ATAAAGTA 6180

TTAATGAGGT AGGTAGAAAC CAGTACTAAA ATTATATCAA TCATATTACT GCAAATAG 6240

GAGAAAGATG TAAGGAATTG ATTTTAAGTG TATATAAATA ATATTTTTTA AAGACTTA 6300

TTAGAAAGGG AACGTTCATA AAACACAGGT TTGTCTAGTG TTTGCTATAT TTTAGTGT 6360

ATTATGTATT GATTTTATTT GACAAGCAAG GTAACATGCT ATTTGGCTCT CTGAAGGA 6420

AGAGCCAAAT GCTTAGAGCT GAGAAAGTAC AAAGCCACTG AGGGCAACTG CTTCCCTA 6480

GTAAGGAACA GAAATATAAC CAAAGAGAAA CGAGTGTGAG GGAGACTTGT AGGAAACA 6540

GCTGGAAAAG AGGCTTGGGG CCAGTCAGTT AGGGCATCAG ATTGTGTGAA TTGGACTT 6600

TGTTTTAATA CTCAAAACCA TCAACAACCA CGGTACAACG ATGGCCAATA GGAAACCC 6660

AGTTTGGGTG TGTGGAGCAG CAGAGTAAAA TGATCCAGAT TTTGTCTTAA AGTGTTTT 6720

TTTTCTCACT GCTGTAAGAA GGTCAGGAAG TTAGATAGGA GGCTTTTTCA ATTGTCCA 6780

AATAGAAGAT AGTTGTACTG GGCCAGTGGA GGTAGCAAGA AATGTAAATG CAGTAGGT 6840

TCTGAAGGCA TACACTGAAG AATTCTAGGT GAATTCCTTA TAAAGGGTGA GGAAAAGA 6900

GCTAGGATGG CCAAGGTATT TTTCTTTTCT TTTCTTTTTC AGTTTTTCGA GACAGGGT 6960

CTCTGTGTAG CCCTGGCTGT CCTGGAGCTC ACTCTGTAGA CCAGGCTGGC CTTGAACT 7020

GAAATCTGCC TATCTGCGCC TCTCAAGTGT TGGGATTAAA GGCGCCCGGC TTAAGGTA 7080

TTTCTTGAAT GACCTGATGA CTGGCAGTGC AGGATGATAT GAAGAGTATG TTTTGGTT 7140

AAAAAATCCA CCAAAGTTGC AACGTGGACA TGAAAAAAAA CTAGAGGTGG ATTTTGAT 7200

CCACGAACGG CTCCATACTA GTTATTTTCT GTTACTGTGA TAAAACACCG TGACCAGA 7260

GGTCTTTAAG GAAAGGAGTT TCTTTTTGCT CACAGTCCCA GAGGGAAGTC TTCAGTGG 7320

CTGCGGGAGC ATGGCAGAAA GCAGCCGGCT TGGCAGTGGG GCAGGAAACT GTTAGGTC 7380

ATCTTGAACA GCAGTCTTGA AGCAGAGAGA GCAAACAGGA AGTAGGGTGA AGCTGTGC 7440

TCTCAAAGCC ACCCCCAGTG TCAAACTTAC TCCCGGAAGG TTGCACCACC TAAACCTC 7500

CAAATGGAGT CACCAACTGA GCATCCAGTG TTCCACTGCC CGCGAGCCTG TGGGAAAT 7560

TTCCCACCTA ACCACCACTG CACTGTGAGA AATGGAATTC CAGAGTACAC GGCGGAAG 7620

GGGGTTAGAA ATATAGATTG TCCAGTGGTG AAACTGGAGA TAAAACTGGG AGTGAATA 7680

CTGAAGAATA TAGGTGGTGT CAGCTTCAAG GTCACACTGA CATTTAGAAA ATGAGAGT 7740

CTTGAGGGCG GAGACGGGGC ATCAGTGAAT GAGGAGGGGG GCGAAGGACA TGCTTTAA 7800

AGGAAGGAGA CATCAGCCCC TTAAACCTCG GAGGAGTTGA ACGATGCACA GATCGTGG 7860

TAACTATTAG GGTTGATAAT GTGGTAGCCT TCCCAGAGGA AGCTGTGCTG CTGAGGGC 7920

AACTCTTGAG TTGGAGTTAG TTTAGGAGAA AATAAGAGCA GAACATTCGA GGATGAGC 7980

CAGGCGTTGG AAACGTAAAA GAGAAAGAAG AGGTGTAAAA TTGTCATCTT AAGATAAG 8040

GGGTCTGCGT CATGAGTTTA AAACTAAACC GGCCATTATC ATTTTGTTTT AATTTCAA 8100

ATGTCCAGCT ACTTAGGCAC CGATTAGCTA AAGAAGTTGA GTATGATTAG AGTAGATT 8160

GCCCCGTGAG TTCCACGGAG TTGGGTAAAG AAGGCAGAAG TGGAGAGTCT GTATCAAA 8220

AATGGCTAAG AAAGGAAAGG AGACCAGGTA GGGAGAGTAG GAGTGGGTGC TGGAGGGG 8280

GGATTCAACA GGTTTCATTC TGAAGTGTTA ACTCACTGAG CTGGGGTAAG CAAGCCAG 8340

AGAGCGGTGG GATGGCTCTA TTTATGGTGG AAAGTGTTTG TAATAGAAGG TTTGGGTG 8400

GTGGAGGTTT TATTGGGCAG TTTTAAGGTC GAGAGTCTGA TTGTGGGAAT GAGTAGCT 8460

GATTAGATGA GGAAGATTGT TGGAATGAAG GGTGACCCTT GGGCAAGGGT TCCAAACG 8520

GTTAAGTTTG AACGTGCCTG GATTGGGGCT TACTGACTTC CAAGTCAGAA ACAGTGTC 8580

GTGAGTTTAG AGTCCCAGGC TTGTCCTCTG GCCCAGGTCA GTAACATTTA GATTGGAT 8640

TGTATACATT TGGAATTCAC TCTAAATTTC AAATAGCAAA AATTTGAAAG GAACATTA 8700

ACAAGGGAGT AAAGAGGAAA GTGATTTAGA GATCCGAGAG GGAAGTGTTC TGTTAGAA 8760

CATTGTGCGA ATAGATGAAA ATCTGGATAC TAATACTATG CTGTGATGTG GTTAAATA 8820

ATCTCTGCTT TCTAATTTTA ATATTAATCT TTTCTCTCTC TCTCTCTCTC TCTCTCTT 8880

TCTCTCTCTC TCTCTCTTCT TTTATTTAGC AGAGGAAAAC CTACCTCTGG AGATGAAG 8940

ACAGTTGAAT TTAATCTCCG AAGAAATGAG GGATCTAGCC AATCGTTTTC CTGTCACT 9000

CAGAAATTTG GAAACTCTCC AGAGGTTAAA TATTGTGCTT TTTAAAATAT TTATTTTA 9060

TTTAATTGTA TGTGTATGCG CGTTCAGTCA CCTTTTATGC TATTTTCTTA AACATGGA 9120

TCTGATTTTT ACAGAATGCC TGCTTGTTAT AAATTACATA TACCTACAGC TTGGCTTT 9180

AACAGCAAGT TAAGTAGGAT TTATTAGCAT CAAGAACTCA CAACAGAGTG GTTTGAAG 9240

TATTGTAGGA AGGAACAGTT GTTTTTGTCT CAGAGGACCC TAATAGAATC GATGTGAT 9300

AGTATTGTTT AGTCATTTAT TTACATTCAG TGTGCTGCGG TGTTGCTGCA GTGTGATT 9360

CACTCTACTG GCTGTTGAGC TTGTCTGCTG CTAACTAATG AGCAGGATAG AAATCTTA 9420

GAAGGAAATG TGCATGCCAC CATGTATGCC TTCCTAGTCC AGCCTTTAAC GTTAGAGT 9480

GTGGTTATGT CTTACTCTGA TGTGAGTGCT TGGTAAATAA GATATTATAA TAGTATCA 9540

GTTGCTATAG CAACACATTT ATTTCACAAT TAAATTGAAT CATAACTTCT CATACCAT 9600

TATTTATACA CAGTTGTTAT ATATAAGCAG TATATGTATA TACATATAAT TATATACT 9660

GTATGTAGTA AAATTTACAA AATTGCCAGG CACCACGGTA CATACCTGTA ATCTGTGC 9720

TCAGGAGGCA GAGGCAGGAG AATTCCAAGC TCAAGGCCAG CCTGACTAAT AAAAAGCT 9780

ATAAATTTTT ATTATTTTAA AATAACTTGT TATTAGATTT TGAATTTAGT TAATAGTT 9840

AAAAGTTTTT TTTTTGTATC ATTTTATGTG TATGGCTGTC TTTGCCTGCA TGTATGTC 9900

TGTACAACTT ATGTGATGTA TTCCTGAGAG GTGCAGAGGA GGGTATTGGA TCTTCTGG 9960

CTGGTGTTAC ACACAGTTGA AAGCTGCCAT GTGGGTGCTG GGAATCAAAC CTGGGTC 10020

TAGAAGAGCA GCCAATGCTC TTAACTGCTG AGCTATCTTT CCAGCCCTGA ATTTAAT 10080

GATCTTGATT TTTGCTTATG TTAATATAGA CTTTGACAGT TTAAGGTTGA GCTAAAG 10140

GGAGAGTTGA TAATTGTGTA GTTTTGTTTT TTTGAGTATT TTTGTACATT TTATTAT 10200

CATAATTACT TTCCATTACA CTCTCTTATC CCCCTGATTC CTGCTGACTC CCTCTTA 10260

AAGTAGCTCC TTTCCTTCTT TCACGTCTCA TGTGTGTTTG TGTATTTGTG TGTGCAT 10320

TGTGCATGTG TGTGTGTGTG TGTGTGAGTG TGTGTGAGTG GCACTGTGTT TATTTAG 10380

TATTTGTATG AGCATGGTTA AGAGGCTGCT GACTAAGCAC TGGCAACTTT ACCAGTG 10440

ACTGAAGAGA ATGATGACTG TTTGCCTAGA AGCCAAGCAA AAGCTCCCTA GGGAAGG 10500

GGGTGGGTCA CTTTTGAGCT TCACCATCCA CGTGGGAGCG GCAGAAGGCC CTGTGTT 10560

TGGGTTTTAT GCAGATATCC ATAGCTGCTG CGTGTTTATG ATTTCAGTAG CCATGCA 10620

TCTACATGGC AATGTTTCAC AGCACTCCCC CACATCGTCT GACTCTTACG GTTTGTC 10680

CCATCCTGTT ATGTCCACTG GGCCATTGAA GGAGTTTTAT GTACAGGCTG GTCCCAA 10740

AGGCAGAGCA CCCAGTATTC ATTTATGCTC AACACTTTGA TCATTGTGAG TCTTCTT 10800

CCAAAAGCTT CTTTGACCAA GACTGAGAGT AGCACTCTGG ATAAGAACAA GAGTTCG 10860

GCAATATGAT ATGTGTCTAT CTAGCAATGT GTCAGCAGTT GGTACCCCTC TGCTATG 10920

TGTGATCTCC CCAGCCAAAG GCTTCTGACC AGATTTATAC TTCCAGTCAC GTATTCC 10980

CTGAAGGTCC AGGCTTCAAA TGCCTCGATT GCTGATTGAT GTGACCCACC CCCAGTC 11040

TCATTGGTTC TCCAGCAGAC ATACCTTGCC TGGCAGGTTG GTACTGTAGC ATGCAGG 11100

CAGAGTTGGG TAAGACCCTT GATGACCATC GCCACCCCTC CCCCCTGGCA GGTGGCA 11160

TACCTTTTCC AAGTATGAAT GCTGACTGGC AGGATGAAAC TGAAGCATCC GGTCAGT 11220

AGTTTGATTT TTCTGTGTCT TGTAAGAATG AGCTCCCAGT GTAGGACCAA CCCCTGG 11280

AACTCAGACT TTGATGGTTT ATTCTCATAG AAGAGCAGAG TTTCATCTGA ACCATTA 11340

TAAAAATTAG CTGGAACTAC CTGAACATTT CTGGTTTTAT AAATCATTGA GTTAAAT 11400

›Example 10 · 39 of 49

GGAAAATTAG AATACATAGT CCAAAGCACT TATTACATAA CAACATACGT CTCTTTG 11460

ATTACCATCT TTTGTCTTTC TCTAATTTCC TCACTTATTT AGGTAATTTT TCTTTCT 11520

GTGCTGAGGA TTGAGCTTGA AGCCTTGTGC ACTCCAGGCA AGCATCACAG AGTTGTC 11580

AAAGTAGTCC TGTTGTTTGG TGTTCTGCAC AGTGTTTCTT ATTTACACTA CGTTCAG 11640

GTATTACCTA CAATTTCTAC TTTTAGTTTC TTTAAAGTGG AATGATAATT CAATATA 11700

GAAGTCATGT GACTACAAAG TCCTAAGAAT TTTTAAGTTT TTTTCTTATG AGCTTTT 11760

GTTATTTTGA CTATGGGGCA TAATTTTTTG ATTATAATTT TTATGTAATA GATAATT 11820

TTTTTCCTAT CCCCCAACCC TTTCCAGATC CTAACCACCT CCCTATCCAC CCAAGGT 11880

AGCCCCTTTC TATCAACAAT GAACAATCTA ACAAAGAAAA ATCAGAACAA AAAACCA 11940

AGGAAAAACA GATACCTCAA CAAAATGAAA TTAAAAGCCT ACAAAAAAAA AAAAAAA 12000

AAAAACCAAA ACAAAACAAG GCGTTCATTT TGTGTTGGTT ATCTTCTCCT GGGCATG 12060

CCTGCCCTGG ACTGTTGCCA ATACATCCAG TGACACGTAA TTAGAGAAAG CAGATTT 12120

TTCTTTCCCA GCTTTTGCAA AGAAGTTTTT AGTTAGGAGT GCTGGGATTT TGTCTAG 12180

GAACCTTTGC TATTCATGTG CAAGCTACCA CAGTCTCTGG GAGTTCATAT GTGCATC 12240

CTTGTGTCTG GAAGACAGTG TTTCTGTGTC ATTTTATTGT AAAATTTACT ACTTAAC 12300

GAGTTATCAA TAATTTTTTT TTCTTTTTTA GTTTTGTTTT TTGACTTTGT TATTTTG 12360

TTAAAGTGTG GCTTGCTTCC TCCTCTTCTG ATTTACTGGT CTGGGATTGT TCCTTCT 12420

TTCTTGGATG TGATTAACTG CTTCAGACTA AAGTTTTCCT TCTAATGCCT TCAGTAG 12480

TGGTTTAGTA GACTGATATG CTTAAAATTG GTTTAATCAC AGAATGTCCC CCTCGCC 12540

AAGCTACTGT GATTGATAGT TTTGCTGGGT ATAGTAGTCT GGGCAGGGAT TTGTGAT 12600

TCAGAGCTTG TAGACTATTT GCCCAGGTCC TTTATGGGTT TTTAAAATCT CCATTTA 12660

GCCAGAAGAT ATTTTAATAG CTCTGCCTTT ATATGTTATA TGGTCTTTAA ACCTTGT 12720

CTTTAATATT CTTTCTTTCC TCTGTATGTT TAGTATTTTG ATTATGTGGC GAGGGAT 12780

TATTCCTATC TATTTTGTTT TCTGTATACT TCTTGTACCT TAAAACGCAT TTCCTGC 12840

AGATTGGGAG AAATTTCTTG TATGGTTTTG TTAATAATAT TTTCTGTGAC TTTACAT 12900

TTTCTTCTCC TTCCTTTATA TCTACTTTTT ATAAGTTTGA TCCTTTCATT GTATTAC 12960

ATTTCCAAAT GGCTTGTGCC TGCGTCTTTT TAGATTTAAC ATTTTTTGAC TGAACTG 13020

ATTTTTTTCT ACCTTGTTTT TAAGACTTGA ACTTCATTCT TCCATGTTGT GTGATAT 13080

GATGACACTT ACCTCTCAAG TTTTTCTTTA ACACCCTGAG TTTTTCATTT TAGAAAA 13140

ATTAACAAAT AACAAATTTA CGAACAGAAC TTTATTGGCT TTTCCCATGT GTTTAGT 13200

GAATAGAATG AAATAGTTTT TGCTTTGTTT TTTGTCATAT CTTATTGCTG CAGTTTA 13260

TTCATTAAAT TAATTATCAA AAAGGGCCAT CTGGCATAAA GGGGATGGGG ACTCAGA 13320

AGTAAACTCT GAGTGAGTAT GCAAGGCTAC TTCTACAATG AGAAGCACCT GATCACA 13380

GCAAGTTGGC TGTTACTCAT ATTCACGTGT GGCCACATGG AAATAAGGAA CAGTTTT 13440

CCCAATGGGT CTCCTCAGTA AGCCTTCGTT CAGTAAGAAC TTTTAAAGCT CATCTTT 13500

ATGAATAAAA TTAGAGCTGA ATAATGCTTA TTGAATTTTT TTTAGGGTTC CTGTAAT 13560

GAAGAGTATT TCAGAAAATC TCTGTTCATT GAGAAAAGTG ATCTGTGGTC CTACAAA 13620

TGAGACTAGA CTGAAGCCGG GCAGTAGTTT TAATTTACTG TCATCAGAGG ATTCAGC 13680

TGCTGGAGAA AAAGAGAAAC AGATTGGAAA ACATAGTACT TTTGCTAAAA TTAAAGA 13740

ACCATGGGAC CCAGAACTTG ACAGTTTAGT GAAGCAAGAG GAGGTTGATG TATTTAG 13800

TCAAGTGAAG CAAGAAAAAG GTGAATCTGA AAATGAAATA GAAGATAATC TGTTGAG 13860

AGATATGGAA AGAACTTGTG TGATTCCTAG TATTTCAGAA AATGAACTCC AAGATTT 13920

ACAGCAAGCT AAAGAAGAAA AATATAATGA TGTTTCTCAC CAACTTTCTG AGGTACT 13980

TCAAGAGGGA ATAATATATT CATCAGTGGT TGGTTTACTT TGTTGTATAA ATGCACA 14040

AACAAATATT TTAGTTTTTG TGGGATGCAT GGTCTCTGTT GTACCTATCC AGTTCAT 14100

TTGTAAAGCT GCCATAGACA CATGCAAGCA GTGGTACCTG TGTGCTTCAG TAAAACT 14160

TTTAAAAATA CAAACAGAGG GCCATGTTAA CTTGTGAGAT CCACTTAATA CAATAAG 14220

AATTGTATAA GTGAAAAATT TTGCTGCTTT ACTATTTATG TTTTTTATAT GATAGGT 14280

AGTTTTTTGG TGGATTCTTC CTAAGTATTT ACTCATTCAA ACTTGATTTG GGGGGTG 14340

GGGTTTTATT CCTTCAAATA GAAATTATTT GTTAGGGTGA AAGGGTCCTT TGATTTA 14400

GCATCCATAC TGTGACCTGG AGAGCCAGGA AGCTCTTGTC TCCTTCCTAA TTCTTAT 14460

CTTGCAAATT ACTGAAGACA TTTATCATTT CTGGGAGGTT TTTCTTTTTC TTTTCTT 14520

TTTTCTTTTC TTTTTTTTTC TTTTCTCTTC TCTCTTTTTT TTTGCAATAA CAAATTT 14580

TTTAGATTTT GAAAAGATTG TATAGGTTTA AACCTCTCAA TTTCATTACA GAAGTGG 14640

CCCAGTCTTA TATACAATTC TTTGATTTTT TTTTTACAGG AGTTTTTCAA TTGTTTC 14700

TGAGTATATA AATGTAAATT GTTTTAAAAA TTTCAAAATA TTCTCATTCT AATTTTT 14760

GAACCAGATT CCCTCTCTAG AAAATGCTGT CTTTCACTTA CATGTGCATC ATTCTAA 14820

TGTAGAAATT TCTAATTAGA TCTGCACTTT CATATTTTTA TATATTAGAG AATTATG 14880

ATGAGTTTGA TTTGACTGAT ATCTTTTATA TCAATTATTG CCATTTTATT ATGTAAT 14940

TAGCATCATT TTTATTATTT AAGACTGCGT TTAGAAGTCA AGAAAACCTT ACTCAGT 15000

AAGTGTACTT TAATACATTT TAATAGCTTT AAATTAGCAT GTTAATTAAG GCTATTT 15060

TTTTCCCATT AACAAATTAA ATATGAAGCA TTTGGGGAGA TATTCCTTCA AGTTTCT 15120

TGATTTGTGT GTGTGTGTGT GTGTGTGTGT GTGTGTGTGT GTGTGAAGGG TAGATTT 15180

GCTTGTTAGG CACCCGGTTC CTTGGGATTG CCAAATTATT GTAAAGATTC TTCATAT 15240

AACATCAACA ACAGATCAAG AAAATAATAT ATTTAGTATT TTTTCAAATA GATGGTC 15300

GTAAAACACT AATTTATTGA AAGATTATTA TGTATTAGTC TTTGGTATTT TTAAGTC 15360

GTATGTAAGA AAACCATTGA TTTTCTTGGT TTGTACAGAC TTTTTTCAAC ATTGATT 15420

ATGCCATCTA TTGGAAAGTT GGGGAGACCC AGGTTGACCT GGTTGACCTT CAACTTG 15480

TTTCTCTTCT TTTGCATGTA GATTCTACTT GACGTCTGTT TATCTAACTT GCCTGTC 15540

TTAATTACGC TCTCTCTCTC TCTCTCATTA TTTGAAGATT AAAACACTCA TTCTCCT 15600

TCTCCCGTCC TCTCTGTGCT CATGCTGTGA ACATATAAAT ATGCTTTAAA CATCTGC 15660

TTAAAGAAGA GGAAGATGTC TAAATACTTC AGTGAAAGCA GCTGAGAGCA TAGTGTC 15720

CTCGCAGAAC GTTAATCTTT GAAATCCTTT TCTTTAAAGC ATTTATCTCC CAATGAT 15780

GAGAATGACT CCTCCTATAT AATTGAAAGT GATGAAGATT TGGAAATGGA GATGCTG 15840

GTATGTTTGA ACACAAGAGA AAGTTACTTC AAGTTTTTAA AAGAACACTT TAATAAT 15900

AATATTATCC ACTTCCAAAT CAGATGCCAC CACAATGATA TTCATACCCA TTATTTA 15960

TTAGACTTTA AGTTTTCAAT TTACATGTCC TCATCTGTAA GTAGTCTTAG GTGTAAC 16020

GGGAGTTCTC ACGGGAGTTC TGTGTCCTCA TACGTCTCTC TCTCTGGAAA CTGGGCA 16080

ACTAAGCACT TGAGCAGGAA ACTCATTATT TCTTCTTCTT CTTCTTCTTC TTCTTCT 16140

TCTTCTTCTT CTTCTTCTTC TTCTTCTTCT TCTTCTTCTT CTTCTTCTTC TTCTCCT 16200

ACTCCTCCTC CTCCTCCTCC TCCTCCTGCT CCTGCTCCTC CTCCTCCTGC TCCTCCT 16260

CCTCCTCCTC CTGCTCCTGC TCCTCCTCCT GCTCCTCCTC CTCCTCCTGC TCCTCCT 16320

CCTCCTCCTC CTCCTGCTCC TCCTGCTCCT GCTCCTCCTC CTGCTCCTGC TCCTGCT 16380

CCTCCTCCTC CTGCTCCTGC TCCTCCTCCT CCTCCTCCTG CTCCTGCTCC TCCTCCT 16440

CC 16442

51259 base pairs

nucleic acid

single

linear

209

GCTCCTCCTC CTCCTGCTCC TCCTGCTCCT GCTCCTGCTC CTCCTCCTCC TCCTGCTCCT 60

GTTCCTGCTC CTGCTCCTCC TCCTCCTCCT CCTCCTCCTC CTGCCCCTCC TTCTCCTCC 120

TCTCCTTCTC CTCCTTCTCC TCCTCCTCCT GCTCCTCCTC CTCCTCCTGC TCCTCCTTC 180

TCTCCTCCTC CTCCTCTTCC TCCTCCTCCT CCTGCTCCTC CTCCTCCTCC TCCTCCTCC 240

›Example 10 · 40 of 49

CCTCCTCCTC CTCCTCCTCC TTCTTCATGT ATTTGTTGTG TTTTAGACAT TCTGTGTTT 300

ACTCATTCAA TCATTTACAG GGTCTGGATT TTCTTATTGT GTGTTTTTTT TTTTTTAAA 360

ACTGATTATA TATAATGGCT GTTTACTCTG TTATCAAAGC TGAAGTATGG ATCTGTGCA 420

TTCTATCCTG TCACTCATCC TCCAGCTTAT CAAGTGTCGT AAGCCATGTG CAGACAGAA 480

AATCCAGACT GAGAGAGTAA GGGAAAGCAC AGTTTAGTTA AATCAAATGA AAAATAAAA 540

GAAATAGAAG TATGCTTTTG TGTCTGCCTT TTAAGCTGCC ACCTGTAGGT TAGTGTGCT 600

TTTCTTTTCA TTAAATGAGA GTAATTTTCT AGTTCTTTAG TTTTGAGTTT TAGATAAAT 660

AGGATAAATA AAGATGTGGA TTCCTAATTG AATGTAGACC TGAGTCCTCC CTTCCCCAT 720

GGTGTCCATT GCTAACATCA CAGTTTACCA GGGAGCCTGT CTCCTATTTA AGAAATATG 780

GCTAAATCAC AATCTATTCA CTAGGTATCC ATTTTTCTAG TGCATTCAGT TCAAGTGGT 840

CCAAGTGTAG GATGCTTGTA GACATCTGTA CCATATATTA TACACTGGAC ATCTCTGTT 900

TCTGGATATG TTGGTAGAGT TAAAGAAATA TCATCACCTC TTTTTTCCCC TCATTTTTC 960

TTTATAGGAC GGAAATATTA TACTTTAAAG GACATTCTTA AAACCAAACT AAAAAATA 1020

ACGCCTCATA AAAAGTGAAG ATAACTTGTG TTAAATGAAT AGTCTATGTA ACTCCTTA 1080

AAAAAGTTTT ATAGATACAG CGATTTGAAA TATACTAATA TTTTTGAAAT AGTGGAGA 1140

ATACATATCA AAACACCTTT TTTTCACATC AGTAATATTT CTTTCCTAAA ATTATTTG 1200

TCCTTTTTTA CAATTCCAAA ACACATTTAT TGCTTGCTCA TAATTTAAGC ATCATCTT 1260

CTCAAGAAAA ATGCAATTGA CATGTAACAT AGAGAAATCT ATGATAAAAA TAGCATTA 1320

ATGTTTCATT TTACCACTTA GAATTCTAAA ACGTTGAAGT CCAATAAGAA AAACTGGT 1380

AATTATGCAA ATTTTAAATT TACGATACGT TTCCCAGAGG CCGTTCATTA TGTGCTAT 1440

CTGAACCTTG TTTATGCTGG CCATGCTCCA TCCTGGCCTC GTGCCTTGGA GCATCTTC 1500

CACGTATTTA TAGAGGAGCA CACATGTTCT TTTGTGCTGT TGTTTGCACA TCTGCCGG 1560

TTCAACCAAA TTGTAGGCTT TGTTAATAAC CCTCCTTTTG TACTCAGTAA AAAGATAC 1620

TATTGTCAGT GTTCTGCCTC AAATTTCTTT TAAACTTCCA GTCTTTAGAA AACCTAAA 1680

GTGACATGGT GGAACCCACT CACTCTAAAT GGTTGGAAAT GGGAACCAAT GGGTGTCT 1740

CTCCTGAGGA GGAAGATGGA CACGGAAATG AAGCCATCAA AGAGGAGCAG GAAGAAGA 1800

GTAAGAATCA GGGTGGAAAC AAACTCACCT TTCATGGATT TCGTGTCAGT TTTCCCGT 1860

TTGGAAGTTT AACAAGTTGG TGGCACGTAG TTACTTATCC AGTCTATAAA CCAACCAC 1920

AAGTCCTTAG TGCTCCTGTC TCTCGGGAAC TGTGGATGAT GAAACCTTTA ATCCTGAA 1980

GAAAGATTTG GTTTGGGTCC CAATGACAGT GGTGAAATAG TTTACTAATT GTTCATAT 2040

AATGCCCTTG TTGGTGATAC AAATACATGC AGTCTGCTAC CCACCAGGAG CTTATGGT 2100

AAACAAGTGC CACACCATAT GTTCAATTAA ATGTATAGAA TAGTAAATGA GTGTGCAA 2160

GATAGAACTG TCATCTACGT GTAACCAATC ATGGTCATTC GGTCAACTTT GTAGTACT 2220

CACTATACTT ACAATATATT GTGGTGGGAA AATGTGGGCA TTTCAAAATC ATTTTGTA 2280

TAGAAGGTAC TTATAAATGT ATTGATGAGT TATTCTCCTT TGTTTCCTTT TATTAAGT 2340

AGCCATCTGT TTGTTAAGAT GTGCCATAGC ACTTATTTTT CATGTTTAAT GATAGCTT 2400

CTAGAATCTG TGTTTTATCC TTTCTTGGCT GCTTGTGAAT CTTTGCATCA ATGGACAG 2460

AGTGGTGGGA CTTAGGGAGA GCTAACATAG TCCACCATGT GGTACCATTA AAATTTTT 2520

CTAAAGATTT AAGTAGCTAT ATTAACCTAA CTAAATAGGA TAGGTAGCTA AATTAGAT 2580

AGGTAACTTA ATTTATATAA CTAGATTTAG TTTTAAACAG CTAAATGAAA ATTTTATT 2640

TTTTCTGTAC ACTTAATTTG GGATACTAAT ATAATTCATG TTTATCATTA ATTGAAAA 2700

ACTTCTAATA TAAAATTTTT ATCGGCATTT CTATTGTTTG CTTGGTTCGC TTCATTCT 2760

ATTGTAGATC CTGCAAGTTT CCCAATTACA GGATGTTGGG CCTCTTCTTA CCACTATT 2820

TAAAGCGGGC CACAAGGATA GGTCTAGTTT GTAAGTAGTG ATCAGAGGAT TTGCCTGG 2880

TCATGCTAGA TATCTGTAGA GTCAAGTGTG ACTGGGATGG AAACAGTGGA TGTCACCC 2940

CACTCTGTTC TTTATCACAG CAATGGAATG AACATTTTCC TCTTCTTGCA TAGCATAT 3000

GCTTTTGAAC ATAAATGTCA ATTTTATTAT TTTATTTATT TTTAAGACCA TTTATTGC 3060

GAACCCAACG CAAAGCAAAT TAATTGCCTC AAGACCTATT TCGGACACAG CAGTTTTA 3120

CCGTGAGTAT GATCTCAATT AACTATATTA TGTACATATT TTTTTTTCAC AAAGAGAA 3180

AGTAAATAAT CCATCCCCAT ATCCTAACAG CAGCAGCCTA ATTTTATTGT AGGCATAT 3240

GTCAGGTATA GATTATATAC AACTGTAAAA TTATTGGAAA TATTAATTAC ATAAGTTT 3300

TTGTCCTTTT AATAGGAAAG GAAGCGGTTC TATTTTTCTT TAACTGAGTG CTTCTATG 3360

AAAACTATAT AATAATAAAA AAAGAATTTT TCTCACTGCT GAGTTATCTT TTATTGAG 3420

TGAATTCAGA GGAAAGGCAC ATTGCTTACT GCTTTCTGCA GGTGTTGCAA GGCACACT 3480

TGTGAGTCTC TGAGAGAACA GTTTGAGAAG CTGAAGGTTT ATTGTTTTAA CATTTCAA 3540

TATATTTCCA TCTAAAGGGC TGTCTTAGTC CATGTCCCAT TGTCGTGAAG GGACACCA 3600

ACTACAGCAA CTCCGATAAA GGAAAACATT TGATCAGGGC TGGCTTACCA GTTCAGAG 3660

TTAGTCCATT ATCATGGAAG GCATGGCAGT GTACAGGCAG ACATGGTGCT GGAGAAGG 3720

CTGAGAGTTC TACATCCCAA TTGGCGGGCA GGAGGAAGAG AGAGTGAGAC ACTGGTTG 3780

GCTTGAGCTT TTGACACCTC AAAGCTCACA TCTGGTGACA TACTTCCTCC AACAAGGC 3840

CACCTGGTCC AACAAGGCCA CACCTCCTAA TCTGTTCAGA TACTGCCAAT CCCTGTGA 3900

CTTAGGGGAG TGTTTTCATT CCAACCATCA CAAGGGCACA CTAATAACTA GAAACAAT 3960

GATGAACACA AACGAGATTA GGAACAAGTG CATTTGAATA AGACCAGTAA GTAACTAA 4020

ATCTAGACAG GGTTTTTTCA ATTTTTTTTA TAACTTTTTT TTGGGGGGGG GTGCGTGT 4080

CGAGACAGGG TTTCTCTGTG TAGCCCTGGC TGTCCTGGAA CTCACTCTGT AGACCAGG 4140

GACTTTGAAC TCAGAAATCT GCCTGCCTCT GCCTCCCAAG TCCTGGGATT AAAGGCGT 4200

ATCACCACTG CCCGTTTTTT GTTTTTTTTT TTAAATAACT TTAAAAAGAA TTCATCGG 4260

CATTTTTCCT TCTTTTAATA AACTATCACC TCCAGTTGAT TTCACCTTAG TCCATCAC 4320

TACACAGGTC TCATTTCAAA CCTATAGCAG TCCTCTTATT TATTCTAAAA TATTAACT 4380

TCGGTCTATA GTACAAAGCT GGGTATTTGT TTTATACTTT AGATATATGT AATAAAAT 4440

CATATACATA CTATATGGCA ACTCATGGTT ATTCAGTCAG TCTGAATGAA AAGTTAAT 4500

AATGATCAAA TTTTTTCTCT CAAATTTCTA GGATTTGAAT ATATTTTTAT AGGTAGCT 4560

AAAAAAAAAT CTGAGTTTAT TGGAGAGAAG TTAAATAGAT TTGAACTTGT GCTTTGGA 4620

CTATTGATAA AACATTTTAC TTTGTACCTT CAAGGGTTCA GTGGAAAGTC ATCCATTC 4680

TATTAGAAGA GAGAAGAGAT AATGTTGTTG TCATGGCAAC TGGTAAGCTA TACTTAAA 4740

AAATAATTTA ATCATCTAAA AGTCATAAAG GGTCTAAAGT GCTTAATCTT TCAGAAAC 4800

ATAAAATATA GGAAGGAATG ATTGGGGGAA AAGCCTTCAA ACTTATGCAT GAATTACC 4860

GTCAGTCCAC TTATTCTGCT ATATAAGCAC ACTGTAAGAA GAAAGTAAAG CATCAAGA 4920

TTCTTTTTAT TTTTTTGTGT TATTTTTTTT TTATTCAAGG ATATGGGAAG AGTCTGTG 4980

TCCAGTATCC GCCTGTTTAT ACAGGCAAGA TTGGCATTGT CATTTCACCT CTCATTTC 5040

TAATGGAAGA CCAAGTCCTC CAGCTTGAGT AAGTAATGCT TGCACTGCTG CAGCGTCG 5100

TTGGATAAGC AAGTGGAAAG AACATGGCAA GGCAGGATCT TACTACACAG GCTTAGCT 5160

GCTCTTCTCT CAGTGCAGTG GCCCTTTGCC CAGTTGTCCC TCTCTGTTCT ATCGATGA 5220

TATCAGAAGA TGAACGTGAA TCTAGGTCAC AGGATTACGT TTTGGGAAGT AACTTGAT 5280

TCTTTATTTC TATTTTTAAT TTTTGAGATA GGGTCTTGAT ATATATATAG TCCAGGGT 5340

TGTCGCTCTG GCCTCTTGCC TTGCCCTTCA TGCCTTGGGC TCACAGAGCA TGCACTAG 5400

CCCCTGGCTG CATTCATTAG TAGCAAACGA AGTGTTAGTG GAAGAGTTTA CATTCATT 5460

TGAGGTCTCC AATGCAAGGC TACCTGTTTT CTCTGATCAG GGTTTAAAAG GACTGATT 5520

TTTATGCTAG TTAGCTGTCT CAAATTCTTT TTTTTTTGTT CTGCTCTCTG GGCTCCCA 5580

›Example 10 · 41 of 49

CTTGCAATGA GATATATATA AAAGTTTACT TTTTAAGATA TGTTTTTATT AGTTCTTT 5640

AAATCTCCTA CATGTTTTGA TTATAGTCAC CCCTCTTCTA ACCCTAAGTT CACCTTTC 5700

TTCCTTCTTG AAAGATCCAC ATTAAAGACT TGCCTCCTCA TCAGGCTTTT GAAGGAAT 5760

ATCAAGTTAT ATAGACACAA AAAGGAAGAA CATTAGAAAG ATGAGGAACA TAGGAGGT 5820

ATGTTTATGT GTGTATTCAT CAGAGCGTTT GTCTCTTGTA GGCTATCCAA TGTTCCAG 5880

TGTTTACTTG GATCTGCACA ATCAAAAAAT ATTCTAGGAG ATGTTAAATT GTGAGTAA 5940

TATATCATGT CACATAATAT TGTAAGATGT ATATAGAGTA AGAGAATTTT GTATATAT 6000

TTACTTATAT GAGTAAATTG CCCATATTTG AAAACATACT TTAAAAAGCC TTATTTCT 6060

AATAATAACA TAGTTCCATT TCTTCCTTTC CTTTCTTCCT TCCAAACTCT GCCAAACA 6120

CTTCCTTGTT CTCTTTCAGA TTGATGGATT TTTTTCCCAT TAGTTGTCAT TACATGGA 6180

CATGTTTATA CATATGTATT ACCAAATGCC CCGTTTTTTC TCAGCAGAAG TCATGTAA 6240

CTCCTTTATC CTTAAGATAA ATATTCACTT TTGGGGGGCT GGTAAGATGG CTCAGTGG 6300

GAGAGCATAC TGAGTGCTTT TCTGGAGGTT ATGAGTTCAA ATCCCAGCAA CCACATGG 6360

GCTCACAACC ATCTGTAATG AGAAACAAAT AAAAAAAATC CCTATGGGCC AGAACGAG 6420

GGGCCCCGGA GTGAGTGGGG TCAGAGCAAG AGGGAGAGAA AGGGAAGTGG ATTTTTAT 6480

ACTTTTTGTT TAAATTATTA TTGTATTTGT ATTATTAACT TGTCTTCCAT TATCTTAT 6540

TATCATATCT AGTATTATAT GTTATACATA TATATCGTAT ATATGTATTT ATATGTAT 6600

TACTTTATAT TATATGGTTA ATTTGCTATT ATGATAATTT TTATAAAAGA AGGCTAGA 6660

TTACTTATGG CATGTCTCTA CCATATAAAA GCAGATAAAA TTAAATTAAA AATTTTAA 6720

TAAAAGTTCT TTAAGTTTTT AATTTATCTA TTCCACTAGT ATTTTAGTGT CTATTACA 6780

CTAAACATTA TGTTTTCACT AGTAATTTAT TAGGCATGTA ATAAATTTTA TCGTATCT 6840

AGGAAATTGA TGCAGTTTTC TAATTACTGT AAGAAACAAT AAAAATAATG AAGGCTAA 6900

TCACTGTACC CAGGTTTGGA ATCAGTTCTC CGTCCGACTA GGAAACTGAT CTGAGATG 6960

CCAGTCAACT CCAGTGTATC CCAGTTTCTT GAAAATTAGC TGTTTACTTA CAGAGACA 7020

CTTAGGACAT CTCAGTTAAG AAACGGACAC TGGAACCTTC ATGGAACCAA AGAGCAGC 7080

GGAAAACTAA CACACCCCTG AAAACAAAGA GCATAACTGG GGGCTTGTCA TCGAGACT 7140

CAGGCTTTTA CTGTAGCTAC AGCAGCCAAC ACAGGCAGAC GGAGCCACAG AAGCAGAT 7200

CAGCAAGGAA TCTGCACATG CCTACAAAGC TCATCATCTG AGAAAGGCTC AAAGGTGA 7260

CAGTGGAAAA GAGACAATCC AGAATAATGG CTTATATGAA AACAATGGCC TTATAAGA 7320

AACAAACCAA ACAAACCAAA CCAAAACAAA CAAAACCCCC CAAACTAATA CACCACAC 7380

TATAAACATT TTTTGCTAAA AGCGAATTAT GCGTCCAAGC ATAAAATTGT GAAATGTT 7440

AGGAAAAGCA TGCCATCTTT ATAACCTTCA GTTAGGGAGA CTTCTTAAAT ACCCAAAG 7500

AAATCTATAG GAACAAACTA GCAGCTGGAC TTTTACAAAC TGAAAACCTA CTTCTCTT 7560

AAAGAATTAT TGAAAAAGGA AGAAAGGCCA TAAACTAGCA AAGTATATGC AAAGTACA 7620

TCCATACAAG ATTTCTACCT ATAATATAGA AATTACCACC AAAAGAGAAT TAAAAAAA 7680

TAAAGTGTCA AAAGATTGGA ACAGACACTA GCACAAAGAT ATACAAACAG CAATAAGT 7740

AAGATGCTTA TATAATTGGT CACCAGGCAA AAACAAATTC AAGGTACAGT GAGATTCT 7800

CCAAGTGGCT AAAGCCAATG ACTGGCTAAG AAATGTCAGG GGTAGTGAGC AACAAGAC 7860

TTCACACACC ACTTCTAGGG ATGAGAGATG GTAGAATGTT TGTTTGGGGA GTAGACTG 7920

AGAAACCATA ATTTGGCTTA TAATTCCAGC TTAGTGGTGA ATCCTACACA TCAAGAAT 7980

TTATATTTTA TTTTGGTGAA TTGAAGATAA ATGAAAGGAC TAACATCTGA ATTATGTA 8040

TATATAAAAT ATTCCTTTGG ATTTTAATAA TCAGCATGAT GCATTACTTA AAAACCTA 8100

GAATGCTTCT TTCCAGTCTA GGGCAGGGAC CTTAGCTGAC CTTGGGTGCT AACTCTGC 8160

CCAGCCCCAC AATACCCAAA GGAAGCTCCA CTTCTAGGCG CTCTAACACG CCAAGTCC 8220

AGGATTCCAG GATCCCAGGA ACTTGGTCAC ACCAGGATCT CAGGGTTTTA GAGGAACC 8280

GGCTCCCAGG AGCTCTGACA CACCCAGGAT CTCAGGATCA CAGGATCACA GAGACAGC 8340

AACTCTGAGA AGGTCTGACA CGACCAGGAT CACAGGAAGG ACAGGCTCCA GTCAGATA 8400

GTGAAGGCAG GTAGCACTAT AGATAACCAG ATGGTGGGAG GCAAGGGGAA GAACATAA 8460

AACAGAAACC AAGGTTACTT GGCATCATCA GAACCCAGTT CTCTCACCAT AGCAAGTC 8520

GGATACCCCA ACACACTGGA AAAGCAAGAT TCAGATCTAA AAATCACTTC TCAGGATG 8580

GATAGAGGAC ATTAAGAAGG ACATCAACAA CTCCCTTAAA GAATACAGGA GAACACAA 8640

AAACAACTAG AAGCCCTTAA AGAGGAAACA CAAAAATCTT TTAAAGAACT ACAGGAGA 8700

AAAATCAAAC AGGTGAAGGA AATGAACAAA ACCATCCAGG ATCTAAAAAT GGAACTAG 8760

ACAATAAAGA AATCACAAAG GGAGACAACG CTGGAGACAG AAAACCTAGG AAAGAGAT 8820

GCAGTCATAT ATACAAGCAT CACCAACAGA ATACAAGAGA TAGAAGAGAG AATCTCAG 8880

GCAGAAGATA CCATAGAAAA CATTGACACA ACAGTCAAAG AAAATACAAA ATGCAAAA 8940

CTCCTAACCC AAAACATCCA GGAAATATAG GACACAATGA GAAAATGAAA CCTAAGGA 9000

ATAGGTATAG AAGAAAGTGA AGATTCCCAA CTCAAAGGGC CAGTAAATAT CTTCAACA 9060

ATTATAGAAG AAAACTTCCA TAACCTAAAG AAAGCGATGT CCATGAACAT ACAAGAAA 9120

TCCAGAACTC CAAATAGACT GGACAAGAAA AGAATTCCTC CTGTCACATA ATAATTGA 9180

CATCAAATGC ATTAAACAAA GAAAGAATAA TGAAAGCAGT AAGGGAAAGA AGTCAAGT 9240

CATATAAAGG CAGACCTATC AGATATAGGA CTAGACTTCT CACCAGAGAC TATGAAAG 9300

AGAAGATCCT AGGCAGATGT CATACAGACC CAAAGAGAAC ACAAATGCCA GCCCAGGC 9360

CTATACCCAG CAAAACTCTG AATTATCATA GATGGAGAAA CCAAGATATT CCATGACA 9420

ACCAAATTTA CACAATATCA TTCCACAAAT CCAGCTCTAA AAAGGATAAT AGATGGAA 9480

CACCAACACA AGGAGGGAAA CTACACCCTA GAAGAAGCAA GAAAGTAATC TTTCAACA 9540

CCCAAAAGAA GATAGCCACA CAAACATAAT TCCACCTCTA ACAACAACAA AAATAACA 9600

AAGTAACAAT CACTTTTCCT TAATATCTCT TAACATCAAT GGACTCAATT CCTCAAAA 9660

GGACATAGAC TAACAGACTG GATGTGTAAG CAGGACCCAG CATTTTGCTG CATACAGG 9720

ATGCACCTCA GTGACAAAGG CAGACACTAC CTCAGAGTTC AAGGTTGGAA AACAATTT 9780

CAAGCAAATG GTTGTTTCCC AAGAAACAAG CTGGAGTAGC CATTCTAATA TGGAATAA 9840

TCAACTCTCA ACCAAGTTAT CAAAAAAAAA AAAAGATAAG GAAGGACACT TCATACTG 9900

CAAAGGAAAC ATCTGCCAAG ATGAACTCTC AATTCTGAAC ATGTATGCTA CAAATGCA 9960

GGCACCCACA TTCATAAAAG AAACTTTACT AAATCTCAAA GCACACATCA CACCCGA 10020

AATAATAGTG GGAGATTTCA GCACCCCACT CTCAGCAATG GACAGGATCA CGGAAAC 10080

AACTAATCAG AGACACAGTG AAACTAACAG ATGTTATGAA CCAAATGGAT CTAACAG 10140

TTTATAGAAC ATGTCATCCA AAAGCAATAA ATATACCTTC TTCTCAGCAC CTCATGG 10200

CTTCTCCAAA ACTGACCATA TAGCTGGTCA CAAAACAGAC TTCTACAGAT TCAAGAT 10260

GGAAATCATC CCATGCACCC TATCATCAGA CCACCACGGC CTAAGATTGG TCTTAAA 10320

CAACACAAAC AACGGAAAGC ACACATACAT ATGGAAGCTG AACAGCGCTC TACTCAA 10380

TACCTTGGTC AAGGCAGAAA TGAAAATGAA GACACATCAT ACCAAAACTT CCGGGAC 10440

GTGAAAGCAG TGGTAGGAGG AAAACTCATA GCTCTAAGTG CTTCCAAAAA GAAACTG 10500

AGAGCTTACA CTAGCAGCTT GACAGCTCAC CTGAAAACTC TAGAACTAAA AGAAGCA 10560

ACACTCAAGA GGAGTAGACT GCAGGAAATG ATCAAACTCA GGGCTGAAAT CAACCAA 10620

GAAGCAAAAA GAACTATACA AAGAATCAAC AAAACCAGGA GCTCGTTCTT TCAAGAA 10680

AACAAGATAG ATAAATCCTT AGCCAGAGTA ACCAGAGGGT ACAGAAACAG TATCCAA 10740

AATAAAATCA GAAAGGAAAA AGGAAACATA ACAACAAAGT ATATCTTAAA ATAACTA 10800

TGTTTGTTGA ATATCAATAG TTGAAAATAT TAAAATCATG TTCTACAAAC ATCATGG 10860

TATTATTGAT AATTTTTCTC ACTGTGCTTG AAATTAGCAT TTTCTTAATG TTTATGT 10920

›Example 10 · 42 of 49

AGTGTTTTTG CTATTTTGAA ATGTTTAAAA TATACTTACT GATAAAATAA TTTCTCT 10980

AGAAACACTG ATAATCTTTT TTCTGTAAAC TGATTTTTGG ACAATGTACA CAGATAT 11040

ATGTGTTTTA AATACTCTCT CACTATGTCA GGTGTTATTA TATAAAGGCT TTCAAAT 11100

TTTCTTAGTG ATTCTTTTTA AATATTTTAT GCTCTTTTAC TATGCCTAGC TCCCAAA 11160

TATTCTGTAT GTTTTGAAAC AATTTAGTAT TCAATATTAG GTACAGGATC CTCAGTT 11220

GATAGTATTA AATATTAATT AATGATATTT TTAGGATATG AAAGGATATG AATATAA 11280

TTGGACAAAA TTTTAAAGTA TTATCTGATA TCAAAATACT CAATATTATT GATATGT 11340

ATGTATAAAA TACATTTAAA TAATAAGTTT TAAAAAATGT CTATTGAACA TTTTGAT 11400

GTTATCATTC ATTGACTGCC TTTTTTTCCT ATTAGAGTGT TTCAATTTAT GTTTCTA 11460

TTGTTTGTCT TTACAGAGGC AAATATAGGG TCATCTACAT AACTCCAGAG TTCTGTT 11520

GTAACTTGGA TCTACTCCAG AAACTTGACT CTAGTATTGG TAAGTAATGA AGTAGGA 11580

CGGTGAATAC AAAGTAACCC ATTTATGGTT GAAGACCAGA TTCCAGTTTT GTTAAAG 11640

TATTTCAAAC ATTTGCTCCT CTAGGAAATT TCTAATCAGT TTTACATTTG TCCCATT 11700

CAATGCTGTA TAATTCCTCA TTCCATAGAG GTGGTACTCC TGGGTGGGTG TCATATT 11760

ATATAAGCAT GTATGTATCC CTGTCACACT CAACCCTTTT GAGGCTTCTC TGCTCTT 11820

GGCCTCCCAA CTCCTTCATG CAGGATGTGG CACACAGTTG TCTATCCTGT GCATTGC 11880

ATGAACGCTG AGTCTTGTTT CATATTCTGA GTCTAAATGA AATCAGTGTG TGGTTCC 11940

TTCTTGCTCG TCAGAATCGC CCTTCAAGCT CTAGAACAAT GCTGTTAAAT GGCGTAT 12000

TTAGAAAATA TAAATATAAA ATAGGTTAAA TGCTGTGATA TTGTTTATGC TGAAACT 12060

GTTTTTTGGT GGTGGAAGTG TGGTCAGGTT TAGCTAAGAG CTCCAAAGGA AACAAAC 12120

ATCCATATTC AAAACTTTCA TTTAAATTTT ATCCAACTTA TCAGATAAAA TTGTTTT 12180

AATTTGTGGG ATTTTCGTTT TTGAAGAATT AGGTATTAAG TAATTTCATA TAGGTTA 12240

TTTCAGTATT GTACTGGACT AGCTAGTGGA GTGTCAACTT GATTTAAGCT ATGGTCT 12300

AAGAGGAGGA AACTCAGTTA AGAAAATGTC TCCTTAAGTC AAGATGAAGG CAATCCT 12360

GAACATTTTC TCAATTACGG ATTGATGGTA GAGGGCCATT GTGGATGGTA CTATCTC 12420

CCTGGTGGTC TTGGGTGCTA TAAGAAAACA GGCTGAACAT GCCATGGAGA GCAAGCC 12480

AAGCAGCATC CCTCCGTGGG CTCTGCATCA GCTTGTATTG ATTGGTGTTG CTTGTTG 12540

CCACAGTAGA GAGAGGAGCT CACCAAGTTC CTAAGCCATC CTTTTTGGAA GGAGCAG 12600

GGTTCAGCCT TCCTGGGAAG GCTCACTCCA GTTACTTTAT TCAAGCATTG TTCAAGG 12660

ATTGGGGCTG GGAAAGGTTT CAACCACCAC AGTTGTTATC TTGTGTTTGC TGCTCAA 12720

ACAACATGAC CCACACAGAT CTTAGTCCCT TTTGACCATG GCTAGGCATA ATCAAAG 12780

AGAACTCCAG GTTTGCCAGG AGTGTCTTAG GACCAAGGTT GATGCAGCTG CAGGCCT 12840

GGTAGTACTG AGTGCAGACT TTGCAGGGAG ACAACATTTC TTCAAATAAT CTCAAAA 12900

TTTCTCAGCC TCTACTCATT AACCCAAACA CAGCAGAGGC TTCGCTGAAA CATTTCA 12960

AAAGCTAGGC ACAAAGGCTT CACTGAACAT TTCACTTCAG GCTCCTGCCT CCAGGTC 13020

TCCCTGCTTG AGTTCCCACA TTGGCTTCCA TCAATAATGA GGATGATGTG GAAGTGT 13080

CCAAATAAAC CCTTCCTCCA CAAATCGCTT TGGTCATGGT AACAAAGACA TGTACCC 13140

CACTTAATAG TATTTCTCTT ATCAGGCATC CATGGGAGGA GGGGCCCTTG GTCCTGT 13200

GGCTCCATGC CCCAGTGTAG GGGAATTCGA GGCTAGGGAG GCAGGAGTCG GGGGTGG 13260

GAACACCCTT ATGGAGGCAG GGGGATGGAG AATGGGACAG GGGATAACAT TTGAAAT 13320

AATAATGAAA ATATCCAATA AAAATAAATA AATAAATAAA TAAATAAATA AGGAAAT 13380

AAAAAAAAAC AAAACAAAAA GAGAGTAGAC TTTTATATTT CAGTATGTGT TGAAAGC 13440

AAAGAATGAG GACCTACATT AATATTTATG GAAATATATT ATCACAGTGT ACCTATG 13500

TCTCTCTGTT AGCTCTCATT GCCATGTTTT TGCCTGTAAT GGAAAACAAG TTTGATG 13560

AGTCTGTAAT AGCTGGAAGG TGTTCCTTCA AGCATCTCTC TATGGGTTTA GCCTTAT 13620

TTTACCTTAT AGATCTATAG CCTTATAGAT CTACCTTATA GGTCAATTTC ATGGTTG 13680

CTAAAAACCT GGTTATCAGT AACTCTGTAT TCTGAGTATA TTTTTTTCCA CTTTCAG 13740

TTATTTGTTT TAATTTATAA TGATGTTAAA TTAATAACTC CTGTAAGTAA ATAAACA 13800

AGAGCCTTTG ACAAGTAGTT ATAACTTTTT ATGAGGTAAA TGGTCATTGC TGCCGAG 13860

AGGACACTGT TCAATGATTC TGTTTGCCTA GCATGTTCCA GGCCTGGCTT CAAACCT 13920

TCAGTTTCAC TTATTTTTGT TTTTACTCCA TGTGTTGGTG TTTGTGGTCA CAGGGTA 13980

TGAAGGAGAA GGGGAGATGG TCCTCTCCGT CAACCATGTG GGTTCTGGGC ATTTGCT 14040

ATGCCAAAGG GAAGTGGTTT TACCCACTCC CTCTTGCTCA CCTTAGACAC TGTATGT 14100

GTTTATTGTG CTTTTCTCCC CCCCCCCCCG TGAATCAGTT TAGGAGAATG ATACAGG 14160

ATCAGATAGT CTGACCTCCC TTCTGTTTTA AAAACATACA CACAAGTGAG CAAACAA 14220

CAGATAACAC GTGTAAGTTT TTCATCACTA GAGCAGAATT GTTTGCTTTT AATAGAT 14280

AATATTTCCC TGGGTGATTT AGAAAAAGGG ATAAGGAAAA TGAAAATTAT TTTTTTT 14340

TATTTCCACT GGCTTTTGTT TGCAGGAAAC AGTAAAAAGT CTACAAAAAT GAATATA 14400

GGGATGTTAT TTGTACAGTA GTCTGACATT TAACTAATCA GATTTGTCAT TTTTAGG 14460

ATGTTACATT TTTTTTTAAA GTAGTCCGGG TCTATAACAG AAATAGCAAG CATACTT 14520

GGGGTGCCTT CCCAGGCGTA CTTGTGATTG TCTTTTAACT TTGGGAATGA GACTTGA 14580

GCAGATGCCT AAATGAAATC TCTACAGGAC CTTGGAAGAC CCTTGAACTT TTGCATT 14640

AGTGAATTTT GCCAAAGCTT GTCTGAACTA ACTGTGTAGG TGAAAGTTCA ACTCTAT 14700

CTGCTTGTCA GATCTCTTTT AACTTAAAGT CTAGCCATGT TAATTTCTAC ATTCAGA 14760

AGTGTATGAG TGACACTGGA ATTTCCGCAG TCACTCAGTG GTATAAAGTC AGCGTTT 14820

TCTTCGCTTC CTTCCTTCTC GCAGTCTGAG GACATTGGTG TAATCTCAAT GAGTTGC 14880

TGTTTCTTTT GTTTCCTCTC TGGATTGTGA GACCCTTGAG GTCAAGTATA CTTTGGT 14940

CAAGAAAAGG GTTAATTCAG TTTTCTTATT TAGATAGAGC CTCCAGCAGC TCAGGCC 15000

CTTGAACTTT CTATGTGGCT GAAGAGAGCC TTGAATTCCT GATCCTGAAT TACATGC 15060

TGGCTCTTAA AAGGGCTTTA AATCATAATG ACCATGTAGT AATAACCGCT GAAGTAT 15120

TTTATTAAGC TCTTTTTGGG CCCATCCTTA TCTGAGTGTT TTATGTGAAT GTTCTAA 15180

AACCTTAGAG GAGTAAGAAG TATTAGGTGC TGTTACTACC TACCGTGTTT TATTTTT 15240

TACGATGCTG TTTGTGCTGC TGGTGCTGCT GGGGGTGATG GTGGTGATGG TGATGGT 15300

GGTGGTAGTG GTGGTGATGA TGTTTGTGGT GGTAGTGGTC AGTGTGTGTG TGTGTGT 15360

TGTGAAATAC CACAGTGTGT TTGTAGAGGT CAGAGAACAC CTGTGTAAGT GGGAGAC 15420

TCTCTCTGTG GTTTCTGAGG GTTGAACTCA AGTTCTCAGA CTTTTACCCA CTGAGCC 15480

TCAGCAGGTC CACGATGTAG TTTTGAGGAA ACTGAGAACT GAAAAGATTT GTAGCTT 15540

CAAGGCTTTG TGTACAGCTA ATCTAATTCT AAAGCACATG TTTTAAATCA TCTCACT 15600

AGGGTATATC AGCAAATAAC AGAAGGTTAT TTTTCTCTTA AAAGTACTAA TTTGATA 15660

GTAAAGGCAT TACTAGTCAG TTCTTTGAAA TGTCTGAAGA TGTCATGATG ATTACAT 15720

GAAGCCCTTT CAGATGCATT AAGACACCAT TGATCTTGTA TTAGTGTGTG GTGTGGG 15780

CCGTGGAGGG TTATGTTCTT TTTCACTACT TACTTTGCAC ACGGTGGGAA TTAGTTC 15840

CCAAGCCGTT TTATGTTAGC CAATGTGGAT GTCATCTCGT CTTCAGTTAT TGGCATT 15900

GAGGAACTTC CTGTAATATG ATATGTGCCG GATTGCAGAT AACGATGTAC TTAATCT 15960

TAGAAATGTG CTGACTATTT GTCTCCGTTG ATAGCTAATC TATGAGATAA GATTAAC 16020

ATTGCCAAAA AGAAATGGAA CAATTCTTTT GAAAGGATAT TGTTGTAGAT GTTATAA 16080

ATAATTTTGG GACACAGTAA TAATAAGCAA TTTATGTCTT TGAGGAATAG TAATGAA 16140

TGAAAGATAG TGTGTTGTTT CAATTACGAC GTAAATATTT CCTGTATGCG AACCTCT 16200

ATTCATTTCT CCTCTTACCT CCTATTCTGC CTTCGGAAGT TTGATGTTAT CTGGTAT 16260

›Example 10 · 43 of 49

TTATGCTTCT TATATGTGTG TGTGTTTGAG CCCAATACTT TGATTTGACT TATACTT 16320

GTGAGGTATA TGTTCTAATA GGAACAGACA ATATTGACTT AGCTAGCATT TTCCTTC 16380

GCCTTATTTC TCCTGTATAT TTTCTTCTGT GTAGGCATCA CTCTCATTGC TGTGGAT 16440

GCTCACTGCA TTTCAGAGTG GGGCCATGAT TTCAGAAGTT CATTCAGGAT GCTGGGC 16500

CTTAAAACAG CGCTCCCATT GGTAAGCCTT GCCAGATCTC ATGCCCCCAC CCCACCC 16560

TCAGCTGAGG ACTGACCCCA GGGCTCCTAC CACCAGGCTA GACCCTCAAT CCCGAAT 16620

CTGAAGTGAC ATTTTCATCA AGGCCTTTCC AGGACTGGGT AATGTCCACC CATCTCA 16680

CTTCTCTATA AAAGGGATCA GATGTGAGCA ATGGGGCATA TTTAGTTTTA AAATTTT 16740

AATTCTCACG CTGGCTTCCT TTTGAGGTTG ACGTGTAGCT TACTAAGGAA TACTCTT 16800

AGGAGTGTCC AGGCTGTGAC ATTGAGCTAC TCCAGTGTCA TCTTCAAGGT TCTCCCT 16860

GAACCACAAA ATTGTGTTAT TCAAAGACAT CACAAAGATG CCTCTGTTTT AGTTCAC 16920

TGACTTTGTG TTGTGCCACA TTCCTACTGT CAGGGCACGG GCTGGATGCT CTTCACT 16980

ACAAGAGCTG GAAAACAAGT TTTGAACATG GCAGATAAAA ATGGCAGTTA CTATTCC 17040

GTGAAAGGGG ATACAGTTTC AAGAATCCGT GGATGCCTGG AAACACCCCC TCAGTGT 17100

TTATGCACAG TAGAAGAATT TTTAAAATGA CTATCTGTGA CAATATACTA TAGCAAA 17160

GACCACAGTC ATTATTCTTG ACCGCGTGGC TCATGATTAA GTAGAGTAGG TAGCACC 17220

CCACAAGCAC TTCCTAGTCT CCTAACTGAG ATGGTTAGTC AGTAGGTAAT GGGGGAG 17280

GTGGATTGTG TGGAAACTTT GGACCAAGGG GAGAATGGGG TGATATCTTT GAGAGTA 17340

TGCAGAATTT CATCATGTTA CTCAGCACGC CTTTAATCCC AGCACTCGGG AGACAGA 17400

AGGTGGATCT CTGAGTTTGA GGCAGCCTAC TTTAGTCCTG TCTTAGGAGA AAGATAA 17460

AAAATGTAAG TTGGGTTTTA GGTTTTTTTG GTTTTTTTTT TTTTCTATTT GTTTGTT 17520

GTTTTGTTTT TTGTTTTTTG GTATAACTTT TCATTTAGTA TATTCAGATT TGGTTGT 17580

CAAGAATCTG AAATCAGAAA ACGCCATTGT GGATAGAGAA GGTGGGTGTG AAGTGGA 17640

GAGGGCGGGT GTGTGGTGGA TAGAGATGGG AGTGTAGTAG ATGGAGGGGG CGGGTGT 17700

GTAAATGGAA AGGGCGGTGC GTAGTATAGT ATGGCTTTCA CATACAGTTC TCTTTTC 17760

AATAGTCCAT AAAAAATGTA GTTACCTGGT GTTCCTCACT AATGGCCTCT GTAAAAT 17820

CTGGGGACTG CGATAGTTCT ACTTATCACA GTTTGTAGAA ACTTTTAGGT TGTTTGT 17880

AGTTAGGATA TTATGAATGG GGATACTGTA AACATTTGTC TATAGTCCCA GGGTCCA 17940

CAGCGGTTAC AAAGTTTGTG AACATAAGTT TTAGTTTTCT GGGATAAATG ATGTTCT 18000

TTCTATGGGA AGTGCTGGTT TCACTTTTAG GAAGACCCCA GTGCTACTCT CTAGACT 18060

TGCTCTGTTT TGTATCGTCC CCTCCCCAGC AGCTTAGGAA CAATAGCTTC TTCTCTT 18120

TGCCACTGTT TAGTCTTATT ACTATGTAGT ATTTTAGCAA TTATGATACG AGTGGAG 18180

TAGCTTGTGT TTTCAATTTG CATTTCTCTA ATAGCTAGTG GTGTTGAACA TCTTTTG 18240

GCTTCTTATT TGGTTAAATG CCTAGTTTAA TTGGGTTGTA TTTTTTCTGT TAAGCAC 18300

GGGGAGGTGG AGGGAGAGAA AGGGAGGGAG AGGGATAAGG AAGGAGAGGA GAGAGAA 18360

AGGAGAGAGG GAGGGGGAGG GTTGTGCTTA TGCACATATA CCTCTGCGGT GTGCTCT 18420

GTGCAGCCCC TGCAGGCGCC AGATGTTGAC GCTGCTGTCC TCCTCTGTTA CTCTCTA 18480

CATTTTATTT GAAACACAGT CTCAGTAGCC AGGGAGCTCC TCATTTGTGC TAGACTA 18540

GGCCACCAAG CCCCTGGGCT CTTCCTACTT TGGAACATTG GGCTCCTAGG TGTGCAC 18600

GTGCCTGGCT TTTCTGTTGG TTCTGGGAAT CCTTGCTCAT GTCCTGATAC TCACTGA 18660

ATCTCTTCAG TCCCTCTGTT AACTGCTAAG AATTAAATGT TTATAAGTGT GAGTTAT 18720

TTGGATATTG AGCTTGTAAA TATTTCTTTG TAAATTTTAT TTTTTTCTCC TATTTTC 18780

ATCTTTTATA AAAAATATTA TAAGTTGGGT AAAATTCAGA ATATTTTTTT TCCTTTA 18840

GCTTTCTTTC TCAGTCTCAG ATCTTGAAAG TTTGTCCCTG TAGTTTTTCC TAAAATG 18900

ATGATGTAAA TTTAGGTCCG ACAGGGTACA GAGATGTCAT GGCAGGTAAA GAGCTTG 18960

TGCAAGTGTG AAGACATGAG CTTGAGTCTG TGAAGTACAG TGACATGTGC CCCATCC 19020

ACTATATGGC AGAGGAGACC CAAGGGCCCA CTCCTCCCCT AACTGGGTAA AAAGAGG 19080

TTTTATCTAC TTAATTGCTT TTGCCTCTTT GTTGAGAATC TTTTGAGTGT GTTTTGT 19140

CCTGTTTCTC TGGGCTGTAG TCATTTGGAT TGAATTAACG AAGCGGCCTA TATTTAG 19200

CTGGTGCTAG AGAGACGGTG TGCACAAGCC TCACAGTTAA ATGGGTCAAA CCAAGAG 19260

CATTCAAAGT TCTTATCCTT TTGGCGAGAT TGTCTGACTT AGTTCCCTTA ATCATCA 19320

TTACACATTA ATAGCAAATT GCTATGTTTA AAATGACTTC TTTCTGTTCG GGTTTTC 19380

TCAAGATTTG ATTGAGCAGT GATTAAGTAA GTCAAAAACA GTAGGAGACA GGTAATG 19440

CAGCTAGCAG ATACTACATC AAAGGAAAAG AAACTAATGT ATTTGGGGTC TAAGTAT 19500

TCTGGCCTTG GGTCAGACAC TCTTGTCTCA GTCTTCAGGA CTGTTAATTA AGTTAGC 19560

AATGCCATCA TATTTCATCA TTTGTCAAAG GACAGCTCAT TCCCCTTGCT TTCTTTC 19620

GCATAACCTT CTCCTCAAGT CTCTTCTGTT CCTTTGTACC TTCTTGTTTT ATTAGGG 19680

GTGTCCTGGT CCCTGTTTTA GACTTACTCT CTCTCTCTTC TGTGCTCTCT TTTCTGT 19740

TAATTGGATA CCATCCATCC CATTATGGAG AACCCTCAAA TCTACAACTT GGATTAG 19800

CAGATGTGAC TGAGTTCCTC CGCCTACTTA CCGGCACTTG CTGTTGTACT ACATTTT 19860

TTAGCAATTT TATTGCATAT AAATCACACA TATTATAGGG GATTTATAGG ATATGTA 19920

ATACACAATT GTCAACTTGA GGGTTTGCTC TTTGGGTTCC TAATAGGTAT CTCAAAC 19980

ACCCCTCCAA AACTGGCTCC TGATGTTCTT CGCACTCTGA GTGCTTTTCC CGCAGAC 20040

ATCACCTTGT TTAATAGCAG CACCAGAGTG TTTTGCTATG CAGCCCGGAC TAAACAA 20100

ATCCTCCTGC CTCAGTGTAC CCAGTTGCCT GGAATGCAAG TGTGTACTAC TCTGCCT 20160

AGCTTGATTA TTGTTACCAC TCTGCAGCAT ACATTTCACC AGTAAGGAAA GCCTGTG 20220

GATCTTCCGA GCCTATACAG CTGCTAATCG CTTCCCTCTT GATCCCTGCC GTAGCCC 20280

TGCTGGCTTA CATCTTCCTT CATGTAGGCT GTTACAATAA TCGCCTGGTT TCCACCT 20340

GTCTATTTCT ATACAGCGTT CAAAGTGATA CTTCTGAATC TGTCCCCTAG TTCTGTG 20400

TCTGTGCAGG ATGTGATGGC ATCGCCCCTC ACTGAGGTTA TGCTATGTCG TCTTTCA 20460

TCATGCCCGA ATGGTGATGT TAGCTTCTTA ATGCAATCCA TCAGTGAATT AAGTCTT 20520

GTCAGGTTAC AGCCATCGTT ATCTAATCAC CTCTCCGTGG TTGGGTCTGT GACTTGG 20580

TTTTCACCCT TCTACACACA GAGAGGGCAG TTTGTATCTA AACCATAACA AGAGGGA 20640

TTTCTTTTTC TTTTTGTTTA TATAAGCAGG GGTACTATCT GACTCATAGC AGTTGCT 20700

TAATTACACG AATCAATTAA TTCTGGTCAG AAAGCTGGGA ATTAGCGAAG TAACTTT 20760

ATATAGGTAG TTATAAAAGA GTTGGGTAAT AAATAGCTAT ACCATAATAT ACTGTGC 20820

TTTCAACACA AATGATTTGA AAGAGACAAG CTATATTTTC TACCCTTAGG TAGTTCA 20880

CCCCGAGAGG GAGTTGAGAT CCACATCCAG GAAAGTAGAG GCAATAGAAA CAAACTG 20940

ACCATGCATG GAAAGATGAG TAGTGCCCAT AGCACAGTCG CACATGGGAG GGCAAGT 21000

GGTGTCCCAC AGTGCAGTCA CTGAGCGCTG CTCTGAAGGA CTGGTTCCCA CTGACTT 21060

AAGATTTAAT GAGACAGAGC GAGCTGTGGA ATTGAAAAGC AAGAGGATGC TTGTGTA 21120

CTTTCTTAGG CCTTTGATTC TAGGATTGCG TTAAAGGAGT TTTAAATAAT TTAAGTG 21180

CTCAAATATT CTTCAGGTGG AAAAAAAAAG AATTAAATCT TTTATTATAT CTAACTC 21240

ACATAATGAG ATCGCTTTCA GTTCTTGCAG TGATGAAACA GCGTATTCCT TCAGCTG 21300

GTCTTGGCAG GTTGTTCCTC CTGCAGAGGC CGAGGATCCT TAGCCCCTGT GCTTTTA 21360

ATGGACTCTG TTGGGGGTGG TAAGAAACGC CACCTGGTGG ATATTCCTTT TCTTATT 21420

CTTGATCTTA CTGTTTTAAC CCTGTTATGC TGGGATTACT GTTGGGTTCA TTACACC 21480

TTAGTATAGC AAATCTAAAA GTGCTGGAAA CCACCAAACA ATTAACACAG AGGACCC 21540

TGGAAGGAAT CACAAAAGTG AGCCCAGAGA GGTGAAAGCC AGGTGAAAGT TCTGCAT 21600

›Example 10 · 44 of 49

CGTCAAAGTT TATATCTAAC CAGGAGGACG GACTTTTGAA GACTATGAGG TATATTG 21660

CTTCCCACTA ATTTGTCGTA AGGACCCATT AAAAAGATCA GAATAGTAGA CACTAAA 21720

CTGGAAGAAG AGATTAACTA AAATCTGTGT GCAGAGTGTG AAGTAGTTAT GTCATCC 21780

TTAGAAAAAA GATTGTTATG TTTTCTTTCA ACCGTTGTTT CATGGAGCAT GTAGTTA 21840

TTCATCTCAA TGTACAGTGT CATAAGATTA ATCTGCATTA TATATTCATT GGGTTTT 21900

GCTTACTTTG TCAACAACTG GTGTCTCTTA CCAAGGAAAT CAAGGCAGGC AAACTTA 21960

AACAAATTCC TGGTGCTAAG TGCTTGATAT ATGTAGACAC CAGTATAATT CAGCACA 22020

CCAGCTTTCT TCTCAAACAG GTTACACTAT TTATAATTGT GCTGTAGCCA CAAAAAC 22080

CTGGAAATAG CCCATCCAAC AAGGGCATAT GGTCCCATTT CTCAGTACTG ACCCATG 22140

TATTTGTAAG CATTGTCCTT GACTAAAATT TTCACATTAT AAAATGCTGC AGACTTC 22200

GGGATCCGTT CTAGTCACAT TCATTTTCAT GAAGACTGTT ATTTTTTATT CTACTTT 22260

GTTGGAAGAG CAGTATTCCT CTCTGTGTCT TTGGAATGTT GTAGTGAGTT TACAATA 22320

TCCCTGCTAG CAGTCTGCTT GACTTTTTGA GGACCTTATA AGAAAAATGA AAATTTT 22380

TAAAAGATCT ATCAATCTTG TAGCTCTGTG TCTCTCACTT CACTTTTCCT TAAGTTG 22440

CCTTGCTGGA GTCAGTGGGG AATGCGCTAG CATTTGAAAT TCTCCACCAT TGACATT 22500

ATGCAGAAAG AAATGTCTTC TGTTGTTTTG TGACTGCACT AGTTATAAGG AACATTT 22560

GTGCTGGCTC TAATACCCTG AATAGAATTA AGCACTTAGC ATGCTTTTGT AGATATG 22620

ATGTGTTTTG TGTGGAGTCC AGGTGTGTAT AAAGACTACA GGTCATTCTT GGGTGTT 22680

CCTCAGGTAC AATCCACATT GTCTTTGAGA AACAGGATCT TTCACTGGCC TGGAGCT 22740

CAAGTAGGAT GGAGTGACTG GCCCTAGAGT CCTGGGAACC TCCATATTTC TTTTATA 22800

GGCATAAGAC CGCTGTCCTT TTTCTTTGAT TCTTAAAATA TTGTTCAGCC TCTTTGC 22860

TGCAAAGGCG ATCTATCAAT CAGTAAAGTT CTGGCCTGAG AAGTCTGTTC AGGAAGA 22920

GCCATTGGCT GAGATCATCT ACCCAGTGCC GGTATTACAA ACTGGAATTT CAAGTGT 22980

TCACAACATC TAGGTGTGTG TGTGTGTGTG TGTGTACACA TATATATGTA TATATGG 23040

TGCCCAGCGT CCTGAAGGCG CTGTTTGACA AAGTTCCAGT TCTTGGACCA AGCCTTC 23100

GCCCTTGGTG GATATTCGCT GCACACCTCT TGCTAGTCTT ATGTTTCTCA CTGTTAA 23160

CCTCTCTCTG AAAGCTAGAG GTGGGATAAC AAGAAGCTAG TGTAAACAAG AATCAAG 23220

ATTAAAGTTC CCTGGGGGGG GGGAAGTTAT GCAGAAAATT GAGTCTCTTC TAAGAAG 23280

TTTCTTAAAT AAACATTTAG ATCATTAATG AATGTTGTTA GTAAGCATGA GATAGAA 23340

TTGAGAAGAA TTATTAAAGA AGTAAAACTT AGGGAGAACT TAGAAGTTGA GAAGTTG 23400

TTGGATTGCT AGGTTTTTAA GGTTCAACTT GAGAAACGAG CAGTTTGTAT GTATAGG 23460

GGATTTGGAT CATGCAGGTT TATGACAAGC CTCGGTGCCT TCCTGAAGGC AAAAGTA 23520

AGGTTTAGGA ACCCTGATGT TCTTCTGTTC TTCACAGAAT TGTTGTAAAG ATAGGGA 23580

TATTGAAACA AGGGTTCAAG ACAGAGACAC AGAAGAAGGC ACTCTGGCTC AGTGAAC 23640

CTGCCTTCCT GAACATGTAA GGTTAAAAAT GTAAATTCCT AGGAAACTGT TATATTT 23700

TTTAAAATGT TAGGTTTTGT TTGTTTGTTT GTTTGTTTTG TTTTTTAGTT TTAGTTT 23760

TTTTTTTTAG ACAGGGTCTC ACTGTGTAGC TGGGGACAAG CTCCACCCCT GTTCCCC 23820

TCCTCACCCT CCTGAGTGCT GGGATCACAG GCGTGTGCCA CCACCCCTGT CAGGGTC 23880

TACACACCCA GGAGTCCTTA CTGTCAGGCT GTGTCTGTTA TCGTATCTTA TATCAAC 23940

TAATCAACCA TTGTAATGCT TGATTAGAGA ATCTGATTTC TTCAAAACAA ACAAGGC 24000

GCATGACTTA ATCACTACAT ATACATTCCT AACGCAGAGA GCAGTCGGAT TATTGGC 24060

AAGATTAATG TGGGGTTACA TTTTAAAGTG GTTTCACAAA TTTAAAAATA GACAATA 24120

AAAATTATCC TAATTACTTG GTTTCATTGA GTTTATTTTT GTATGACTTT GGATAGG 24180

TAATCTAATT AAGTTATTTT AATCGTAAGA GTAGCTGTTT CTTAATTAAT TTACTGC 24240

AGACCAAACC CAAGGCCTTG ACAGGCTCGT ACATTCCCAA TGAGCCATGC CTTCAGC 24300

TTAACTATTC CTTTCTGTGT GTGACTGAAA ATAAGCTTTA TTTTTCTAAG CCAACAA 24360

TGAAATAATG CTTGAAGCTT TGTCCAAGTC TATATTATTT TATGGGTAAT ATTTATT 24420

TATTGAACAC TTTTATTTTT TAACTATGAA GGTCTTTTAT TTTCATAGAT ATCTATT 24480

GTAAAAATTT AAAGGTAATA AACTATGATA AATTGAGCTA AAGATGTGGC TCAGTGG 24540

GATGTTCATA TTGCTCTTAC ATGAGAGGAG AGTTCAATTC CGATCACCCA CATTAGG 24600

CTCACACCTA ACCATAACCC CAGCTCCAGG GGTGTCTGAA AGCTCTGGCC TTTGAGG 24660

ACTTCACACA CACACACACA CACACACACA CACACACACA CACACACAAA GTAATAA 24720

AAAATGATCC CTAAGTACAT AAATCATAAT TGAAGTAACA TTCAATGTTG TTATGGA 24780

TCAGCTTATT GGGAGGTTAT GTAACTATAA TATTTACATT TTTAAAGAAT AGAAAAA 24840

TATTTCTATA ACAAAGCTAA CTGAAACAGT AGAATATAAA AGGCAAAAAC ATTGATA 24900

ATATTTTGTG AAATTTAAAT AAAAACCAGC AATCAACTGA AACTGAAAAT ACCATAA 24960

ACAATGCTCT TTCTTAGGTA TTTCTTAGTA GTTTTGTTTC GCATTCTTAA TTTACAT 25020

TGTATAAAGA AGAATAAACC GAGTTACTGA ACAGAGCAGC AAAGCTTGTA ATCTAAA 25080

TAAAGATGTT TATGTTTTAG TTTTCGAATT AACAATTTAT AATTCTGAAG ATAATTT 25140

CTTAATTTGT TTATTATCTA AATGCATTTT ATACATCAAC CATATTAATA ATATTGA 25200

TTTTGAGACT CAAATAATAC ATAAAAAATT TGTTCAACTT TTATTTTCAT ATCCTGA 25260

TATCATTAAT GAATATTTAA TACTATCCAT AACTGAGGAT CCTATATCTA ATGTTAA 25320

CTAAATTGTT TCAAAACATA CAGAATATGC TTAGGGAGTT AAGCATAGTA AAAGAGC 25380

GAATATTAAA AATGAATCAT TAAAAAATAC ATTAAAAAGC CCTTATATGA TACCACA 25440

CATAGTGAGA GAGTATTTAA AACGCATTAT ATATCTGTGT GCATTGTCTA ACAATCA 25500

TACTTAAAAA AGATTATCAG TGTTTCTAGG AGAGAAATTA TTTTATCAGT AAGTATA 25560

TAAAAATTAC AAAATAGCAA AAACTCTTTG AAGTTAACAG TAAGAAAATG CTAATTT 25620

GCACAGTGAG AAAAATTATC AATAATATTT CCATGATGTT TGTAGAACAT GATTTTA 25680

TTTTCAAATG TTGATATTCA ATAAACAGAA AAGTTATTTG AAGATATATT TCATTGT 25740

GTCTCCCTTT TAATTTTTGA TTTTATTAAT TTGGATACTG TCTCTATGCC CTCTGGT 25800

TCTGGCTTAG GGTTTATCTA TCTTGTTGAT TTTTTTTTCA AAGAACCAGC TCCTAGT 25860

GTTGATTCTT TGTATAGTTC TTTTTGCTTC TATTTGGTTG ATTTCAGCCC TGAGTTT 25920

TATTTCCTGC AGTCTACTCC TCTTGAGTGT TTTTGCTTCT TTTAGTTCTA GAGTTTT 25980

GTGAGCTGTC AAGCTGCTAG TGTAAGCTCT CTTCAGTTTC TTTTTGGAAG CACTTAG 26040

TATGAGTTTT CCTCCTACCA CTGCTTTCAC TGTGTCCCGG AAGTTTTGGT ATGATGT 26100

TTCATTTTCA TTTCTGCCTT GACCAAGTTA TCATTGAGTA GAGCGCTGTT CAGCTTC 26160

ATGTATGTGT GCTTTCCGTT GTTTGTGTTG GTATTTAAGA CCAACCTTAG TCCGTGG 26220

TCTGATGATA GGGTGCATGG GATGATTTCC ATCATCTTGA ATCTGTAGAA GTCTGTT 26280

TGACCAGCTA TATGGTCAGT TTTGGAGAAG GTTCCATGAG GTGCTGAGAA GAAGGTA 26340

TTTTTGCTTT TGGATGACAT GTTCTATAAA TATCTGTTAG ATCCATTTGG TTCATAA 26400

CTGTTAGTTT CACTGTGTCT CTGCTTAGTT TCTGTTTCCG TGATCCTGTC CATTGCT 26460

AGTGGGGTGC TGAAATCTCC CACTATTATT GTATCAGGTA TGATGTGTGC TTTGAGA 26520

AGTAAAGTTT TTTTATGAAT GTGGGTGCCC TTGCATTTGG AGCATACATG TTCAGAA 26580

AGAGTTCATC TTGGCAGATG TTTCCTTTGA CCAATATGAA GTGTCCTTCC TTATCTT 26640

TTTGATAACT TGGTTGAGAG TTGAATTTAT TCCATATTAG AATGGCTACT CCAGCTT 26700

TCTTGGGAAA CAACCATTTG CTTGGAAAAT TGTTTTCCAA CCTTGAACTC TGAGGTA 26760

TCTGCCTTTG TCACTGAGGT GCATTTCCTG TATGCAGCAA AATGCTGGGT CCTGTTT 26820

CACCCAGTCT GTTAGTCTAT GTCTTTTTTT GAGGAATTGA GTCCATTGAT GTTAAGA 26880

ATTAAGGAAA AGTGATTGTT ACTTCCTGTT ATTTTTGTTG TTGTTAGAGG TGGAATT 26940

›Example 10 · 45 of 49

TTTGTGTGGC TATCTTCTTT TGGGTTTGTT GAAAGATTGC TTTCTTGCTT TTTCTAG 27000

GTAGTTTCCC TCCTTGTGTT GGTGTTTTCC ATCTATTATC CTTTTTAGAG CTGGAAA 27060

ATTGTGTAAA TTTGGTTTTG TCATGAAATA CCTAGCAGCT TGACAGCACA CCTGAAC 27120

CTAGAACTAA AAGAAGCAAA TACACCCAAG AGGAGTAGAC TGAGATTGGG AGTTTTG 27180

GGGCTGGCAT TTGTGTTCTC TTAGGGTCTG TATGACATCT GCCTAGGATC TTTTAGC 27240

CATAGTTTCT GGTGAGAAGT CTGGTGTAAT TCTGATAGGC CTGCCTTTAT ATGTTAC 27300

ACCTTTTCCA TTGCTGCTTT TAATATTCTT TCTTTGTTTA GTGCATTTGG TGTTTTG 27360

ATTATGTGAC AGGAGGAATT TCTTTTCTGG TCCAGTCTAT TTGGAGTTCT GGAGGCT 27420

TGCATGTTCA TGGGCATCGC TTTTTTTAGG TTAGGGAAGT TTTCTTCTAT AATTTTG 27480

AAGATATTTA CTGGCCCTTT GAGTTGGGAA TCTTCACTCT CTTCTATACA TATTATC 27540

AGGTTTGGTC TTCTCATTGT GTCCTGGATT TCCTGGATGT TTTGGGTTAG GAGCTTT 27600

CATTTTGTAT TTTCTTTGAC TGTTGTGTCA ATATTTTCTA TGGTATCTTC TGCACCT 27660

ATTCTCTCTT CTATCTCTTG TATTCTGTTT GGTGATGCTT GCATCTCTGA CTCCTGA 27720

CTTTCCTAGA TTTTCTAACT CCAGGGTTGT CTCCCTTTGT GATTTCTTTA TTGTTTC 27780

TTCCATTTTT AGACTCTGGA TGGTTTTGTT CATTTCCTTT GCCTGTTTTA AAGTGTT 27840

TGGTAATTCT GTAAGGAATT TTTGTGTTTC CTCTTTAAGG GCTTCTAGCT GTTTACC 27900

GTTCTCCTGT ATTTCTTTAA GGGAATTATT TGTGTCCTTC CTAACGTCCT CTATCAT 27960

CATGAGAAGT GATTTTCGAT CTGAATCTTG CTTTTCCAGT GTGTTGGGGT ATCCAGG 28020

TGCTATGGTG GGAGAATTGG GTTCTGATGA TGCCAAGTAA CTTTTGTTTC TATTGTT 28080

GTTCTTCAGC TTGCCTCCCG CTATCTGATT ATCTCTAGTG CTACTTGCCC TCGCTCT 28140

TGACTGGAGC CTGTCCTTCC CGTGATCCTG GTTGTGTCAG AACTCCTCAG AGTTCAG 28200

TCTCTGGGAT CCTGTGATTC TGGAATCCTG TGATCCTGAG ATCCTGGGTG TGTCAGA 28260

CCTGGGACTC AAGCTGCCTC TAGGAACCTG AGATCCTGGT GTGACCAAGC TCCTGGG 28320

CTGGGATCCT GGGATCCTGT GGACCTGGGT GTGTTAGAGC TCCTGGGAGT AGAGCTT 28380

TTGGGTGTTG TGCTACTGGC TGTGGAGTTT GCTCTCAAGA TCTGCTCTGG GCAACGG 28440

AGAGTGGATG GGACCTGTGC CGCTGGTCAG GTGGAGTTCC TGGGTGCCTG GGTTCCA 28500

CTCCCAGTTA CTCCCGGTGT TGGGGCAGAT GTTGTGCCCT CCTCACCTCT GATCCTA 28560

TCCTGGGAAT GTTTAGGGCA CTTGGGAGTG AGCTTCCTCT GGGTGTTGTG GGACTGG 28620

CGGAGTTAAT GCCCAAGGTC TCTGCTCAGG GCACTGGCCC TGACTGGAAG GAACCTG 28680

CAGTGGTGGG GCGGATTTCC TGGGCACCAG CCCAGACTGG AACAGAACAC TTTTATT 28740

ATTCATTTAT ATTGTTCAAA ATAATGAGTT TCGTTTCATT TCCATAACAT ATTTAAT 28800

CTTTGGTCAT ACTTATTCCC TAAGAGATCG TATTTTGTTT TAATTTTAAG TCAAATT 28860

TACATATTTC TTTGTAAATT AGCAAACTGC ATACACATTT ATACTTAGAT ACAAGAT 28920

TGCTTAAATT ATTTTATGAG GTATTTACCG TTATGTTTGA ATAATTTTAT TAGGATG 28980

TTTCCTCTAT CTGTAACAGG TAATAAAATA AAAAATTGAA TTCTTAGCAA TAGAATA 29040

AATGATTTAG AAATAAATTT TAAGACAGCC TTTTTCTTTT CTGATAATGA AATGGTT 29100

TACCCTGGTT GAGTGTGTCC CCATTGTAAT AGTTATAAAA CATGAGCCAT CTACATG 29160

GATACCTTGC TCACCTACAT GTGAATTTCT GAACGAAATA TTCATGGTCT TCCTGCC 29220

TATTGTGCCT CTTGATTTTG ATGCTCACCC TATGGAGAAA TGCTAGAAAA TAGCCTA 29280

GTCAGTTGCT TAAAGAATCG GGTAGTCATA CATGTCTCAC TTTCTACATA TTGATTA 29340

CCAGAATGGC ACTGAGAACT CAGTAAGACA GGAGAGAGGT TGTAATGGCT GTTGGGA 29400

TTGCTTCCAC AGCTGGAAAG CCACATGCCA ATATAATTTT GAAGAACGCT TCTCACA 29460

TAAAAGATAA ATTGTTTTAT GTAGCTAGGC TATTAATTTA TAACCCTGCC AGGGCTT 29520

TATTGCAAGT TACAGATTAT TAAAAAAGAA CGAGATGTAT TAATCCCCAC TTCTATT 29580

ACTAAAGTAT AAATGGCTAA TAAGTAGTTT TAATTTAGTG GGACAAGATA AATTGCA 29640

AAATCTCATG ATTTAGTGTT TGATTTATTA AGTAGGAGAT AACTTTTCTC GTTTAAA 29700

ATTTTTTTTT CTCTTTACGT AGGGCTCGTA GCTTGGTGGT AGAGCACCCA CTAAGCA 29760

CCAAGGTCCT GGGTACCATC CCCAACATGA CAAAAAGAAA TAAATATTCT AATAAAC 29820

AACGTTAGCA TGTGTGTCTT GGCCATGGTT CCTGTATGGT TGTGACTGTG GATGTGT 29880

AAGACAGTGA GAAGTCAATG CGCCTTTTAA ACGTCCGTTT GTATTGGATT TCCCCCC 29940

TTCCAGTCAT TGCACTCTCC GCTACTGCAA GCTCTTCCAT CCGGGAAGAC ATTATAA 30000

GCTTAAACCT GAAAGACCCT CAGATCACCT GCACTGGATT TGATCGGCCA AATCTGT 30060

TAGAAGTTGG ACGGAAAACA GGGAACATCC TTCAGGATCT AAAGCCGTTT CTCGTCC 30120

AGGCAAGGTA AAGATAGGAC GCTAGACGAA AGGATCTTTT AAAGAAGTTA TTTTATT 30180

TTCTATTTCT TTTTTTGATA TATATTTAAT GTCTCAAATT TTATGTAGCC TTGGCTC 30240

TGAGTGTAAT ACTACATAAT CAATTCAGTG ACCAATATGA AACCACTAAA AGAAATA 30300

CCATTCATTC TTTTAGAATT TCATATAGTA TACTTTGATC ATATCCACCC CTTATTA 30360

TCCCAACTTC TCAACGGAAA CTAGCTCTCC CTCTCCCAGA AGCTATCAGC TGTCTAC 30420

CTACTGCTTG GTTAGGGGTA GGGGCTTGGT CTAGTGTAGA CAAGGGTTCA TGAGCGC 30480

GGTCCTGCCA TGACCAGGAC ACATGGCTTT GCTTCAGTTT TCTCTGACCA TTGGCCT 30540

TGTTCTATTT GTCCACTCTC CCATGGTGTT CAAAGCATTT GTATTTTGCA AGGGCAG 30600

AGATGTGGCC AGGAACTAAT TTGTCTAATA TTATTTTTCT TTTATATTGT TATTCAA 30660

AGAGATATTC TTTTAATAAT TTACAACTAA ATGAACAAAT ATGACATGAG CATTTCT 30720

GAGTTCTGTC TGCTTTCATA TTTAGATGAT CTACCTCTGC TGGAGGGGCT TTTTAAT 30780

CAGTATAGAG TCTGTCCATG TTCCAAGGAC TGTCCTAGAT GCTTTATACA AGTGATC 30840

TTAAATCCTC TAGCATAAGG AAGTTCCTGT GTACATCTAT ATTTTACTGA TGAAACT 30900

CATTACACTT CTAAGATTTG TATTTTAAAA TATACTTTAT GCTTTATTTT GTATGCG 30960

AACCTTTGTA ATGCCATTAT TCTCTGTCCT GCCTGCTGAG TTAAAAGTTG ATATTTT 31020

TATATTAAGT ATTCTGAATA ATGAAAAATA ATTTTCTCCT ACCAATACCA ATGCAAA 31080

AGTCCAAGCA AGAAAGAGCT GAGAGCATTG TTAGTGTTTT CCTCGTCCAG AAAGGAT 31140

AATGGGAAGA GAGATCCTAG GTTAAGGAAG TGATAGTGTT TGTTGTAGAT ACTAGGA 31200

AGTTTAAGTA CCACCTGAGA AGTGCTCGCT ATTCCGAGTA GAATAGGAAG ATGGGGA 31260

TATTGATAGG GTTTTGCTGC TCAAGCTGCC TCCTTGAACC TGCTGTTCCA TGGTCCT 31320

CAGTAAAGGA AAAGTTCTCT TGTCAAAGGC TTCTTCTAAA CTGGATGTTT CTACACT 31380

GTCATTACTA ACCCCTGATC TTTTAGTTCT TGTCAATGCA CATTATTTTT AATATCT 31440

GCTAATTTTT ATAGTGACCC TCTTCTTTCA TATGTATATG TGTGTGTGTG TGTGAGT 31500

TGTGTGTGTA TGTATATATG TGTGAGTGTG TGTGTATGTA TGTATATGTG TGTGTGT 31560

TGAGTGTGTG TGTGAGTGTG TATCTGTGTG TGTGTGTGTG TATGTGTGTA CACACAC 31620

AAAGTGCCTT CCCCCATCTT TTCTTGTGAT GTTTTGTTTT CCCATTTTTG GCATCAT 31680

CCTTACAATA TCTTATGCAA ATGCCTTCTT CCCAATTTAT ATTGATATTC TGGTAAC 31740

GATTAATTTA ATTTTTAGCC CAGATTTTTC TGATCACTCA TAACACATCT ATATCCT 31800

TGCTACTTGA TATATTCCAC AGATAACTTT CAGGTTTATC ATCTGCAGAC ACGTCCT 31860

ACCTTGGAGT AAAATTTTAT TTTTAAACCT TGTATAATAT TTTATGCAAC AGTGAAA 31920

TTCTCTCACC TCTTAAATAA GAATAGATTA ATCTATTGTG CTGCCTTTCT AGACTCA 31980

TTATCCATAC CTTGTAAGTT TTAGAATCAT TTTTTTCCTA AAACAAAGTG ATTCCTG 32040

TTAACTTTAA TTTGGGCCAA TGTTGAGTGC CAGAGTTTTG CTTTCACACA ATACGTT 32100

ACGTTTGTCT TTCCAGAATG TTCTGGAGTT TCAGGGAGTT GAAGTGTTTT TCAGTCT 32160

GACTTCTTTA AGACTTTTGC TTAGTGAAAG CAAAGATTAT GAAAGATGAA TCCCAAA 32220

CGATGAAACA TACATGTAAC AGGCGTGTTT GCTTTCTCTG TCTCCCTACC TCTTCCC 32280

›Example 10 · 46 of 49

CCTTCCACAG TTCTGCCTGG GAATTTGAAG GTCCAACCAT CATCTATTGT CCTTCGA 32340

AAATGACAGA ACAAGTTACT GCTGAACTTG GGAAACTGAA CTTAGCCTGC AGAACAT 32400

ACGCTGGCAT GAAAATTAGC GAAAGGAAGG ACGTTCATCA TAGGTTCCTG AGAGATG 32460

TTCAGGTGTG CAGAGCAACC ATCTTTCTCT GAATTCTTCA CAGGAAGTAT ACGTATC 32520

CAAACATTTA TGTCACCAAT TTTTTTTTTA AAATTGTTGT ATTAAGCACA GTTTCAC 32580

TCTGATAAAG GTAATGACTG TATAGTGAAA TTGGATTAAA TAAACCCTAC AGCTTAG 32640

AAATAGCAAA GACTGTCATC TGTTACTGGG CTACACAGAG AATCAACACC AGTTCTG 32700

GAGTAGGTTA TGTAATGAGA GTGGTCATCA GGAAGCTGAA ATCTGAGAAG AGTCTTA 32760

ATGTCAAGTT TACCAGGTCA GTAGGTAACG AGGGCTGTAG AGTCCCAGGA AGCAGCA 32820

GGTGCAGAGA CACACGTTGA GTGCATCCTG GGCTCAGAGA GGAAGAGCCT GAGGTGA 32880

GAGGAGAAGA TGAGCGGTAG GAATGGCACA GTCAGGGGAC ACAATGAGAA GGTTAGA 32940

TCTCAGGAAG GCTGCGTTGG ATGGTTGGCC AGCTTAAAGA TGAGAAGGAT CCCTGGT 33000

TGGTGCTCGC CCCCTACCAG AAAGCATCTA TTGTCACTCT TCCTGTAGGA ACGGCAC 33060

TGCTTATGAG AGGTTGTTGT GCACACTTAT TAATACTTTT ATTACTTTAG CGACTGG 33120

CTTTGGATGC ATCTGGCATA CTGCCTGTCT TAGGTACTTT TCTGTTCTAC TACTGAC 33180

GGCAACTTAC AGAAGAAATA GTTTATTGGG GCCTACAGTT TCAGAGAGGG GGTCTGT 33240

CACTGTGGAG AGTGTGCAGC AAGCAGATAG GCATGGTGCT GGCGCAGCGG GTAGGCA 33300

TGCTGGAGCA GCGGGTAGGC AAGGTGCTGG AGCAGCGGGT AGGCAAGGTG CTGGAGC 33360

GGGTAGGCGT GGTGCTGGAG CAGCGGGTAG GCGTGGTGCT GGAGCAGCGG GTAGGCG 33420

TGCTGGAGCA GGAGCTGGCA GCTTGAGCAC CAAGAGAGAG AGCTAGCTGG AATGGCA 33480

ACCTTTGAAA TTTCAAGGCC AGCCTTTAAA GCCTGCTCTT CCCCACAAGG ACACACG 33540

TAACTCTTCC CAAACAGTTC TCTCACCTAT GGATCAGCGT CCAAACATAT GAACCTA 33600

GGGCCATTCT TGTTCAAACC ACCACACTGC CAATGTATAA CTTGATTGAA GCATTAA 33660

TATATATATT AGTTTTTTGA GACAGGGTTT CTCTGTATAG CCCTAGCTGT TCTGTGG 33720

TATTAATATT TTAAAAGAAG GCTTAAAAAT CTTTAGTGAT CTTTCATTAC AGTTAAT 33780

GAAGGTTATC TATCTACCTA CCTACCTACC TACCTACCTA CCTACCTACC TACCTAC 33840

TCTACCTACC TACCTACCTA CCTACTTACC TACCTATCTA TATTTTGCAT GCCCTGC 33900

ATTTTCTCTT TCTAGTACAG GAAGTCATCA ATTCGAATCC ATATTATAAA AATTAAA 33960

TAGATGAATA GTTGCATTCT AGGTAGCCCG AGGTAGTGTT TTGTCTAACA GCTGAAC 34020

TAGACTCCTT CCTGGTCACA ATTCAGAAGC CTGGCATATG CTTCGAACCT TCCCCTT 34080

TAGCACAGTG AAAGGCATGT TGTCATCAGT GTAGACTTAT CTGGACTCTT AGAGCTG 34140

ACTTTTTGTT GGGTGTTCGT TGAGTGCCGA CTGAATTCAT AAATGTAATG ACTTCTA 34200

AGCTACTTCC TGACCATTTT ACAGTGGATT TTTACTGTAT GGCAGGCACA GAGGCTG 34260

TCTGTAGCTC TTCATATGTT AGACTGATGC ATAAAGCCAT TTTCTGTTTT ACAATTT 34320

AAACAAAGGG AATTTCCTTT ATGTCATATA TACTCAAATC CCATGCACAT TAGCTTT 34380

TGATTTGTTT ATAACTGTCT GTTCTCAAAT TTTATCCCAA CCCTTAGTTT CGTCCTT 34440

ACATTTGCCA TTTTAAGGTG GCTTTTTAAA AAATGAAATG ATGAATAACT TATTTGG 34500

AATAGTTTTC ATTTATATCT AAAAGTTTAT AGGGACAGTG TGAAAATCTG GTTAATA 34560

TAGTTAACAT CAAATGAAAG AATAATCCGG TGAAGCTTAG AATTCCATTG GTTATTG 34620

GCTAGCTGGA CTGAGCTGTT AGAATTCCAT TGGTTATTGA CTGCTCGCTG GACTGAG 34680

TTAGAATTCC ATTGGTTATT GATTGCTCGC TGGACTGAGC TGTTAGAATT CCATTGG 34740

TTGACTGCTA GCTGGACTGA GCTGTTAGAA TTCCATTGGT TATTGACTGC TAGCTGG 34800

GAGCTGTTAG AATTCCATTG GTTATTGACT GCTCGCTGGA CTGAGCTGGC TTCTTGC 34860

AAAGCTTTTG CTTCCCACGT CTGTGCCGTT ATCCCCGCTC CCTCACCCCT CACCCAT 34920

TTGCGTGTTT CCTATGCTCT TCCTTTCTCC TTTCTGTCAA TCTCCTGGGC CATCCTA 34980

CATACCCTAT GAGCTTATTT TACTGTTGTC TCTTCAATGA GGCGTCTTCT CCCCTCC 35040

CTCCTAAGCC TTCGATCTGA CTTTGGAGGT GTTTATTGCT CTACCCTGAC ACAATTT 35100

TATACTGCTA TCTTAATTTA TTGTCAGTTT TTATGATTCT CTATTGATTC CCCACTA 35160

ATGCCGGAAA TTCACCAGCC TTTCCTCTGT GTTCCTGCAG CCCTGGACCC CTTTCCC 35220

GCCTGTTGGT TTATATCTTA ATTCTGCTTA AATGTCATAT GGTTATCAAC TTAAGCA 35280

TACCTTTAAT TTTTATAATA TATGGTTATA GTTCTCACAT ATATTTTTGT ATTCTTG 35340

TTAAAGGATT TTTTTTCTGA GTATTTGTCC CTAATTCTCC TGTGAGTTTT TTCCAAC 35400

ATGAACTTTA TTTTGTTAGG TTCATTCACA TTAGGTCATT TGACAGTTTT ATCCTCT 35460

TATTATACCC GTCTTTTTTG TTTTTGTTTC TGTTTTTGTT TTGTTTTGTT TTGTTGT 35520

CTATTGTACC CATCTTAATG ATGCTTCATT AGCTGTATTT CTCTTTGCAG TAGTGAA 35580

TATTATACTT AGATTCTGTC ATCAGGAGAG GACATTCGAA ACTTGATAAT AATACAA 35640

TTTTATTCAC TACAGTAACT GTTTCTCATA GCTTCGGGTC TCCAGAGAAA CTCCTTT 35700

TGCTCCTTTT TATAGAGATG AAGAGAAGTC ACATTTTTTT TTTTAAAGAC AGGGTTT 35760

TGTATAGCCT TAGCTGTCCT GGAACTCACT CTGTAGATCA GGCTGGCCTC AAACTCA 35820

ATCCGCCTGT CTCTGCCTCC CAAGTGCTGT GATTAAAGGC GTGCACCACC ACTGCCC 35880

CAGAAATCAC ATTTTTATAG CCACTATTTA TCCAAATCTG TATTTGGATA GATTATC 35940

TAGTCTGTAA GTAAAGTTAT ATTTAATTTA GTTTTACACT GGCGGGCAAG CTGCTGT 36000

ATTTTGTAAG TTTTAGTTAA GTTGAAATGT GATTCTTACT CTGCGTTGTT GTTCATT 36060

AGTGTGTTGT AGCTACTGTA GCTTTTGGAA TGGGCATTAA TAAAGCTGAC ATTCGCA 36120

TTATTCATTA TGGTGCGCCT AAGGAAATGG AATCCTATTA CCAGGAAATT GGTAGAG 36180

GCCGGGATGG ACTTCAGAGT TCCTGTCACT TGCTCTGGGC TCCAGCAGAC TTTAACA 36240

CCAGGTATAA ATGCTTATTG TTTTCACCTT ACAAATTCCT TTTTCCTTTC CAAGAAA 36300

TTTGAGGGAG TATCCAAAAT ATCAAGTGAC CCCTGAGTAT ATTTAAAGGG GTCGCCA 36360

GAAAGTGAGC AAAATGAACA GAATATCCCT GAAGAGTGTT TTTGGTAAGT CTTCCCA 36420

AGCAGGTGAT CCAGTTGGAG TTAACAAGAT CGGGACTGCA CTTGGACGTA TAACATA 36480

CTTATGGCAT CCTGTCCTAT TGTGCAGCAG TAAGCAGTTC CCACATTTTA AATCCTC 36540

TCATATGGCT CTAGGTTTAA GTAAGTACCA TGTGTCCAGT GCTATAATGG TGGTTAT 36600

AAAAGATGTA TCCAATTCTT GTTTAACTCT CTTTACTATT GTTTCTGTGA TTAGTTC 36660

AAGTGCATGC CACTGCTCAT AGACTGAAAA CTCACCTGGT TGATAGTGCC TAAATAA 36720

AACAGCGTAG TGTTAGAGTG CTGTCATAAA ATAGTATATG TTCGTGGTTT AAATTCA 36780

AAAGGGAAAC TGCCTACTTA AATGCTAACT AAATTGTAAC TTACATCCTG CCAGATT 36840

TTAGAAGCAA CAGCTTCAAT TTCCAAAATC ATAGGGACAT TATTTACCAG TTATCTA 36900

ATAGGGAACC AGGAAAAGAA GCCAGTGCAG CCCAGCCAGT GAACGTGCCA ACATAAA 36960

CCTTTCAGTG CTCCTCCAGG CTGATGAGTA AGCTAGACAC TGGTAGCTAA AAGAGTA 37020

TTAGATAAGT AAAAAGGGTT GTTACAAAAT CTAAGATCTT GCTAGGAATA GTCAGTA 37080

TTTACTTTGT AATAAGTAGA GCTGAACTCT GATCCCCTGA AAGCAAGCAT TCTTAGC 37140

TGAGCCATCT CTCCAGACCA GGCGCCAGAG TCTTTACCCA GCCTTTTAAA AACCAAT 37200

AAGTAAGTTG GATAGAACAC ATCTCTGCAA GCTACTATTA AATTTGGAAT ATATCAA 37260

TCACTTGGTT AAGACCAGAT CTTATTTTAT TTGTGTATTA TGCTAACATG CTGGAAA 37320

TATAGGCCTG AGTTGTATAA TGCAATCTCA CCCGTGGATA TAGTGTTGAT TTATGTG 37380

TTTGAAAGAT ATGCTGAGTG GTTTATCTCA TTAAGATTGA TCAGGAAATA ATAGTTG 37440

CAGAATACCC GTGCAATTGT TACTTAGTAT CCATGGTGAC TGGTTCTGAG TTCCTTA 37500

TAGAAATAAA TAAATAATCT CCCTATACAT GAGGCTCTTA TACAACATAG TATTTGT 37560

CAGGCTGTGT ACTCTTCTAC ATACTATCTT CCTAGCTCAC ATATAACATC TATTATA 37620

›Example 10 · 47 of 49

TAATTGATGT GTAAGCATTT AGTTTTACAC TGTAATCTTT AGAGAATAAC AATAAGA 37680

ATGTCTCAAT GTGTTTAGTA CAGATGCAAC TACTGTAAGC CTAATTGGGG TTTAACT 37740

GGTTGACCGA CTCTCAAGTG CTGAACTAGT GGGTGCAGAG CTGAACCACT CGCTCTT 37800

GTACAGATAG GCTACTCTGT GTATCAGAGA CAAAGGAGAA AAACTGTAAA AGGATAA 37860

GGAGAGAGCC AAGGATTAAG GGTGAGTTTG TACCATCGAG ATCTTGAAGC AGAAGAA 37920

AGTGAGATTC TGGGTCTCAG CTCTAAGGGT CATTGTAACT TATAAAGTTG TAGTCTC 37980

TATGCTAAAA TTCTGTGACA AGGGAAGAGT CTTGTTTGAG GGATCATGCC GTGATTT 38040

CTAACTAATG TTTATTTGTT AGTTTTGTGA TGCTGGGTAT CAAATCTGGG CCACCCT 38100

GCTAGACAGC CTATGTAAGC CACATCCTCA GAGACGATTA TGTAGTTTTA TGTTCCC 38160

TTGTGTGATT TTTGTGTTTC TTACTGCCGA GCCGTAACAA GGCAGTGTCC CAGTGAT 38220

GTTTATTATA TTTGTAGTCA TACCCAGTAG TTACTGCCAT CTTTTGTTTC AAAGTGA 38280

ACTTAGAGAA TAATCTCTAA TAAATCTTTG AATTCTCTTA AAGTTAATGA ATTGTTA 38340

TTTATGGTTT TTTTGGTGAA ATAAGTTGTA TTGCGCATTT AATAGTAGCA AAAGAAG 38400

AAACTAATAA ATATTTAATT GAGTTTCTTT TTCTCAAATG AACATGTAAA TGAGCAT 38460

TGAAATCAAA TAAATATATT TCATCTCAAT CCAATATACT AAGATATAGT TCTGAGT 38520

GTTGACTTTA TCTCTGAAGG ACAAGGGAAC TAAATGAAAC TGATTTTTTT ACAAATC 38580

GATCCATTAA GTATGGGCTT GGATAATAGC TCAGGTTAGT ATTTTTAGTT CAGGGTA 38640

GGAGGAGAAA ATTCATGTGA AGGGTGTTAT CCATTGAGAA CATATCTTTG AATAATG 38700

CATTTGTACA TTCAAATTTT CTAGAATAGA GATTGTATAC AGATATTTTG ATTAATC 38760

AGGCTGGATG TTACAAACAT TAGTGAGCAA AGTCCCTAAT GATGAAGTTC AGTATTA 38820

TTTAGTTCTT GTATATTAAA TCAGAATGTT ATATTGCAAT ATCTAAAATT CATTTCA 38880

AGGTTTTTTT TTATTATTAT TCTTGGAAAG ATGTGGAACA CTGCCTGGAA GATTTCA 38940

CCTAATGCAA TAGCACTGAT GTTTAAAGAT AAAAACAAAC ATACTGGTAC TGTTATT 39000

CAATTATAAA CAACTTCATT ATTGTGACCA AAAAAATTCA TTACAACTCA CCAAGGA 39060

CACTCAATTC TAATACTTTA CTCCTGTCCT CAAGGGCTTC GCAATACAGA GGGACAG 39120

TGGAGCTGAG CTGTCCTCTG AAAAGCCAGT AGGAGTAGAT GAAGGTTCAG ACTGGAG 39180

CGGGGATGGA GACTAGAGCG ATGGGGATGA AGGGTCATAC AGACTAATGA GCCTCTT 39240

GTTTTCCTTA CATAGATATT TTAACTTTCT CAGAGAACAT TTATTAAAAT AAAAGAT 39300

TTTCCAGTGA AAGGTCCAGG ATCCATGTGC TAGAAGGCTT ACTAGAAACT GTGATGA 39360

AGGTCTGTAA ATCAAAAGGA AACCTTGAAA GTTATCAGTG GAACTCTCTT GTCCAGG 39420

TGATTAGGAA GAATGCAGGC ATTTGGGGGA GCAAAATAAT AAAATTAACA GTATAAT 39480

AGATATTCTT GTGATTTTTC CATTGGCAGG AATCACCTTA TTGAGATTCA TGATGAA 39540

TTCCGGTTAT ATAAATTAAA GATGATGGTA AAGATGGAAA AATACCTTCA CTCCAGT 39600

TGTAGGCGAC GGTATGTATT ACCTGCTTTT TCCAATTGGA AGCATAGGTC TTTAGCT 39660

ACTTTTTTTG TTGTTTGTTT TTTTGAGACA GGGTTTCTCT GTGTAGCCCT GGCTGTC 39720

GAACTCACTC TGTAGACCAG GCTGGCCTCG AACTCAGAAA TCTGCCTACC TCTGCCT 39780

GAGTGCTGGG ATTAAAGGCG TGTGCCACCA CTGCCCGGCT AGATGGTACT TTTTTTT 39840

TAAAGTTAAT TAAAAGTGTT TTTAAAGAAT GTTTGCTGTA TACATGCTGA ACTTTAG 39900

AGGCTTATTT CTGTTTAAAT AAATTAATAT GAAATAATGC TGAGACAAGT AAATACA 39960

GTGGTACTAT CGTGTCATTT TGGGTGGTGG GTGTAGTATG TCTATATTTG TTCTTTA 40020

TAAGATTTTC CCTTCATCAG AATCATCTTG TCCCATTTTG AGGACAAATG TCTGCAG 40080

GCCTCCTTGG ACATTATGGG AACTGAAAAA TGCTGTGATA ATTGCAGGCC CAGGTAA 40140

TATCTTCCTG ACGAACCTTC TAGAAACTGT CGATTCTCTT TCTGTTCAAC TCCTGCT 40200

TTAAATTTTT GTTTAATATA AGTATTTTAG GTTTTGTTTT GTTTTGTTTT GTTTTGT 40260

TTTCGAGACA GGGTTTCTCT GTATAGCCCT GGCTGTCCTG GAACTCATTT TGTAGAC 40320

GCTGGCCTCG AACTCAGAAA TCCACCTGCC TCTGCCTCCC GAGTGCTGGG ATTAAAG 40380

TGCTATTTTA GTTTTTTTAA ATGACATAGT TACTTTATTT AAAATAAAAC AAAGTGA 40440

GGTTTACTTT TATACAATAA AGTCTTAAAA CGGTAGGCCT AGTTAGTCAA TAGTTGC 40500

TCAATATGAT TAGCCTAAAA ATACTCATTA AAGGCATAAT TTATCAAAAT TGATTTG 40560

GGCATTCTAC TTGATGTTTA CCATAAGGGC AAGTACAATT ATGTAGATAG TTTTAAA 40620

TGAAATAGAA AACACTGCAA AAACACTAGC CAAAAGAAAC CGTACGTTAC TGTTTTA 40680

TTTAGTGGTA TGGACTTTGG AGCAAAGCAT GCTATCAGGG ATGAATCAAG ACACCGA 40740

GTGTGAAGTA TCAGCGTTCT GCAGAGAAGT GGCACCAAGG AGAGAGCAAG AGGGGCA 40800

GAGGTGTGGG ATGGAAAGAA CAGGACAGAG GTGACAGGCA TCAGTGAGGT GGCAAAT 40860

AAAACTTGTA GCCAAGTTTT GGTCTGAACC CTGCGTCAGG CACACGCTAA TGTTAGT 40920

GAAACAAAGT TTATTGCCCA GCAAGCTTGT TTGTATTAAG GCTTTCAACC CAAAGAG 40980

AGTTATTGGG CATGATTTCC ATTGTTGAAG TCGTCTCATC ATAAGTAATA TTCACAT 41040

CAAAATACAT TTGCTGTGGC ATCTAAATTA TTTTCTGATC AAACAACAGC CCCACTT 41100

CATGCAAGCT ATACAGCCCA GAAGACATAA TCCCAAGTGG GCACATAAGA ACCTGCA 41160

AAGAACCTGC ACATAAGTAC CACAGAAGCA GAAGGCGGGG GGATCAGAAA CCCACGT 41220

TTAGGTGACG TCGGCGTCTG CTTACAAGGC AGTGGAATTA ATGGACAAGA ATGAGTA 41280

CTGCGGGGAG CGATGGGCGT GTCTGCAATG GCAAATTCAG AGGTTCAGAC GGGAGAT 41340

GAGACTGAGA CCAGCCTGTG ATGCAAGTGA TCTCAAAAAG AACCCAGGTC CCATAGT 41400

ACTGTGTCTC AAGATCCCGA GAACAAAAGC AAGCGTAAGA CTCAACAGCA AGCATGA 41460

ACCCCAAAGC CCCCAAACAG CCCCCTACCC CCACCCCACT GACTCTATGA GGAGATG 41520

GAATGAAGAG GGTGTCAGCA AACCAGTTCT AATTAATTTC TTGAAAGCAT TTCAGCC 41580

TGTTCCAATG GCGGCTTATA CACACATGTT TACATAAAGC TAACCTTGAC AAATGAG 41640

CTATTCGATT TGGATCAAGT ATGCTTTTTG CTTTAATGGC ATCAATCTAG AAAGCAG 41700

TGGGAAGAAA AGAGAAATCT CCAAACCCTT AGAAACCGTA CCTCCAAATA ATCTTAC 41760

CACTCAGAAA ATGATCTGAA CCGACGAAGA AGAATATGAA GTACCTGGGA TACAGCT 41820

ATGACTCTGC AAAGATAATT TATAGTGTTA ATACAACATG GAAGAGCACA GGCTTCA 41880

ACATAACTAG CATTCACTTT AAGAAACGGG CAGAGCCGGG CGTGGTGGCA CAAAACA 41940

AAACAAACAA ACAAACAAAA AACAAAAAAC AAAAACAAAA AAGAAATGGG CAAATAT 42000

GAAGATGAAC AGGAAGGGAG TTAAAAAGAG AAGTGCGTAG ATCAATGCCG TAGACGA 42060

AGCCAATAGA GGGGAGTCGG CGAGCTCACA GGCTTCATAT TTTCCAAGAC TGGTGGG 42120

AGGGGAGGAC AGTACCAATA TCAAAATGAA GGAATTTCAC TGCAGACCCC ATGAATG 42180

TGAACAAGCC AGGTTACTGG AAATGCAGTA AAACTGATCT AATAGACCAG TTTCTTA 42240

GGCTCTAATT GACAGTGCTC AGGCATGGTG AAACTTAGGA AGAATACTCC TCTAACT 42300

ATAAGGATTG AGTTCTTCCT TAAAAAACCT CTGAAAAGAG AACTCTCTAG CCCACCT 42360

TTTAGTGACA AATTCCAGCA CCAGAAGAGG ACATCAAACT CATTACAGAT GGTTGTG 42420

CACCATGTGG TTGCTGGGAT TTGAACTCAG GACCTTCAGA AGAGCTGTCA GTGCTGA 42480

ACTGAGCCAT CTCGCCAGCC CTCCAGCAAA CATTTAAATG AGGAGATATC CCTGCTT 42540

TAGTGTGGCT GCACATGCAC ACTCTCTGAA AGGCAGAGCT GTAGGGAAGA TCAGCCG 42600

GCAGAGGTTA AAGGCAGGCA GAATAGATCT GAGAGCAGGG CATTCAGTGG GTCTTGA 42660

TGACGAAGGT TCGATGGGTC TGCTTATAGG GATATGTACG CTTTATTATA CTGTAAA 42720

AATAAGTATA AGTGGTGCCT CTTTGAGTTA ATCGTGTCTC TAGGTACAGT AGCTGTA 42780

CAGAAGCAGC GCTGTTAGAG ATAGAAATCT AAAGATGTTT GGAAATTAGT GATAACC 42840

ATAACATATA TTTAAGGTGG TAAGATAATA TGTATAGGTC ATACTTCATG GGAACTT 42900

AACTTTAAAT TCTCTGAAGA AAGTCACCTG AGCATCCTAC TAAAGAGGTA AATGGGA 42960

›Example 10 · 48 of 49

TAAACCTAAG GCAGGGGATT TCTTCTTTAA ATCAAAACAT AATGGCTTTA ACTGGAA 43020

TGACTGCATT CTTATTGCTA CTTTAAAGAT ATATGTGATG TGGAAAGTAG TTGAATT 43080

TAATTGAATA TATTAGTTGA TAGTCTCTAA GGACTTCTTT TGTTCTCAAG CTAAAAA 43140

AATCCTCATT TACACCAATG ATAATTTTAC ATCTACTTGG AGGATGACTA AGGAATT 43200

CTGCTGAATG TACCAGCAGG ACAAGCTTAT AGGCTCGGTG CTCTGTTGTA AAATTAT 43260

GGTTCAAGCT AACATGTTAC TGCATAGCAG CTTTTTACTT AAAACCAATT TTACCCT 43320

TGGTGTAACG TAGCACAAGC TTCCGTATTT ATATAACTGA TCGTGTGGAG CTGCCCT 43380

CGGGATGCTT TCCTTGAGCC TGGCATCTTC CCAGCGCCTC CATAACATTT AGCTTCT 43440

TGCCACAAGA AAGCGCTGTC TGTAGTGCCG TATTTGTTAT TTGTGTCTCA TACGCAT 43500

TCACACACAT GCCCTTGATT GTAATAAGCT TTATGTGTAG AGTTGGAAGT GTCAGAC 43560

TTTGAGAATT TTTTTTTTTA CGTGGTCTAT GTTTGTATCT TTCTATTTCT AAGGGAG 43620

GCTTTTGTCA GTGTTTTCTT AGGCTGTTCT TACTTTCCTT CAGGCTGAAT CATTGCC 43680

CTGCTAACAA CTCAGAGGAC GCATCCCAAG ACTTTGGGCC ACAAGCATTC CAGCTAC 43740

CTGCTGTGGA CATCCTGCAG GAGAAATTTG GAATTGGGAT TCCGATCTTA TTTCTCC 43800

GATCTGTGAG TGTATCTGTG ATAGCTCCTG GGACTGTTTC TGACAGTGCT TTCCACT 43860

TGGCTATGGC TTTGGCTTTC TTTAGATGGC TAACTAGCAA CCCGTGTTAG CAACACC 43920

AGTTCCATCC TAACCCTGCA TTCATTGTCT TGGACAAATC TTGTCTCACG TCAGACG 43980

TTTTGCTATG TTGGATGCTG GCGGTCAGCT GTGTGCTGCA GTCTGAAAAT AGCCTAT 44040

TTTACCACAC TGCAATTGCA TTAATCCCTA GACTGGTTTT TCTTAGGATA ATTAGGG 44100

GTTAACTCCC AGTGTGTCAA GGGACTGGTA GAACAAAGTT GCAGCTTCTG GTGCCCA 44160

ACGATTATGT TCTTTGCGCA AAACTTGAAT TTCAGGGATT ATGTTGTCAG AGGCTGG 44220

CAGCAACAGT GTACAGCAAC ATAGTCTCCC TCCGATGGTG TTTTATGTCA GAAGTAC 44280

ACATGCTAAG AAAGGGCTTT TGCTTGTTTT AGTGGTTTAC CAGTGAATAC CTGATTT 44340

TGGACTCCTT TCTGTTTTGA GTGATTCATG TGGCCTCATT ATGCTGCCAA ATGTCAC 44400

CAAAGTGACA ATAATAAGGT ACAAATACAC ATACAGAGCT GGTTTTCTGT AGTCCTT 44460

CTTTTATGAT AATTTTATTT CTGAATTAAG AGTCTGTAAA TTTAAGAATT GTATATT 44520

ATCACTTAAA TAAACCAAGA GTAGAAGAAG GCAGAGTACT TTGTAGATGG ATCTATC 44580

TTATTTAAAA CATGCTTTAG AGTAGAGGCT AAATGTTCAT TTTGTATATA GAATTTT 44640

ATAATTTAGG TAAGCTTTTG CTGCTTAAAT ACTCAAGAGC TTCATGTAAA TGCATTT 44700

TGTGCTTGCT TGTGCTTAGA AAGTAATCTA TGGAGTTAGT TATGAAATAT TTTTAAT 44760

ACACATTGAA AACTTGTACT ATCCTTTCAA GTGTCAGTGC TTTCAAGATA ATAGAGT 44820

AATTTTTGGT TTTAAATGGC AAAAAAGCAT ATAAATGTAA CAATAGAAGT GTTACTT 44880

CAGTTTTTAT TTCTATCAGC TCTGCAAGAA ATCTCAAATG CCACTGAAAT CCGTACA 44940

GTTTTCTATC TTTGTCACCT TTAAAATCCC TGTAGCCAGT GTGAGTATTT AATTTAT 45000

AAGTGTCCTT GTTTTGGTTT GGTGCGATCT AGCTGTATCC AATATCAATA AATAAGT 45060

TTTCTCGTCA AACTTTCAGT GGTCACAGGA GGGATCAGGT TTCACTTATT ATTTGAA 45120

CAAGTCAGAC GTCCTCTACC GGCAGTGTCT TCTGGGAGTC CTCAAATTAA GCAGTTC 45180

CTTAGTGAAA CTTTATACTA CCCTTGCTAG CGCAACGTGT AAAGCTTTTA AAAAGTA 45240

CTTAATGAAA ATGTGTAGAT GCTAACAATA GTGAAAATAA GACAGGCTTC CTTTCTC 45300

TTTCAGTGAC TTTGATATCT ATTGGGATAT CGGTGAAAAA GTATGACTGT AATTCTC 45360

AGAACTGAGC AAGTTGTTCC CCTTAACCAA TTTAGGACAA GCTAATACCT TTGTAAT 45420

AATTTGTAAG ATGATATATC AAACTGTCTT GGAGTTATTT TGAAGAGATA ATTTTTA 45480

GCATAAATTC GGTTTTGGTA GTGCTTGATT CTCTCCTACA TGTTTTTTTA ATATTAT 45540

CACTTAATTT ATCCATAAAT TTGTTAAATT TAGTTTAAAA ATTTGTTTTA ATGTGTC 45600

TTAGAAAGTA ACCAAGATTG TCTAGAGAAC TTTGTTTTAA CTGACTAAAC AGTTCAC 45660

GTTCAGCAAT CTTTGACATT GCTCAAACGT GTCATAACAT AATCAATAGC CATAATT 45720

GGGAAAAAAA CCACATTGAT CATTTGCATA CCAAGATTAG CATCTTCCCA AATGCCT 45780

CCAAGTGCTA ATCTTTATCA TGGCCTCAGG AGTAGGTACC ACTTAATATT TTAGGAT 45840

TGTATATGCA CGTGTTCAGG TGCTCTCACA TCTGTGTGTG CATATGAACA CCAGAGG 45900

ACATTGGATG TCTCCCTCTG GTACCCTCCA TTTCATTCGT ACTCTTTTGA CCCAGTT 45960

CACCGAACCA GGAGCTCAGT GTCTTGGTTA GACTGGCTTG CCATTAGTCC CTGACAT 46020

CCTGCCTCCG TTTCCTGCCA GCCAGCTGAC ACTGTAGTAA CAGCACCCAG CTTGTCT 46080

TAAATTATAG TTTACTGGCG TTTCAAGAAC ATCATAACGG ATGCAGTGTA TTTTGGT 46140

AATCAACCTC AGTATTCTCC CAGCTCTTCC CAGACTGATC CCACTGCCTC TTCACCA 46200

CCAACTTTAT GACCTCCCCC GCCCAACTTC CCCAGCCATG GGTATGGGCA TCTGTTA 46260

TGTGGTCAAC CTATCAGGAG CTATGCCCGT AAAGAATGAC GATCTCCCTG AAGAGCC 46320

AGCTGTGAAT AGTTGTTCCC CAGGAGCTCC TGAACCCTTT TCTCCATCCC TTGATGA 46380

TTTTGCTAAC TTGGTTCTGT GCAGGCAGCC ACAGATGCTG TGGGTTAACG GGTGCAG 46440

TCTGTCATGC CCAAAAGACA CTGTTTGGTT CTGGTTCTAC ATGACCTCTG GCTCTAA 46500

TCTCCTTTTG GGACGAACCC TGAGCCTTGA GGGAAAGGAG TGTGACCCAG ATCTCCC 46560

TGTAGATGAA CACTCTATAT AGACAATATC CTCTGTGCTG TGCTTTGACC AGATGTG 46620

TTCTGCGTTA ACCGCCATCC ACTGCACAAA GAACCTTCTC TGATGAGGCT TGAGAGT 46680

ACCAATCTAT GGCTATAGGA ACAGGAACTT AGAGACAAGT ATAATTCTAT GTCAGTT 46740

CAAAATAATA GTAAGAAATA TACTGCTGGG GCCGTGAGCT CCTTGACCAA ATGTTCT 46800

CAGATTTACA GCATCCTGTA TGGAATGGGT GTGGGAACGG TAGGGAGAGG ATGGTAC 46860

TTAAATCCTG TCAGAAAGTG CTATGATATT GAGGCCACTT TTGCACCCAT GGGCATA 46920

GCCATGCTGG TTGTCATTTT AGTGTACAGG GTTAATAACT GGAGGAGAAA TTGACTT 46980

CTTCCCCAGT AGCCTGCATA GCACCTTCTG GTATTGTGAA AGCTAGCCAG CAGAAAG 47040

ACTTCTGGGC CAGGACCAGC GTGATTTCTC CATGTTCTAT GGCCAAAGCA GGTGGTG 47100

TCAGCAATAC AGCCTTACCA CTAAGTTCTG ATGAGAAACC AAGAACAGTA GCGGTGA 47160

GTATTATTTG AGGTGGGGCA TCTGTAGGAA AAACTGAGCA ACAGTTTGAG AGGAGGT 47220

TCACACTGGA CTATTTGTTT GGTGACCTGT GGCTTCCTTG AGTAACATTA GCTTTTA 47280

AGCCTGATTC CAATTAAACT CTTATATAAG TGTGTGTGAG TTTAGGAAGC TTATAAA 47340

TAAGTTTCCA TATGGGTTTT AATTTTTTTT TAATTTTATT TTGTGATTTT ACTAATT 47400

TTTACATCCC GCTCACTGCC CTACTCCTGG TCACTCCCTC CCACAATCCT TTCCTTA 47460

CTCCTCCCCC CTTCTCCTCT GAGAAGTTGG GCCCCCCTGG GTATCCCTCC ACCCTGG 47520

TTCAAGTCTA TGCGAGGATA GGGTCTTCCT CTCCAATTGA GGCCAGACAA GGTAGCC 47580

CTAGTAGAAC ATATCCCACG TACGGGCAAC AGCTTTGGGA TAGCCCCCAC TCCAGTT 47640

TGGGACCCAC ATGAAGACCA AGCTGGACAC CTGCTACATA TGTGTAAGGA AACCTAG 47700

CATATGTTCT TTGGTTCGTG GTACAGTTTC TGAGAGCTCC AAGGGTCAGG TTAGTTG 47760

CTGTTGGTTT TCCTGTGGAG TTCTATCCCT TTCTGGGCTG CAATCCGTCT TCCTAGT 47820

CCAAGAGTCC CCAAGCTCCA TTCACTGTTT GGCTGTGGGT GTCTGCATCT GTCTAAG 47880

GCTGCTGTGT GGAGCCTCTC AAAAGACAAC ATGCTCCTGT CTGCAAGCAT AACAGAA 47940

CATTAATAGT GTCAAGGATT GGTGCTTGCC CATGGGATGG GTCTCAAGTT GGACCGG 48000

TTGGTTGGCC ATTCCCTCAG TCTCTGCTCC CTCCCCTGTG CCTATATTAC TTGTAGA 48060

GATAAATTTT GGGTTGATAA TTTTGTGGGT GGGTCAGTGT CTTTATTGCT CTACTTG 48120

TGCTGCCTGG CTACAGGAGG TGGCCTCTTC AAGTTCCATA TCCCCAGTGT AGTAAGT 48180

AGCTAAGGTC ACACCTATTA ATCCTTGGAT GCCTCCCTTA TCCCAGGTTT CTGTCTC 48240

CTGTAAATGC CACCCACTTC CCCACTTTTC CTCTGCAGAT TTCCATTCAT TCTCATT 48300

›Example 10 · 49 of 49

TCTAGCTCTC TCCCTGCCCT TCCCTACACC CAATCCTGAA CTCCCATCTC CCTCCGC 48360

CCCCGTCCTA GTTCCCTCTT TCCATGTGCC TCTTATAACT ATTTTATTCC CACTTCT 48420

TGAGATTCAA GCATCCTTCT GCCTTCCTTC TTGTTTAGCT TCTTTGGGTC TATGGAG 48480

ACCATGGTAC TTGTATGTTT TGGCTAATGT CCGCTTATAA GTAAGTACAT ATCATGC 48540

TCCTTTTGGG GTTGGGTCAC CTCACTCAGG ATGATATTCT CAAGTTCCAG CCATTGG 48600

GCAAAATTCA TGATGTCTTT CTTTTTAATA GCGGAATGGT ATTCCATTCT GTAGATG 48660

CACATTTTAT CCATTCTTCA GTTGAGGGAC AGCTAGGTTG TTTCCAGCTT CTGGCTA 48720

TGAATAAAGC TTTAGGAACA TAGTTGGGTA TGTGTCTTTA TGGGATGTTG GAGCATC 48780

TGGGTATGTG CCCAGGAATG GTATAGCTGG GTCTTGAGGT AGGACTATTC CCAGTTT 48840

GAGAAACTGC CAAAGTTTCA AGTGGTTGTA TAAGTTCCCC TCACTCCACA CCCTTGC 48900

CCTGTGTTAT CTTTTGAGTT TTTGATCTTA GCTATTCTGA TGGGTATAAG ATGGAAC 48960

AATGTTGTTT TGATTTGCAT TTCCCTCATG ACTAAGGACT TTGAACATTT CTCTAAG 49020

CTTTCAGCCA TTTGAGAGTC CTCTTTTGAG AATTCTCTGT TTAGCTCTGT TTCCCAT 49080

TAAATTGGGT TATTTGGGTC ATTGTTGTCC AACTTCTTGA ATTCTTCGTA AATTTTA 49140

ATTTGCCTTC TGTCCGATGT AGGATTGGTG AAGATTCTTT TCCAATCTGA AGATTGC 49200

CTTGTCCTAT TGACAGTGTC CTTTGCCTTA CAGAAGCTTT GCAATTTCTT GGGGTCC 49260

TTATCAGTTG TTGATCTTAG AGCCTGAGCC ATTGGTGTTC TGTTCAGGAA CTTGTCT 49320

GTACCAATGC ATTCAAGGTA TTTCCCTCTT TCTCTTCTAT GATATTTAGT GTATATA 49380

TTAAGTCGAG GTCTTTCATC CACTTGGACT TGACTCTTTT AATAAATGTG TGTGTGT 49440

TATGTGTGTG TTTAGGAAGC TTATAAATAG TAAATTTCCA TGTGTTTTTT TTAAACT 49500

TTTTTTACCT CTCTCTCTCT CCCTACCTCT CCACTCTGCC CTCGCATCCC ACTCTAC 49560

TTAAACCTCT TCCCCCTTTA TATCACATAT TGTTCCAGTA TCCCCGTCAT AATGTTT 49620

TCTTTCACCT ACCTCTACCA ATAAATGGTC CCTTTCTAGT TTCTTGGATT CTTCAGG 49680

TCCAAGTTAA ACACACTATG TGAAACATTC AATGGTAGGA TCACATGTGC GAACATG 49740

TGATGTTTGT CCTTCTGGGT CTGGGTTCCC TGAATCACTA TTGTTCCCCA GCTCCAT 49800

TTTCCCTGCA AATTGTTATG ATTGTAGTTT TCTTTATAGC CAAATAAAAC GGCATTG 49860

ATAGGTGGTC CCACACTTTC GTGATCTATT TTGTAATTTA ATGGCTGTTT TCATGTC 49920

GCAGTCATGA ACATAGCAGC TAGACCATGG CTGAGCATGC ATCTCTCTGG TAGGAAA 49980

AGGCCTTTGG TTATATACCC AGGGGTGATT TATGTGGGCC ATCGGATTCA TCATTTT 50040

TGTTTGAGGA TTCTCTTTAC TGATTTCGAA GGAGCTGCAC CAGCTTTCTG TCTCACC 50100

GGTGCACAGG GGTTCCCCAG ATCATCACCT GCATTTCTTG TCTTTTATGT TTTTTAA 50160

TATCCTCGAA GTAGTTTCAA CTTGAGTTAA GGATGGTAAA CTCTCCTGAA AGCATTT 50220

TTCCTAGGCA CCTGCATTTC TTCTTCTGCA ACTTCTGTTT CATTCTATAA CTCACTT 50280

GTTTTTAGTT TTTTCAACTC TTTTTTGTAT TCTGTAGACT AACCCTCTGT CAGATGT 50340

GCTGGAATTA TACTCTAGGC TGCTCCTTTG GTCATGTAAT GGTTTCTTTC TTAGTAG 50400

CTTTTCATTT ATAAAATTCT ATTTGTTGAT TAGTGGTCAT ATTTTGTAGA TGACAGG 50460

CCTTTTCAGA GTCCTTACCT GAGCTGGTAT ACTGAGGCAT ACTTCACATT CTTCTGG 50520

TTTCAGATCT AGCATTGAAA CCTTTGATTT CATTTGGAAT TTATTTGCCA TATCTTA 50580

GTCCTGGGGA TCCAATCTCA GGTGCTTATA TTTAGACATA GAGCCCTTTG TCTCATG 50640

TATCTCCCCA ACCCAGATAA TGCTTTTAAG AAAAGATTGG ACCTATTCAG CTGTTAG 50700

TGTTGATAGA TTTGTGTGTG TATGTGTGTG TGTGTGTGTG TGTGTGTGTG TGTACAT 50760

TGTACCTATA TGCACACATC TGTATGTATC TATTTTAAAG ACAAGATCAT GCCTAGG 50820

ACTCTCACTC AACTGGAAAT TCTCCTGTCT AAGCCTCCTG ATTACAGCAG TAGGATT 50880

GGCATGTACT ACTATAGTCA ACGGCAATTG CTGTAGTTCT AATCACTCTC CAAAGTT 50940

AGAACATGTA GCTGGGGTGG GCTATTTCGT TTAATTTTCT AGACAAATAT TGAGTCT 51000

AGAAATATAT TACTATGGGT TAGGTCTGCT TTTCAGGACT AAAGAACTTG GCTAAAT 51060

CAAGGCACTT GGTTCATGAA GAATTACCTA TTGAACCCCT GAAATGGCAG CTGGGAC 51120

CTCTGGACTA TAGGAGCTGG AAAGGGGCAG GGCTGGTGGG AGGAGAAGGT GGAGAGG 51180

GCTAGGAACT TAAATGTCTT TGAGCTATTG AGCATCTGTT TTTATGTAAG GCATGAC 51240

GATTTTGTAG AGGATACAC 51259

›Tables in the description — 13
A5′-CTGGCAAGGATCAAACAGAGAG
B5′-CTTTATGAAGCCAATTTCTACCC
C5′-TGGCAAATTGGTAGAAGCTAGG
D5′-AAATAACTATGCTTTCTTACATTTAC
E5′-CTCCCGTCAACTCAGATATGAG
F5′-CTGTTTGTAAATGTAAGAAAGCATAG
G5′-GAGCTATGATGACACCACTGC
H5′-ACTGAGCAACAGAGTGAGACC
I5′-GGATCTGGTCTCACTCTGTTGC
J5′-TTGCCTAGTGCAATTGGTCTCC
K5′-AGTGCAGTGGTGTCATCATAGC
L5′-CCTATTTAATGGCACCCAAAATGC
M5′-CAGTCTATGGCCATCACATACTC
N5′-ACCGCTTGGGATAAGTGCATGC
O5′-GAGAAGAAGTCTAACTTGGAGAAG
P5′-TTCTGGTGACTGTACCATGATAC
Q5′-CCAAAGGAAGTGATACCAGCAAG
R5′-ACAGCAAGAAACATAATTGTTCTGG
5EA5′-GAACTTTGAAGTCCATCACGACC
5EB5′-GCATTAATAAAGCTGACATTCGCC
5EC5′-CATTACGGTGCTCCTAAGGACATG
5ED5′-GATGGATTTGAAGATGGAGTAGAAG
5EE5′-TGAAAGAGAATATGGAAAGAGCTTG
5EF5′-GTAGAACCAACTCATTCTAAATGCT
5EG5′-AATTTGCGTGTCATCCTTGCGCA
E1A5′-TCCTAGTCACCCATCTGAAGTC
E1B5′-CATGAAACTTGCTTCTAGGACAC
E2A5′-CCCAGGAGTTCGAGACCATCC
E2B5′-TTACAATCGGCCACATTCATCAC
E2C5′-TGTAATCCCAACACTTTGGGAGG
E2D5′-AGTGGAAGAATTCATAGTGGATGG
E3A5′-TAGCTTTATGAAGCCAATTTCTACC
E3B5′-AATCCAAAGAATCAATAGACAAGTC
E3C5′-GCTTGAAGGATGAGGCTCTGAG
E3D5′-TGTTCAGAATGAGCACGATGGG
E4A5′-CTTGTGAGAGGCCTATAAACTGG
E4B5′-GGTAAACAGTGTAGGAGTCTGC
E5A5′-GCCATTTTCTCTTTAATTGGAAAGG
E5B5′-ATCTTATTCATCTTTCTGAGAATGG
E6A5′-TGAAATAGCCCAACATCTGACAG
E6B5′-GATTAATTTGACAGCTTGATTAGGC
E7A5′-TGAAATATAAACTCAGACTCTTAGC
E7B5′-GTACTGATTTGGAAAGACATTCTC
E8A5′-GATGTGACAGTGGAAGCTATGG
E8B5′-GGAAAAATGTGGTATCTGAAGCTC
E9A5′-AAGTGAGCAAATGTTGCTTCTGG
E9B5′-TCATTAGGAAGCTGAACATCAGC
E10A5′-GTTGGAGGAAATTGATCCCAAGTC
E10B5′-TGTTGCTTATGGGTTTAACTTGTG
E11A5′-TAAAGGATTAATGCTGTTAACAGTG
E11B5′-TCACACTGAGCATTTACTACCTG
E12A5′-GTAATCATATCAGAATTCATAACAG
E12B5′-CTTTGGCAACCTTCCACCTTCC
E12C5′-GCAAAGGAAATGTAGCACATAGAG
E12D5′-AGGCTATAGGCATTTGAAAGAGG
E13A5′-GTAGGCTCCCAGAAGACCCAG
E13B5′-GAAAGGATGGGTGTGTATTCAGG
gln
wild type:GAAGCTAGG CAG AAACAT(SEQ ID No. 60)
Werners:GAAGCTAGG T AG AAACAT(SEQ ID No. 61)
ter
arg
wild type:TTGGAG CGA GCA(SEQ ID No. 62)
Werners:TTGGAG T GA GCA(SEQ ID No. 63)
ter
phe
wild type:AAGAAG TTT CTTCTG(SEQ ID No. 64)
Werners:AAGAAG TT G CTTCTG(SEQ ID No. 65)
leu
cys
wild type:CCTTCA TGT GAT(SEQ ID No. 66)
Werners:CCTTCA C GT GAT(SEQ ID No. 67)
arg
TABLE 1 — PCR and sequence primers Primers
Frag-Nested on cDNA
ment1st PCR2nd PCRCoordinatesSequence primers
I5EC, J5EN, L2947-50655EN, L, M, N, O, P, Q, R
II5ED, P5EE, B1379-33915EE, 5EJ, 5EK, 5EL, 5EM,
5EB, 5EA, 5EN, B
III5ES, 5EK5ET, 5EH75-15165ET, 5EX, 5E1, 5EP, 5EO,
5ED, 5EH
TABLE 2 — Primer sequences
B5′-CTTTATGAAGCCAATTTCTACCC(SEQ ID No. 2)
J5′-TTGCCTAGTGCAATTGGTCTCC(SEQ ID No. 10)
L5′-CCTATTTAATGGCACCCAAAATGC(SEQ ID No. 12)
M5′-CAGTCTATGGCCATCACATACTC(SEQ ID No. 13)
N5′-ACCGCTTGGGATAAGTGCATGC(SEQ ID No. 14)
O5′-GAGAAGAAGTCTAACTTGGAGAAG(SEQ ID No. 15)
P5′-TTCTGGTGACTGTACCATGATAC(SEQ ID No. 16)
Q5′-CCAAAGGAAGTGATACCAGCAAG(SEQ ID No. 17)
R5′-ACAGCAAGAAACATAATTGTTCTGG(SEQ ID No. 18)
5EA5′-GAACTTTGAAGTCCATCACGACC(SEQ ID No. 19)
5EB5′-GCATTAATAAAGCTGACATTCGCC(SEQ ID No. 20)
5EC5′-CATTACGGTGCTCCTAAGGACATG(SEQ ID No. 21)
5ED5′-GATGGATTTGAAGATGGAGTAGAAG(SEQ ID No. 22)
5EE5′-TGAAAGAGAATATGGAAAGAGCTTG(SEQ ID No. 23)
5EH5′-CATTGGGAGATAAATGCTCAGTAGA(SEQ ID No. 80)
5EJ5′-AGATGTACTTTGGCCATTCCAG(SEQ ID No. 81)
5EK5′-GCCATGACAGCAACATTATCTC(SEQ ID No. 82)
5EL5′-CTTACTGCTACTGCAAGTTCTTC(SEQ ID No. 83)
5EM5′-TCGATCAAAACCAGTACAGGTG(SEQ ID No. 84)
5EN5′-GCAGATGTAGGAGACAAATCATC(SEQ ID No. 85)
5EO5′-TCATCCAAAATCTCTAAATTTCGG(SEQ ID No. 86)
5EP5′-CTGAGGACCAGAAACTGTATGC(SEQ ID No. 87)
5ES5′-GCTGATTTGGTGTCTAGCCTGG(SEQ ID No. 88)
5ET5′-TGCCTGGGTTGCAGGCCTGC(SEQ ID No. 89)
5EX5′-TTGGAAACAACTGCACAGCAGC(SEQ ID No. 90)
5E15′-GATCCAGTGAATTCTAAGAAGGG(SEQ ID No. 91)
TABLE 3 — Primer sequence and PCR conditions for WRN analysis
ProductMg +2
RegionPrimer SequenceSize (bp)(mM)pH
N-domain5E6 5′-GATATTGTTTTGTATTTACCCATGAAGAC (SEQ ID No. 164)1061.58.3
5EY 5′-TCCGCTGCTGTGCAGTTGTTTCC (SEQ ID No. 165)
center5ED 5′-GATGGATTTGAAGATGGAGTAGAAG (SEQ ID No. 22)1582.08.3
domain5E12 5′-TCAGTAGATTTATAAGCAATATCAC (SEQ ID No. 166)
C-domainCD-A 5′-CTGGCAAGGATCAAACAGAGAG (SEQ ID No. 167)1442.08.3
CD-B 5′-CTTTATGAAGCCAATTTCTACCC (SEQ ID No. 168)
TABLE 4 — Intron-Exon Structure of the WRN Gene Exon Note. Exons are in uppercase and intron sequences are in lowercase letters.
cDNASize
ExonLocation(bp)Intron-Exon Boundary SequencesExon Features
11-155>155....TTCTCGGGgtaaagtgtc5′UTR
(SEQ ID No. 169)
2156-327172tacctctcagTTTTCTTT....AAAGAAAGgtatgttgtt5′UTR, ATG codon
(SEQ ID No. 170)
3328-440113taaactcaagGCATGTGT....GATATTAGgtaagtgatt
(SEQ ID No. 171)
4441-586146ctcactttagCATGAGTC....CATGTCAGgttggtatct
(SEQ ID No. 172)
5587-735149aatgttacagTTTTTCCC....ATAAAAAGgtaaaagcaa
(SEQ ID No. 173)
6736-885150tcatttctagCTGAAATG....ATGCTTATgtacgtgctt
(SEQ ID No. 174)
7886-95570ttttttatagGCTGGTTT....AAATAAAGgtatgttaag
(SEQ ID No. 175)
8956-1070115ttccccctagAGGAAGAA....CCACGGAGgttaaatatt
(SEQ ID No. 176)
91071-430ttttttttagGGTTTCTA....CTACTGAGgtactaaaat
1500(SEQ ID No. 177)
101501-81ttttttaaagCATTTATC....TGCTTAAGggtatgtttaduplicated exon
1581(SEQ ID No. 178)
111582-81ttttttaaagCATTTATC....TGCTTAAGggtatgtttaduplicated exon
1662(SEQ ID No. 179)
121663-145aaactttcagTCTTTAGA....TGATAAGGgtaagcactg
1807(SEQ ID No. 180)
131808-76ttatttccagACTTTTTG....TTTAAACCgtgagtataa
1883(SEQ ID No. 181)
141884-68caccttcaagAGTTCAGT....GGCAACTGgtaagttgtahelicase motif I
1951(SEQ ID No. 182)(5′ end)
151952-109tcatttcaagGATATGGA....CAGCTTAAgtaagtcatghelicase motif I
2060(SEQ ID No. 183)(3′ end) and Ia
162061-69cttcttatagAATGTCCA....ATTAAATTgtgagtaatt
2129(SEQ ID No. 184)
172130-83gtttttacagAGGTAAAT....TGATATTGgtaagtgata
2212(SEQ ID No. 185)
182213-107ttttttacagGTATCACG....TGCCAATGgtaagctttghelicase motif
2319(SEQ ID No. 186)II
192320-185catcattcagGTTCCAAT....AAAACAAGgtaaggattthelicase motif
2504(SEQ ID No. 187)III
202505-175ttttctttagTTCCCACT....AAATTCAGgtatgaggathelicase motif
2679(SEQ ID No. 188)IV
212680-182ttgttctcagTGTGTCAT....TTAAATAGgtaaaaaaaahelicase motifs
2861(SEQ ID No. 189)V and VI
222862-102taatcgacagGCACCTTC....AGGAGACAgtatgtatta
2963(SEQ ID No. 190)
232964-93tcttgggtagAATCATCT....AGGTCCAGgtaaagattt
3056(SEQ ID No. 191)
243057-142ttttatttagATTGGATC....GAGGATCTgtaagtatat
3198(SEQ ID No. 192)
253199-171ctaatttcagAATTCTCA....CGAAAAAGgtaaacagtg
3369(SEQ ID No. 193)
263370-95cttttaatagGGTAGAAA....CTGCCTAGgttcattttt
3464(SEQ ID No. 194)
273465-76tattttttagTTCGAAAA....AGAAGAAGgtttgtttta
3540(SEQ ID No. 195)
283541-74ttaaatgcagTCTAACTT....AAAAAAAGgtacagagtt
3614(SEQ ID No. 196)
293615-76aatattttagTATCATGG....AGACTCAGgtaaggcttt
3690(SEQ ID No. 197)
303691-113ttttgttcagATTGTGTT....AAAATGAGgtaaactatc
3803(SEQ ID No. 198)
313804-115ttaaacacagACCAACTA....GTGTTCAGgtaaaatact
3918(SEQ ID No. 199)
323919-132aattctgtagACAGACCT....TGCCTTTGgtaagtgtga
4050(SEQ ID No. 200)
334051-163ctttctctagAAGAGCAT....CAACTCAGgtgagaggca
4213(SEQ ID No. 201)
344214-209tcgtttacagATATGAGT....ATACTGAGgtattaatta
4422(SEQ ID No. 202)
354423-768tttcctacagACTTCATC....TAA codon.3′ UTR
5190(SEQ ID No. 203)
TABLE 5
PCRProductMg +2
FragmentPrimer SequenceSize (bp)(mM)pH
exon 1A 5′-AGGGCCTCCACGCATGACGC5831.58.3
(SEQ ID No. 92)
B 5′-AGTCTGTTTTTCCAGAATCTCCC
(SEQ ID No. 93)
exon 2A 5′-CCTATGCTTGGACCTAGGTGTC3391.58.3
(SEQ ID No. 94)
B 5′-GAAGTTTACAAGTAACAACTGACTC
(SEQ ID No. 95)
exon 3A 5′-ACTATAAATTGAATGCTTCAGTGAAC3161.58.3
(SEQ ID No. 96)
B 5′-GAACACACCTCACCTGTAAAACTC
(SEQ ID No. 97)
exon 4E 5′-GGTAAACCACCATACCTGGCC6911.58.3
(SEQ ID No. 98)
F 5′-GTACATATCCTGGTCATTTAGCC
(SEQ ID No. 99)
exon 5B 5′-ATTCAGATAGAAAGTACATTCTGTG3691.58.3
(SEQ ID No. 100)
E 5′-GTTAAGAAATACTCAAGGTCAATGTG
(SEQ ID No. 101)
exon 6A 5′-GGTTGTATTTTGGTATAACATTTCC3741.58.3
(SEQ ID No. 102)
B 5′-ATATTTTGGTAGAGTTTCTGCCAC
(SEQ ID No. 103)
exon 7A 5′-CTCTTCGATTTTTCTGAAGATGGG2911.58.3
(SEQ ID No. 104)
B 5′-CCCTAATAGTCAGGAGTGTTCAG
(SEQ ID No. 105)
exon 8A 5′-GGAAAGAAAATGAAAATTTGATCCC3164.08.3
(SEQ ID No. 106)
B 5′-CAGCCTTAATGAATAGTATTCTTCAC
(SEQ ID No. 107)
exon 9C 5′-ATTGATCTTTTAAGTGAAGGTCAGC6681.58.3
(SEQ ID No. 108)
D 5′-CTGCAACAGAGACTGTATGTCCC
(SEQ ID No. 109)
exon 12A 5′-GCTTTCGACAAAATTGTAGGCCC3371.59.0
(SEQ ID No. 110)
B 5′-CCAAACCATCCAAAACTGGATCC
(SEQ ID No. 111)
exon 13A 5′-TAACCCATGGTAGCTGTCACTG2851.58.3
(SEQ ID No. 112)
B 5′-CTGTTGCTGTTAAGCAGACAGG
(SEQ ID No. 113)
exon 14C 5′-TTGAATGGGACATTGGTCAAATGG3481.58.3
(SEQ ID No. 114)
F 5′-GTAGTTGCATTTGTATTTTGAGAGT
(SEQ ID No. 115)
exon 15C 5′-GTAAAAAGAAATGAAAGCATCAAAGG2464.08.3
(SEQ ID No. 116)
D 5′-TCACCCACAGAAGAAAAAAAGAGG
(SEQ ID No. 117)
exon 16A 5′-CAAAAAAGAAAATTGCAAAGAACAGG2824.08.3
(SEQ ID No. 118)
B 5′-CAGCAACATGTAATTCACCCACG
(SEQ ID No. 119)
exon 175′-GAAGAGACTGGAATTGGGTTTGG5321.58.3
(SEQ ID No. 120)
5′-ATAGAGTATCATGGGATAAGATAGG
(SEQ ID No. 121)
exon 18A 5′-TTCTCCTTTGGAGATGTAGATGAG2734.010
(SEQ ID No. 122)
B 5′-TCTTCAGCTTCTTTACCACTCCCCA
(SEQ ID No. 123)
exon 19A 5′-CATGGTGTTTGACAACAGGATGG3964.09.0
(SEQ ID No. 124)
B 5′-GTTAAATATGCATTAGAAGGAAATCG
(SEQ ID No. 125)
exon 20A 5′-ATAAAACCAAACGGGTCTGAAGC3424.08.3
(SEQ ID No. 126)
B 5′-AAAAGAAGTATTCAATAAAGATCTGG
(SEQ ID No. 127)
exon 21A 5′-AATTCCACTTTGTGCCAGGGACT3971.59.0
(SEQ ID No. 128)
B 5′-ACTTGGGATACTGGAAATAGCCT
(SEQ ID No. 129)
exon 22A 5′-TTTTTATCTTGATGGGGTGTGGG3561.59.0
(SEQ ID No. 130)
B 5′-AAATTCAGCACACATGTAACAGCA
(SEQ ID No. 131)
exon 23A 5′-CTGAAGTCAAATAATGAAGTCCCA3604.08.3
(SEQ ID No. 132)
B 5′-GTTTGCTTTCTCATATCTAAACACA
(SEQ ID No. 133)
exon 24A 5′-CTTGTGAGAGGCCTATAAACTGG2671.58.3
(SEQ ID No. 134)
B 5′-GGTAAACAGTGTAGGAGTCTGC
(SEQ ID No. 135)
exon 25C 5′-GCTTGAAGGATGAGGCTCTGAG4611.58.3
(SEQ ID No. 136)
D 5′-TGTTCAGAATGAGCACGATGGG
(SEQ ID No. 137)
exon 26A 5′-CTTGTGAGAGGCCTATAAACTGG2671.58.3
(SEQ ID No. 138)
B 5′-GGTAAACAGTGTAGGAGTCTGC
(SEQ ID No. 139)
exon 27A 5′-GCCATTTTCTCTTTAATTGGAAAGG2741.58.3
(SEQ ID No. 140)
B 5′-ATCTTATTCATCTTTCTGAGAATGG
(SEQ ID No. 141)
exon 28A 5′-TGAAATAGCCCAACATCTGACAG2911.58.3
(SEQ ID No. 142)
B 5′-GATTAATTTGACAGCTTGATTAGGC
(SEQ ID No. 143)
exon 29A 5′-TGAAATATAAACTCAGACTCTTAGC3031.58.3
(SEQ ID No. 144)
B 5′-GTACTGATTTGGAAAGACATTCTC
(SEQ ID No. 145)
exon 30A 5′-GATGTGACAGTGGAAGCTATGG3071.58.3
(SEQ ID No. 146)
B 5′-GGAAAAATGTGGTATCTGAAGCTC
(SEQ ID No. 147)
exon 31A 5′-AAGTGAGCAAATGTTGCTTCTGG3041.58.3
(SEQ ID No. 148)
B 5′-TCATTAGGAAGCTGAACATCAGC
(SEQ ID No. 149)
exon 32A 5′-GTTGGAGGAAATTGATCCCAAGTC3511.58.3
(SEQ ID No. 150)
B 5′-TGTTGCTTATGGGTTTAACTTGTG
(SEQ ID No. 151)
exon 33A 5′-TAAAGGATTAATGCTGTTAACAGTG3601.58.3
(SEQ ID No. 152)
B 5′-TCACACTGAGCATTTACTACCTG
(SEQ ID No. 153)
exon 34C 5′-GCAAAGGAAATGTAGCACATAGAG4911.58.3
(SEQ ID No. 154)
D 5′-AGGCTATAGGCATTTGAAAGAGG
(SEQ ID No. 155)
exon 35A 5′-GTAGGCTCCCAGAAGACCCAG4061.58.3
(SEQ ID No. 156)
B 5′-GAAAGGATGGGTGTGTATTCAGG
(SEQ ID No. 157)
mutation 7GD A 5′-ACAGGCCATAGTTTGCCAACCC4261.59.0
(SEQ ID No. 158)
GD D 5′-TGGTATTAGAATTTCCCTTTCTTCC
(SEQ ID No. 159)
DJG RT-PCR5EE 5′-TGAAAGAGAATATGGAAAGAGGCTTG20021.58.3
(SEQ ID No. 160)
B 5′-CTTTATGAAGCCAATTTCTACCC
(SEQ ID No. 161)
P2934AT1A 5′-TCAAAATCAGTCGCCTCATCCC1682.08.3
(SEQ ID No. 162)
B 5′-CAATGTATCAGTCAGGGTTCACC
(SEQ ID No. 163)
TABLE 6 — Summary of WRN Mutations Predicted
Type ofProtein
MutationCodonExonMutationNucleotide SequenceCommentLength
none1432
1116530substitutionCAG (Gln) to T AGnonsense1164
(terminator)
2130533substitutionCGA (Arg) to T GAnonsense1034
(terminator)
31230324 bpgt ag - AC AG to gt-4 bp deletion at1247
deletionAGsplice-donor
site
41047-24substitutiontag-GGT to ta c -GGTsubstitution at1060
1078splice-donor
site
53699substitutionCGA (Arg) to T GAnonsense368
(terminator)
688922substitutionCGA (Arg) to T GAnonsense888
(terminator)
7759-20substitutionCAG-gta to CAG- t tasubstitution at760
816splice-receptor
site
838991 bpA GAG (Arg) toframe-shift391
deletionGAG (Glu)
9697-19-deletion—genomic1186
94223(>15 kb)deletion
TABLE 8 — STRP Genotypes at the WRN gene 1 . Ethnic 1 Genotype data for HH, SK, ST, TH, TK, and ZM was not available. For y896R18, alleles in bp (frequency for Caucasians, frequency for Japanese) were as follows: 136 (0.030, 0.025); 138 (0.020, 0.010); 140 (0.460, 0.576); 142 (0.337, 0.359); 144 (0.084, 0.010); 146 (0, 0.010); 148 (0.009, 0.010); 150 (0.059, 0). For p2934AT1, alleles in bp (Caucasian frequency, Japanese frequency) were as follows: 114 (0.006, 0); 122 (0, # 0.009); 124 (0.011, 0); 128 (0.253, 0.079); 130 (0, 0.018); 132 (0.006, 0.009); 134 (0.046, 0.096); 136 (0.086, 0.009); 138 (0.011, 0); 140 (0.034, 0); 142 (0.052, 0.035); 144 (0.023, 0.061); 146 (0.023, 0.053); 148 (0.034, 0.132); 150 (0.034, 0.105); 152 (0.057, 0.123); 154 (0.063, 0.088); 156 (0.086, 0.070); 158 (0.098, 0.070); 160 (0.046, 0.018); 162 (0.029, 0.009); 166 (0, 0.009); 168 (0, 0.009).
SubjectGroupMutationy896r18p2934at1
FJ, FUW, HA, HW, JO1,Japanese4140/140148/148
KAKU, KY, MIE2, TO
JO2Japanese4140/140150/150
HM, MH, NN,Japanese2140/140144/144
GARHispanic2140/140156/156
OW, KOJapanese5140/140148/148
AG00780Caucasian5142/142136/136
EKL, AG04103Caucasian5142/142128/128
CP3Caucasian5/?142/150128/142
KUNJapanese5/?140/142128/148
DJGCaucasian5/9140/142128/del 2
1 of 78 part labels are ours — the grant heads the rest

Claims as granted

4 claims

Log in to read the claims of this application.

Log in to unlock

Classifications

16 codes
IPC · International Patent Classification
Section A — Human necessities
  • A01K67/00
  • A01K67/027
Section C — Chemistry; metallurgy
  • C12N15/861
  • C12N9/64
  • C12N15/867
  • C07H21/04
  • C12P21/08
  • C12N5/10
  • C12N15/09
  • C12Q1/68
  • C07K16/18
  • C12N9/90
  • C07K14/47
  • C07K14/00
USPC · US Patent Classification
514/2530/350

Claim changes

Soon
Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoomJul 2000Jan 2001Jul 2001Jan 2002Jul 2002Jan 2003Jul 2003USPTOApplicantRestriction requirementRestriction requirementNon-final rejectionResponse after non-finalNotice of allowance
USPTOApplicanthover for detail · click to open
Pendency
2.9 y
1,072 days filing → grant
Office actions
1
after a restriction
Responses
2
no RCE
Examiner
Karen Cochrane Carlson
art unit 1653 · TC 1600
Citations: 25 back · 1 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Log in to unlock

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Log in to unlock

Chain of title

⤢ drag to zoom2020FebMarAprMayJunJulAugSepOwner 1Owner 2
Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.

Log in to unlock