Nucleic acid molecules encoding human luteinizing hormone-human chorionic gonadotropin receptor protein and transformants thereof

This application is a continuation of U.S. patent application Ser. No. 07/757,342, filed on Sep. 10, 1991, now U.S. Pat. No. 6,218,509.

The present invention relates to a DNA containing a CDNA sequence coding for a human luteinizing hormone-human chorionic gonadotropin receptor protein (human LH/hCG receptor protein), the human LH/hCG receptor protein, and a method for preparing the protein.

The human luteinizing hormone-human chorionic gonadotropin receptor proteins (human LH/hCG receptor proteins) exist in the Leydig cells in the testis, the theca cells in the ovary, the granulosa cells, the corpus luteum cells and the interstitial cells, and play a central role in reproductive physiology. In the male and the female who is not pregnant, the LH/hCG receptor proteins are acted on only by luteinizing hormone (LH) produced in the anterior lobe of the pituitary and secreted therefrom. In the pregnant female, however, the LH/hCG receptor proteins in the ovary are acted on also by human chorionic gonadotropin (hCG) produced by the placenta.

LH and hCG are members of a family of glycoprotein hormones also including thyroid-stimulating hormone (TSH) and follicle-stimulating hormone (FSH). Each of these four hormones has a molecular weight of 28 to 38 kD, and is a heterodimer glycoprotein in which a specific β subunit relating to receptor binding specificity is bound to an a subunit common to these hormones. The glycosyl moiety of these hormones seem to play an important role in signal introduction. The β subunits of both LH and hCG are closely related to each other in their structure. These two hormones bind to the same receptor and induce the same biological reaction. The similarity between these glycoprotein hormones and the action by these hormones on the receptors to enhance the activity of adenylate cyclase mediated by G-proteins reveal that these receptors have a common mechanism of hormone-induced activation. The increases of adenosine 3′,5′-monophosphate (cyclic AMP) necessarily lead to the synthesis and secretion of steroids. A family of G protein-coupled receptors are identified whose members are characterized by the common structural feature of having seven transmembrane domains which are known to relate to the signal introduction and binding to small ligands. On the other hand, TSH and FSH receptors have been compared with the LH/hCG receptors. As a result, of the G protein-coupled receptors, these receptors of the pituitary glycoprotein hormones are characterized by the presence of a large glycosylated domain which is grafted onto a structure containing seven transmembrane segments and putatively considered to be positioned on the outside of cells.

The structure of the LH/hCG receptors have not been elucidated so well yet, because the receptors are present in very low amounts and sensitive to proteolysis. For rat and porcine LH/hCG receptors, however, complementary DNAs (cDNAs) of these receptors are isolated and the amino acid sequences thereof are also deduced from these DNAs [ Science 245, 494 (1989) for rats and Science 245, 525 (1989) for pigs].

For the rat and porcine LH/hCG receptors, the structure thereof has been thus elucidated. For the human LH/hCG receptors, however, the structure thereof is not revealed. Considering to use the human LH/hCG receptors as therapeutic drugs and analytical reagents for humans, it is necessary to make clear the structure and properties thereof.

The present inventors have recognized that important contributions will be made to future studies and medical treatments, if an human LH/hCG receptor can be collected from humans and further prepared by recombinant technology. As a result, the present inventors have first succeeded in cloning cDNA coding for a human LH/hCG receptor from a cDNA library of the human ovary by using the complementary DNA of a rat LH/hCG receptor as a probe, and in elucidating a complete nucleotide sequence thereof. Further, the present inventors have also succeeded in elucidating an amino acid sequence of the human LH/hCG receptor from this cDNA and in pioneering the mass production of this receptor by recombinant technology. This receptor is very similar to the rat and porcine receptors. However, the differences are such that each receptor can be recognized to be a different one.

In accordance with the present invention, there are provided (1) a human luteinizing hormone-human chorionic gonadotropin receptor protein, (2) a DNA comprising a cDNA sequence coding for a human luteinizing hormone-human chorionic gonadotropin receptor protein, (3) a transformant carrying a DNA comprising a cDNA segment coding for a human luteinizing hormone-human chorionic gonadotropin receptor protein, and (4) a method for preparing a human luteinizing hormone-human chorionic gonadotropin receptor protein which comprises culturing the transformant described in (3), accumulating a protein in a culture broth, and collecting the same.

FIGS. A 1 - 1 E shows a nucleotide sequence SEQ ID NO:1 of a human LH/hCG receptor protein DNA segment, as well as an amino acid sequence SEQ ID NO:2 deduced therefrom; and

FIGS. 2A-2D shows the amino acid sequence of the human LH/hCG receptor protein (SEQ ID NO:2) and amino acid sequences of other known LH/hCG receptor proteins and proteins (SEQ ID NOS:3 to 6) having similar action, comparing them to one another.

FIGS. 3 and 4 are SDS-PAGE diagrams which show expression of HLHR protein in Example 2.

FIG. 5 is a graph which shows that the protein obtained according to the present invention has response ability to hCG.

The present inventors cloned two kinds of cDNAs of the human luteinizing hormone-human chorionic gonadotropin receptor protein to deduce a primary structure of the complete protein (FIGS. 1 A- 1 E). The first methionine in this sequence SEQ ID NO:1 is considered to be an initiator codon. This is followed by an amino acid sequence having the characteristics of a signal peptide with a cleavage site present. A possible model for construction of the protein was suggested by hydropathy analysis and comparison with the rat and porcine LH/hCG receptors SEQ ID NO:3 and 4 respectively (FIGS. 2 A- 2 D). A putative extracellular domain of 335 amino acids precedes a region of 267 amino acids that displays seven possible transmembrane segments (regions surrounded by rectangles in FIGS. 2 A- 2 D). There is a 72 amino acid COOH-terminal intracellular domain. The mature protein may consist of 674 amino acids (75632 daltons). In addition to this protein, 25 signal peptides (the 1st to 25th amino acids in FIGS. 1A-1E and 2 A- 2 D) exist.

However, these peptides are cut off during synthesis of the receptor, and therefore the mature protein of the receptor is considered to consist of 674 amino acids (the 26 th to 699 th amino acids, SEQ ID NO:10 is the amino acid sequence of SEQ ID NO:9. At the primary structure level, this extracellular domain has about 85% homology with the rat and porcine LH/hCG receptors and 45% homology with TSH and FSH receptors (in FIGS. 2A-2D, hLH/hCGR indicates the human LH/hCG receptor; rLH/hCGR indicates the rat LH/hCG receptor; pLH/hCGR indicates the porcine LH/hCG receptor; hTSHR indicates the human TSH receptor [ Biochem. Biophys. Res. Comm . 166, 394 (1990)]; and rFSHR indicates the rat FSH receptor [ Mol. Endo . 4, 525 (1990)]). Six potential glycosylation sites are found in the putative extracellular domain (underlined portions in FIGS. 1 A- 1 E). Clusters of cysteine residues are present in the NH 2 -terminal portion and between the putative extracellular and transmembrane domains of the above protein. Since these cysteine residues are conserved in the LH, FSH and TSH receptors, while not wishing to be bound by theory, it may be said that the formation of disulfide bonds is crucial for the conformational integrity of the large extracellular domains of glycoprotein hormone receptors.

The domain considered to contain the transmembrane domains has about 90% homology with the rat and porcine LH/hCG receptors, and 70% homology with the TSH and FSH receptors. Serine and threonine residues are found with high frequency in a putative intercellular domain having three sites which is possibly phosphorylated by protein kinase C (FIGS. 1 A and 1 E). Since the phosphorylation by protein kinase specific to the receptors play a role in agonist specific decoupling of adrenergic receptors from the G proteins, it is important to know whether the phosphorylation in at least one of these sites causes any functional changes of the LH/hCG receptors.

In the present invention, in addition to a clone having a large open reading frame, a clone coding for a shorter protein was obtained. The large clone is the 1st to 699th amono acid residues in FIGS. 1A-1E (SEQ ID NO:1), and the truncated-type is one from which a region of the 227th to 289th amino acid residue surrounded by a rectangle SEQ ID NO:7 is lacking. This pattern suggests that the cleavage mechanism necessary to complete mRNA has selectivity. These results are very similar to the data of the porcine LH/hCG receptor. The role of this truncated type receptor is not understood well, and it is not known either whether this LH/hCG receptor is physiologically active as a monomer or an oligomer. In humans, this TSH receptor can be a target of autoimmune reaction which leads to hyper- or hypo-stimulation of the thyroid gland by autoantibodies in Grave's disease and idiopathic myxedema. Thus, not only for contributions to diagnosis and management of ovarian diseases, but also for better understanding of ovarian physiology, it is necessary to isolate the human LH/hCG receptor and to know its characteristics.

FIGS. 2A-2D show the amino acid sequence of the novel human luteinizing hormone-human chorionic gonadotropin receptor protein SEQ ID NO:2 obtained in the present invention, and compares this amino acid sequence with the amino acid sequences of the rat and porcine luteinizing hormone-human chorionic gonadotropin receptor proteins SEQ ID NO:3 and 4) respectively and the FSH and TSH receptors SEQ ID NO:6 and 5) respectively having similar action. The same amino acid residue as appears in the human luteinizing hormone-human chorionic gonadotropin receptor protein of the present invention, is represented by “.”, and an amino acid residue different from that of the human LH/hCG receptor is represented by the appropriate symbol as defined herein. CONSENSUS shown in FIGS. 2A-2D indicates amino acid residues common to all the glycoproteins shown in FIGS. 2A-2D. The illustration of CONSENSUS results in introduction of lacking portions “−” into the formulae ih FIGS. 2A-2D. Accordingly, the number representing the amino acids is counted excluding these lacking portions.

For a DNA sequence, the DNA coding for the human LH/hCG receptor of the present invention contains the nucleotide sequence SEQ ID NO:1 shown in FIGS. 1A-1E or a portion thereof.

As the CDNA coding for the human LH/hCG receptor of the present invention, any CDNA may be used as long as it contains a nucleotide sequence coding for an amino acid sequence of the human LH/hCG receptor. For example, DNA containing the nucleotide sequence SEQ ID NO:1 shown in FIGS. 1A-1E or a portion thereof is preferably used.

The nucleotide sequence SEQ ID NO:1 shown in FIGS. 1A-1E are an example of cDNA sequences coding for the human LH/hCG receptor obtained in the present invention.

In the present invention, for example, an expression vector having the CDNA containing the nucleotide sequence coding for the human LH/hCG receptor can be prepared by the following process:

(a) Messenger RNA (mRNA) is isolated from human LH/hCG receptor-producing cells.

(b) Single stranded complementary DNA (cDNA) is synthesized from the MRNA, followed by synthesis of double stranded DNA.

(c) The complementary DNA is introduced into a phage or a plasmid.

(d) Host cells are transformed with the recombinant phage or plasmid thus obtained.

(e) After cultivation of the transformants thus obtained, plasmids or phages containing the desired DNA are isolated from the transformants by an appropriate method such as hybridization with a DNA probe coding for a portion of the rat LH/hCG receptor or immunoassay using an anti-LH/hCG receptor antibody.

(f) The desired cloned DNA is cut out from the recombinant DNA.

(g) The cloned DNA or a portion thereof is ligated downstream from a promoter in the expression vector.

The mRNA coding for the human LH/hCG receptor can be obtained from various human LH/hCG receptor-producing cells, for example, germ cells such as the Leydig cells in the testis, the capsular cells in the ovary, the granulosa cells, the corpus luteum cells and the interstitial cells.

Methods for preparing the mRNA from the human LH/hCG receptor-producing cells include the guanidine thiocyanate method [J. M. Chirgwin et al., Biochemistry 18, 5294 (1979)] and the like.

Using the mRNA thus obtained as a template, cDNA is synthesized by use of reverse transcriptase, for example, in accordance with the method of H. Okayama et al. [ Molecular and Cellular Biology 2, 161 (1979); and ibid. 3, 280 (1983)]. The cDNA thus obtained is introduced into the plasmid.

The plasmids into which the cDNA may be introduced include, for example, pBR322 [Gene 2, 95 (1977)], pBR325 [Gene 4, 121 (1978)], pUC12 [Gene 19, 259 (1982)) and pUC13 [Gene 19, 259, each derived from Escherichia coli , and pUB110 derived from Bacillus subtilis [Biochemical and Biophysical Research Communication 112, 678 (1983)]. However, any other plasmid can be used as long as it is replicable and viable in the host cell. Examples of the phage vectors into which the cDNA may be introduced include λgt11 [R. Young and R. Davis, Proc. Natl. Acad. Sci. U.S.A . 80, 1194 (1983)]. However, any other phage vector can be used as long as it is viable in the host cell.

Methods for introducing the cDNA into the plasmid include, for example, the method described in T. Maniatis et al., Molecular Cloning , Cold Spring Harbor Laboratory, p.239 (1982). Methods for introducing the cDNA into the phage vector include, for example, the method of T. V. Hyunh et al. [ DNA Cloning, A Practical Approach 1, 49 (1985)].

The plasmid thus obtained is introduced into an appropriate host cell such as Escherichia and Bacillus.

Examples of Escherichia described above include E. coli K12DH1 [Proc. Natl. Acad. Sci. U.S.A . 60, 160 (1968)], M103 [Nucleic Acids Research 9, 309 (1981)], JA221 [Journal of Molecular Biology 120, 517 (1978)], HB101 [Journal of Molecular Biology 41, 459 (1969)] and C600 [Genetics 39, 440 (1954)].

Examples of Bacillus described above include Bacillus subtilis MI114 ( Gene 24, 255 (1983)] and 207-21 [Journal of Biochemistry 95, 87 (1984)].

Methods for transforming the host cell with the plasmid include, for example, the calcium chloride method or the calcium chloride/rubidium chloride method described in T. Maniatis et al., Molecular Cloning , Cold Spring harbor Laboratory, p.249 (1982).

When the phage vector is used, for example, it can be transduced into proliferated E. coli , using the in vitro packaging method.

Human LH/hCG receptor-cDNA libraries containing human LH/hCG receptor cDNA can be purchased from the market, though obtainable by the methods described above. For example, a cDNA library of the LH/CG receptor is available from Clontech Laboratories, Inc., U.S.A.

Methods for cloning human LH/hCG receptor cDNA from the human DNA library include, for example, the plaque hybridization method using phage vector λcharon 28A and rat LH/hCG receptor cDNA as a probe [T. Maniatis et al., Molecular Cloning , Cold Spring Harbor Laboratory, (1982)].

The human LH/hCG receptor cDNA thus cloned may be subcloned, for example, in pBR322, pUC12, pUC13, pUC18, pUC19, pUC118 and pUC119 to obtain the human LH/hCG receptor cDNA, if necessary.

The nucleotide sequence of the cDNA thus obtained is determined, for example, by the Maxam-Gilbert method [A. M. Maxam and W. Gilbert, Proc. Natl. Acad. Sci. U.S.A . 74, 560 (1977)] or the dideoxy method [J. Messing et al., Nucleic Acids Research 9, 309 (1981)], and the existence of the human LH/hCG receptor cDNA is confirmed in comparison with the known amino acid sequence.

As described above, the cDNA coding for the human LH/hCG receptor protein is obtained.

FIGS. 1A-1E show the nucleotide sequence of the cDNA SEQ ID NO:1 determined by the dideoxy method for the cDNA coding for the human LH/hCG receptor protein obtained in Example 1 described below, and the amino acid sequence proved from that nucleotide sequence.

The CDNA coding for the human LH/hCG receptor protein SEQ ID NO:2 cloned as described above can be used as is, or after digestion with a restriction enzyme if desired, depending on the intended use.

A region intended to be expressed is cut out from the cloned cDNA and ligated downstream from a promoter in a vehicle (vector) suitable for expression, whereby the expression vector can be obtained.

The cDNA has ATG as a translation initiating codon at the 5′-terminus thereof and may have TAA, TGA or TAG as a translation terminating codon at the 3′-terminus. The translation initiating codon and translation terminating codon may be added by use of an appropriate synthetic cDNA adaptor. A promoter is further ligated upstream therefrom for the purpose of expressing the cDNA.

Examples of the vectors include the above plasmids derived from E. coli such as pBR322, pBR325, pUC12 and pUC13, the plasmids derived from Bacillus subtilis such as pUB110, pTP5 and pC194, plasmids derived from yeast such as pSH19 and pSH15, bacteriophages such as A phage, and animal viruses such as retroviruses and vaccinia viruses.

As the promoter used in the present invention, any promoter is available as long as it is suitable for expression in the host cell selected for the gene expression.

When the host cell used for transformation is Escherichia, it is preferable that a trp promoter, a lac promoter, a recA promoter, a λP L promoter, a lpp promoter, etc. are used. When the host cell is Bacillus, it is preferable that a SPO1 promoter, a SPO2 promoter, a penP promoter, etc. are used. When the host cell is yeast, it is preferable that a PHO5 promoter, a PGK promoter, a GAP promoter, an ADH promoter, etc. are used. In particular, it is preferable that the host cell is Escherichia and the promoter is the trp promoter or the λP L promoter.

When the host cell is an animal cell, a SV-40 derived promoter, a retrovirus promoter, a metallothionein promoter, a heat shock promoter, etc. are each usable.

An enhancer is also effectively used for expression.

Using a vector containing the cDNA coding for the mature peptide of the human LH/hCG receptor protein thus constructed, transformants are prepared.

The host cells include, for example, Escherichia, Bacillus, yeast and animal cells.

Specific examples of the above Escherichia and Bacillus include strains similar to those described above.

Examples of the above yeast include Saccharomyces cerevisiae AH22, AH22R − , NA87-11A and DKD-5D.

Examples of the animal cells include monkey cell COS-7, Vero, Chinese hamster cell (CHO), mouse L cell and human FL cell.

The transformation of the above Escherichia is carried out, for example, according to the method described in Proc. Natl. Acad. Sci. U.S.A . 69, 2110 (1972) or Gene 17, 107 (1982).

The transformation of the above Bacillus is conducted, for example, according to the method described in Molecular & General Genetics 168, 111 (1979).

The transformation of the yeast is carried out, for example, according to the method described in Proc. Natl. Acad. Sci. U.S.A . 75, 1929 (1978).

The transformation of the animal cells is carried out, for example, according to the method described in Virology 52, 456 (1973).

Thus, transformants are obtained which have been transformed with the expression vector containing the cDNA coding for the human LH/hCG receptor.

When bacterial transformants are cultured, a liquid medium is particularly suitable as a medium used for culture. Carbon sources, nitrogen sources, inorganic compounds and others necessary for growth of the transformants are contained therein. Examples of the carbon sources include glucose, dextrin, soluble starch and sucrose. Examples of the nitrogen sources include inorganic or organic materials such as ammonium salts, nitrates, corn steep liquor, peptone, casein, meat extracts, soybean meal and potato extract solution. The inorganic compounds include, for example, calcium chloride, sodium dihydrogenphosphate and magnesium chloride. Yeast, vitamins, growth promoting factors and so on may be further added thereto.

The pH of the medium is preferably about 5 to 8.

As the medium used for cultivation of Escherichia, for example, M9 medium containing glucose and Casamino Acids (Miller, Journal of Experiments in Molecular Genetics 431-433, Cold Spring Harbor Laboratory, New York, 1972) is preferably used. In order to make the promoter act efficiently, a drug such as 3-β-indolylacrylic acid may be added thereto if necessary.

When the host cell is Escherichia, the cultivation is usually carried out at about 15 to 43° C. for about 3 to 24 hours, with aeration or agitation if necessary.

When the host cell is Bacillus, the cultivation is usually carried out at about 30 to 40° C. for about 6 to 24 hours, with aeration or agitation if necessary.

When yeast transformants are cultured, for example, Burkholder minimum medium [K. L. Bostian et al., Proc. Natl. Acad. Sci. U.S.A . 77, 4505 (1980)] is used as the medium. The pH of the medium is preferably adjusted to about 5 to 8. The cultivation is usually carried out at about 20 to 35° C. for about 24 to 72 hours, with aeration or agitation if necessary.

When animal cell transformants are cultured, examples of the mediums include MEM medium containing about 5 to 20% fetal calf serum [ Science 122, 501 (1952)], DMEM medium [ Virology 8, 396 (1959)], RPMI1640 medium ( The Journal of the American Medical Association 199, 519 (1967)] and 199 medium [ Proceeding of the Society for the Biological Medicine 73, 1 (1950). The pH is preferably about 6 to 8. The cultivation is usually carried out at about 30 to 40° C. for about 15 to 60 hours, with aeration or agitation if necessary.

The human LH/hCG receptor protein can be isolated and purified from the culture described above, for example, by the following method.

When the human LH/hCG receptor protein is extracted from the cultured cells, the cells are collected by methods known in the art after cultivation. Then, the collected cells are suspended in an appropriate buffer solution and disrupted by ultrasonic treatment, lysozyme and/or freeze-thawing. Thereafter, a crude extracted solution of the human LH/hCG receptor mature peptide is obtained by centrifugation or filtration. The buffer solution may contain a protein denaturant such as urea or guanidine hydrochloride, or a surface-active agent such as Triton X-100.

When the human LH/hCG receptor protein is secreted in the culture solution, a supernatant is separated from the cells by methods known in the art after the conclusion of cultivation, and then collected.

The separation and purification of the human LH/hCG receptor contained in the culture supernatant or the extracted solution thus obtained can be performed by an appropriate combination of known separating and purifying methods. The known separating and purifying methods include methods utilizing solubility such as salt precipitation and solvent precipitation, methods mainly utilizing a difference in molecular weight such as dialysis, ultrafiltration, gel filtration and SDS-polyacrylamide gel electrophoresis, methods utilizing a difference in electric charge such as ion-exchange column chromatography, methods utilizing specific affinity such as affinity chromatography, methods utilizing a difference in hydrophobicity such as reverse phase high performance liquid chromatography and methods utilizing a difference in isoelectric point such as isoelectro-focussing electrophoresis. A method may also be used in which an antibody to a fused protein expressed by fusing the human LH/hCG receptor complimentary DNA together with E. coli -derived DNA lacZ is used as an immunoaffinity column.

The activity of the human LH/hCG receptor protein thus formed can be measured by an enzyme immunoassay using a specific antibody.

The cells transfected or transformed with the cDNA of the present invention can allow the human LH/hCG receptor protein to be produced in large amounts.

The human LH/hCG receptor protein produced here is channeled into the study of ovarian physiology, the supply of antibodies to the receptor, the diagnosis and management of ovarian or testicular diseases such as ovulation aberration or oligospermia, and the development of contraceptives. In humans, this TSH receptor can be a target of autoimmune reaction which leads to hyper- or hypo-stimulation of the thyroid gland by autoantibodies in Grave's disease and idiopathic myxedema. The LH/hCG receptor might therefore suppress the LH action in vivo or can conduct hyperstimulation in stead of LH to cause morbidity in the human genital system. The anti-receptor antibody can be detected by producing the receptor by any of the above-described methods, labeling it and examining whether one binding to it (antibody) is present in vivo or not. In addition, it is considered that inhibition of the LH action by an antibody obtained by expressing a portion or all of the receptor cDNA, namely the application of the antibody as a contraceptive, is possible.

There have been described above in detail the cloning of the cDNA coding for the human LH/hCG receptor protein, the preparation of the expression vectors for the human LH/hCG receptor protein, the production of the transformants thereby, the production of the human LH/hCG receptor protein by using the transformants and utility thereof.

When nucleotides, amino acids and so on are indicated by abbreviations in this specification and drawings, the abbreviations adopted by the IUPAC-IUB Commission on Biochemical Nomenclature or commonly used in the art are employed. For example, the following abbreviations are used. When the amino acids are capable of existing as optical isomers, it is understood that the L-forms are represented unless otherwise specified.

DNA: Deoxyribonucleic acid

CDNA: Complementary deoxyribonucleic acid

A: Adenine

T: Thymine

G: Guanine

C: Cytosine

RNA: Ribonucleic acid

mRNA: Messenger ribonucleic acid

dATP: Deoxyadenosine triphosphate

dTTP: Deoxythymidine triphosphate

dGTP: Deoxyguanosine triphosphate

dCTP: Deoxycytidine triphosphate

ATP: Adenosine triphosphate

EDTA: Ethylenediaminetetraacetic acid

SDS: Sodium dodecyl sulfate

Gly or G: Glycine

Ala or A: Alanine

Val or V: Valine

Leu or L: Leucine

Ile or I: Isoleucine

Ser or S: Serine

Thr or T: Threonine

Cys or C: Cysteine

Met or M: Methionine

Glu or E: Glutamic acid

Asp or D: Aspartic acid

Lys or K: Lysine

Arg or R: Arginine

His or H: Histidine

Phe or F: Phenylalanine

Tyr or Y: Tyrosine

Trp or W: Tryptophan

Pro or P: Proline

Asn or N: Asparagine

Gln or Q: Glutamine

The precise chemical structure of the human luteinizing hormone-human chorionic gonadotropin receptor proteins of the present invention will depend on a number of factors. Because ionizable amino and carboxyl groups are present in these proteins, a particular protein may be obtained as an acidic or basic salt, or in neutral form. All such preparations which retain their bioactivity when placed in suitable environmental conditions are included in the definition of the receptor proteins of the present invention. Further, the primary amino acid sequence of such proteins may be argumented by derivation using sugar moieties or by other supplementary molecules such as lipids, phosphate, acetyl groups and the like. Such modifications are included in the definition of the receptor proteins of the present invention so long as the bioactivity of the protein is not destroyed. It is expected, of course, that such modifications may quantitatively or qualitatively affect the bioactivity by either enhancing or diminishing the activity of the protein.

Further, individual amino acid residues in the chain may be modified by oxidation, reduction, or other derivatization, and the receptor proteins of the present invention may be cleaved to obtain fragments which retain bioactivity. Such alterations which do not destroy bioactivity do not remove such receptor proteins from the definition.

Finally modifications to the primary structure itself by deletion, addition, or alteration of the amino acids incorporated into the sequence during translation can be Mmade without destroying the activity of the receptor proteins of the present invention.

The present invention will hereinafter be described in more detail with the following Examples. It is understood of course that these Examples are not intended to limit the scope of the invention.

Transformant E. coli JM109/pUC18 obtained in Example 1 described below was deposited with the Fermentation Research Institute, the Agency of Industrial Science and Technology, the Ministry of International Trade and Industry, Japan (FRI) under the accession number FERM BP-3127 on Oct. 9, 1990. This microorganism was deposited with the Institute for Fermentation, Osaka, Japan (IFO) under the accession number IFO 15096 on Oct. 11, 1990.

Transformants E. coli DH1/pHLHR (UEX2) and E. coli JM109/pHLHR (GEX-3X) obtained in Example 2 described below were deposited with the Fermentation Research Institute, the Agency of Industrial Science and Technology, the Ministry of International Trade and Industry, Japan (FRI) under the accession number FERM BP-3545 and FERM BP-3544 respectively on Aug. 29, 1991. These transformants were deposited with the Institute For Fermentation, Osaka, Japan (IFO) under the accession numbers IFO 15219 on Aug. 30, 1991 and IFO 15218 on Aug. 30, 1991, respectively.

Homo sapiens

2

Met Lys Gln Arg Phe Ser Ala Leu Gln Leu Leu Lys Leu Leu Leu Leu

1 5 10 15

Leu Gln Pro Pro Leu Pro Arg Ala Leu Arg Glu Ala Leu Cys Pro Glu

20 25 30

Pro Cys Asn Cys Val Pro Asp Gly Ala Leu Arg Cys Pro Gly Pro Thr

35 40 45

Ala Gly Leu Thr Arg Leu Ser Leu Ala Tyr Leu Pro Val Lys Val Ile

50 55 60

Pro Ser Gln Ala Phe Arg Gly Leu Asn Glu Val Ile Lys Ile Glu Ile

65 70 75 80

Ser Gln Ile Asp Ser Leu Glu Arg Ile Glu Ala Asn Ala Phe Asp Asn

85 90 95

Leu Leu Asn Leu Ser Glu Ile Leu Ile Gln Asn Thr Lys Asn Leu Arg

100 105 110

Tyr Ile Glu Pro Gly Ala Phe Ile Asn Leu Pro Gly Leu Lys Tyr Leu

115 120 125

Ser Ile Cys Asn Thr Gly Ile Arg Lys Phe Pro Asp Val Thr Lys Val

130 135 140

Phe Ser Ser Glu Ser Asn Phe Ile Leu Glu Ile Cys Asp Asn Leu His

145 150 155 160

Ile Thr Thr Ile Pro Gly Asn Ala Phe Gln Gly Met Asn Asn Glu Ser

165 170 175

Val Thr Leu Lys Leu Tyr Gly Asn Gly Phe Glu Glu Val Gln Ser His

180 185 190

Ala Phe Asn Gly Thr Thr Leu Thr Ser Leu Glu Leu Lys Glu Asn Val

195 200 205

His Leu Glu Lys Met His Asn Gly Ala Phe Arg Gly Ala Thr Gly Pro

210 215 220

Lys Thr Leu Asp Ile Ser Ser Thr Lys Leu Gln Ala Leu Pro Ser Tyr

225 230 235 240

Gly Leu Glu Ser Ile Gln Arg Leu Ile Ala Thr Ser Ser Tyr Ser Leu

245 250 255

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

260 265 270

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

275 280 285

Glu Gln Asn Phe Ser His Ser Ile Ser Glu Asn Phe Ser Lys Gln Cys

290 295 300

Glu Ser Thr Val Arg Lys Val Ser Asn Lys Thr Leu Tyr Ser Ser Met

305 310 315 320

Leu Ala Glu Ser Glu Leu Ser Gly Trp Asp Tyr Glu Tyr Gly Phe Cys

325 330 335

Leu Pro Lys Thr Pro Arg Cys Ala Pro Glu Pro Asp Ala Phe Asn Pro

340 345 350

Cys Glu Asp Ile Met Gly Tyr Asp Phe Leu Arg Val Leu Ile Trp Leu

355 360 365

Ile Asn Ile Leu Ala Ile Met Gly Asn Met Thr Val Leu Phe Val Leu

370 375 380

Leu Thr Ser Arg Tyr Lys Leu Thr Val Pro Arg Phe Leu Met Cys Asn

385 390 395 400

Leu Ser Phe Ala Asp Phe Cys Met Gly Leu Tyr Leu Leu Leu Ile Ala

405 410 415

Ser Val Asp Ser Gln Thr Lys Gly Gln Tyr Tyr Asn His Ala Ile Asp

420 425 430

Trp Gln Thr Gly Ser Gly Cys Ser Thr Ala Gly Phe Phe Thr Val Phe

435 440 445

Ala Ser Glu Leu Ser Val Tyr Thr Leu Thr Val Ile Thr Leu Glu Arg

450 455 460

Trp His Thr Ile Thr Tyr Ala Ile His Leu Asp Gln Lys Leu Arg Leu

465 470 475 480

Arg His Ala Ile Leu Ile Met Leu Gly Gly Trp Leu Phe Ser Ser Leu

485 490 495

Ile Ala Met Leu Pro Leu Val Gly Val Ser Asn Tyr Met Lys Val Ser

500 505 510

Ile Cys Phe Pro Met Asp Val Glu Thr Thr Leu Ser Gln Val Tyr Ile

515 520 525

Leu Thr Ile Leu Ile Leu Asn Val Val Ala Phe Phe Ile Ile Cys Ala

530 535 540

Cys Tyr Ile Lys Ile Tyr Phe Ala Val Arg Asn Pro Glu Leu Met Ala

545 550 555 560

Thr Asn Lys Asp Thr Lys Ile Ala Lys Lys Met Ala Ile Leu Ile Phe

565 570 575

Thr Asp Phe Thr Cys Met Ala Pro Ile Ser Phe Phe Ala Ile Ser Ala

580 585 590

Ala Phe Lys Val Pro Leu Ile Thr Val Thr Asn Ser Lys Val Leu Leu

595 600 605

Val Leu Phe Tyr Pro Ile Asn Ser Cys Ala Asn Pro Phe Leu Tyr Ala

610 615 620

Ile Phe Thr Lys Thr Phe Gln Arg Asp Phe Phe Leu Leu Leu Ser Lys

625 630 635 640

Phe Gly Cys Cys Lys Arg Arg Ala Glu Leu Tyr Arg Arg Lys Asp Phe

645 650 655

Ser Ala Tyr Thr Ser Asn Cys Lys Asn Gly Phe Thr Gly Ser Asn Lys

660 665 670

Pro Ser Gln Ser Thr Leu Lys Leu Ser Thr Leu His Cys Gln Gly Thr

675 680 685

Ala Leu Leu Asp Lys Thr Arg Tyr Thr Glu Cys

690 695

3

700

Rattus sp.

3

Met Gly Arg Arg Val Pro Ala Leu Arg Gln Leu Leu Val Leu Ala Val

1 5 10 15

Leu Leu Leu Lys Pro Ser Gln Leu Gln Ser Arg Glu Leu Ser Gly Ser

20 25 30

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

35 40 45

Pro Gly Pro Arg Ala Gly Leu Ala Arg Leu Ser Leu Thr Tyr Leu Pro

50 55 60

Val Lys Val Ile Pro Ser Gln Ala Phe Arg Gly Leu Asn Glu Val Val

65 70 75 80

Lys Ile Glu Ile Ser Gln Ser Asp Ser Leu Glu Arg Ile Glu Ala Asn

85 90 95

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

100 105 110

Lys Asn Leu Leu Tyr Ile Glu Pro Gly Ala Phe Thr Asn Leu Pro Arg

115 120 125

Leu Lys Tyr Leu Ser Ile Cys Asn Thr Gly Ile Arg Thr Leu Pro Asp

130 135 140

Val Thr Lys Ile Ser Ser Ser Glu Phe Asn Phe Ile Leu Glu Ile Cys

145 150 155 160

Asp Asn Leu His Ile Thr Thr Ile Pro Gly Asn Ala Phe Gln Gly Met

165 170 175

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

180 185 190

Val Gln Ser His Ala Phe Asn Gly Thr Thr Leu Ile Ser Leu Glu Leu

195 200 205

Lys Glu Asn Ile Tyr Leu Glu Lys Met His Ser Gly Ala Phe Gln Gly

210 215 220

Ala Thr Gly Pro Ser Ile Leu Asp Ile Ser Ser Thr Lys Leu Gln Ala

225 230 235 240

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

245 250 255

Ser Tyr Ser Leu Lys Thr Leu Pro Ser Lys Glu Lys Phe Thr Ser Leu

260 265 270

Leu Val Ala Thr Leu Thr Tyr Pro Ser His Cys Cys Ala Phe Arg Asn

275 280 285

Leu Pro Lys Lys Glu Gln Asn Phe Ser Phe Ser Ile Phe Glu Asn Phe

290 295 300

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

305 310 315 320

Tyr Ser Ala Ile Phe Glu Glu Asn Glu Leu Ser Gly Trp Asp Tyr Asp

325 330 335

Tyr Gly Phe Cys Ser Pro Lys Thr Leu Gln Cys Ala Pro Glu Pro Asp

340 345 350

Ala Phe Asn Pro Cys Glu Asp Ile Met Gly Tyr Ala Phe Leu Arg Val

355 360 365

Leu Ile Trp Leu Ile Asn Ile Leu Ala Ile Phe Gly Asn Leu Thr Val

370 375 380

Leu Phe Val Leu Leu Thr Ser Arg Tyr Lys Leu Thr Val Pro Arg Phe

385 390 395 400

Leu Met Cys Asn Leu Ser Phe Ala Asp Phe Cys Met Gly Leu Tyr Leu

405 410 415

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

420 425 430

His Ala Ile Asp Trp Gln Thr Gly Ser Gly Cys Gly Ala Ala Gly Phe

435 440 445

Phe Thr Val Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu Thr Val Ile

450 455 460

Thr Leu Glu Arg Trp His Thr Ile Thr Tyr Ala Val Gln Leu Asp Gln

465 470 475 480

Lys Leu Arg Leu Arg His Ala Ile Pro Ile Met Leu Gly Gly Trp Leu

485 490 495

Phe Ser Thr Leu Ile Ala Thr Met Pro Leu Val Gly Ile Ser Asn Tyr

500 505 510

Met Lys Val Ser Ile Cys Leu Pro Met Asp Val Glu Ser Thr Leu Ser

515 520 525

Gln Val Tyr Ile Leu Ser Ile Leu Ile Leu Asn Val Val Ala Phe Val

530 535 540

Val Ile Cys Ala Cys Tyr Ile Arg Ile Tyr Phe Ala Val Gln Asn Pro

545 550 555 560

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

565 570 575

Ile Leu Ile Phe Thr Asp Phe Thr Cys Met Ala Pro Ile Ser Phe Phe

580 585 590

Ala Ile Ser Ala Ala Phe Lys Val Pro Leu Ile Thr Val Thr Asn Ser

595 600 605

Lys Ile Leu Leu Val Leu Phe Tyr Pro Val Asn Ser Cys Ala Asn Pro

610 615 620

Phe Leu Tyr Ala Ile Phe Thr Lys Ala Phe Gln Arg Asp Phe Leu Leu

625 630 635 640

Leu Leu Ser Arg Phe Gly Cys Cys Lys Arg Arg Ala Glu Leu Tyr Arg

645 650 655

Arg Lys Glu Phe Ser Ala Tyr Thr Ser Asn Cys Lys Asn Gly Phe Pro

660 665 670

Gly Ala Ser Lys Pro Ser Gln Ala Thr Leu Lys Leu Ser Thr Val His

675 680 685

Cys Gln Gln Pro Ile Pro Pro Arg Ala Leu Thr His

690 695 700

4

696

Sus scrofa

4

Met Arg Arg Arg Ser Leu Ala Leu Arg Leu Leu Leu Ala Leu Leu Leu

1 5 10 15

Leu Pro Pro Pro Leu Pro Gln Thr Leu Leu Gly Ala Pro Cys Pro Glu

20 25 30

Pro Cys Ser Cys Arg Pro Asp Gly Ala Leu Arg Cys Pro Gly Pro Arg

35 40 45

Ala Gly Leu Ser Arg Leu Ser Leu Thr Tyr Leu Thr Ile Lys Val Ile

50 55 60

Pro Ser Gln Ala Phe Arg Gly Leu Asn Glu Val Val Lys Ile Glu Ile

65 70 75 80

Ser Gln Ser Asp Ser Leu Glu Lys Ile Glu Ala Asn Ala Phe Asp Asn

85 90 95

Leu Leu Asn Leu Ser Glu Ile Leu Ile Gln Asn Thr Lys Asn Leu Val

100 105 110

Tyr Ile Glu Pro Gly Ala Phe Thr Asn Leu Pro Arg Leu Lys Tyr Leu

115 120 125

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

130 135 140

Phe Ser Ser Glu Phe Asn Phe Ile Leu Glu Ile Cys Asp Asn Leu His

145 150 155 160

Ile Thr Thr Val Pro Ala Asn Ala Phe Gln Gly Met Asn Asn Glu Ser

165 170 175

Ile Thr Leu Lys Leu Tyr Gly Asn Gly Phe Glu Glu Ile Gln Ser His

180 185 190

Ala Phe Asn Gly Thr Thr Leu Ile Ser Leu Glu Leu Lys Glu Asn Ala

195 200 205

His Leu Lys Lys Met His Asn Asp Ala Phe Arg Gly Ala Arg Gly Pro

210 215 220

Ser Ile Leu Asp Ile Ser Ser Thr Lys Leu Gln Ala Leu Pro Ser Tyr

225 230 235 240

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

245 250 255

Lys Lys Leu Pro Ser Arg Glu Lys Phe Thr Asn Leu Leu Asp Ala Thr

260 265 270

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

275 280 285

Glu Gln Asn Phe Ser Phe Ser Ile Phe Lys Asn Phe Ser Lys Gln Cys

290 295 300

Glu Ser Thr Ala Arg Arg Pro Asn Asn Glu Thr Leu Tyr Ser Ala Ile

305 310 315 320

Phe Ala Glu Ser Glu Leu Ser Asp Trp Asp Tyr Asp Tyr Gly Phe Cys

325 330 335

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

340 345 350

Cys Glu Asp Ile Met Gly Tyr Asp Phe Leu Arg Val Leu Ile Trp Leu

355 360 365

Ile Asn Ile Leu Ala Ile Met Gly Asn Val Thr Val Leu Phe Val Leu

370 375 380

Leu Thr Ser His Tyr Lys Leu Thr Val Pro Arg Phe Leu Met Cys Asn

385 390 395 400

Leu Ser Phe Ala Asp Phe Cys Met Gly Leu Tyr Leu Leu Leu Ile Ala

405 410 415

Ser Val Asp Ala Gln Thr Lys Gly Gln Tyr Tyr Asn His Ala Ile Asp

420 425 430

Trp Gln Thr Gly Asn Gly Cys Ser Val Ala Gly Phe Phe Thr Val Phe

435 440 445

Ala Ser Glu Leu Ser Val Tyr Thr Leu Thr Val Ile Thr Leu Glu Arg

450 455 460

Trp His Thr Ile Thr Tyr Ala Ile Gln Leu Asp Gln Lys Leu Arg Leu

465 470 475 480

Arg His Ala Ile Pro Ile Met Leu Gly Gly Trp Leu Phe Ser Thr Leu

485 490 495

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

500 505 510

Ile Cys Leu Pro Met Asp Val Glu Thr Thr Leu Ser Gln Val Tyr Ile

515 520 525

Leu Thr Ile Leu Ile Leu Asn Val Val Ala Phe Ile Ile Ile Cys Ala

530 535 540

Cys Tyr Ile Lys Ile Tyr Phe Ala Val Gln Asn Pro Glu Leu Met Ala

545 550 555 560

Thr Asn Lys Asp Thr Lys Ile Ala Lys Lys Met Ala Val Leu Ile Phe

565 570 575

Thr Asp Phe Thr Cys Met Ala Pro Ile Ser Phe Phe Ala Ile Ser Ala

580 585 590

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

595 600 605

Val Leu Phe Tyr Pro Val Asn Ser Cys Ala Asn Pro Phe Leu Tyr Ala

610 615 620

Ile Phe Thr Lys Ala Phe Arg Arg Asp Phe Phe Leu Leu Leu Ser Lys

625 630 635 640

Ser Gly Cys Cys Lys His Gln Ala Glu Leu Tyr Arg Arg Lys Asp Phe

645 650 655

Ser Ala Tyr Cys Lys Asn Gly Phe Thr Gly Ser Asn Lys Pro Ser Gln

660 665 670

Ser Thr Leu Lys Leu Thr Thr Leu Gln Cys Gln Tyr Ser Thr Val Met

675 680 685

Asp Lys Thr Cys Tyr Lys Asp Cys

690 695

5

764

Homo sapiens

5

Met Arg Pro Ala Asp Leu Leu Gln Leu Val Leu Leu Leu Asp Leu Pro

1 5 10 15

Arg Asp Leu Gly Gly Met Gly Cys Ser Ser Pro Pro Cys Glu Cys His

20 25 30

Gln Glu Glu Asp Phe Arg Val Thr Cys Lys Asp Ile Gln Arg Ile Pro

35 40 45

Ser Leu Pro Pro Ser Thr Gln Thr Leu Lys Leu Ile Glu Thr His Leu

50 55 60

Arg Thr Ile Pro Ser His Ala Phe Ser Asn Leu Pro Asn Ile Ser Arg

65 70 75 80

Ile Tyr Val Ser Ile Asp Val Thr Leu Gln Gln Leu Glu Ser His Ser

85 90 95

Phe Tyr Asn Leu Ser Lys Val Thr His Ile Glu Ile Arg Asn Thr Arg

100 105 110

Asn Leu Thr Tyr Ile Asp Pro Asp Ala Leu Lys Glu Leu Pro Leu Leu

115 120 125

Lys Phe Leu Gly Ile Phe Asn Thr Gly Leu Lys Met Phe Pro Asp Leu

130 135 140

Thr Lys Val Tyr Ser Thr Asp Ile Phe Phe Ile Leu Glu Ile Thr Asp

145 150 155 160

Asn Pro Tyr Met Thr Ser Ile Pro Val Asn Ala Phe Gln Gly Leu Cys

165 170 175

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

180 185 190

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

195 200 205

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

210 215 220

Tyr Ser Gly Pro Ser Leu Leu Asp Val Ser Gln Thr Ser Val Thr Ala

225 230 235 240

Leu Pro Ser Lys Gly Leu Glu His Leu Lys Glu Leu Ile Ala Arg Asn

245 250 255

Thr Trp Thr Leu Lys Lys Leu Pro Leu Ser Leu Ser Phe Leu His Leu

260 265 270

Thr Arg Ala Asp Leu Ser Tyr Pro Ser His Cys Cys Ala Phe Lys Asn

275 280 285

Gln Lys Lys Ile Arg Gly Ile Leu Glu Ser Leu Met Cys Asn Glu Ser

290 295 300

Ser Met Gln Ser Leu Arg Gln Arg Lys Ser Val Asn Ala Leu Asn Ser

305 310 315 320

Pro Leu His Gln Glu Tyr Glu Glu Asn Leu Gly Asp Ser Ile Val Gly

325 330 335

Tyr Lys Glu Lys Ser Lys Phe Gln Asp Thr His Asn Asn Ala His Tyr

340 345 350

Tyr Val Phe Phe Glu Glu Gln Glu Asp Glu Ile Ile Gly Phe Gly Gln

355 360 365

Glu Leu Lys Asn Pro Gln Glu Glu Thr Leu Gln Ala Phe Asp Ser His

370 375 380

Tyr Asp Tyr Thr Ile Cys Gly Asp Ser Glu Asp Met Val Cys Thr Pro

385 390 395 400

Lys Ser Asp Glu Phe Asn Pro Cys Glu Asp Ile Met Gly Tyr Lys Phe

405 410 415

Leu Arg Ile Val Val Trp Phe Val Ser Leu Leu Ala Leu Leu Gly Asn

420 425 430

Val Phe Val Leu Leu Ile Leu Leu Thr Ser His Tyr Lys Leu Asn Val

435 440 445

Pro Arg Phe Leu Met Cys Asn Leu Ala Phe Ala Asp Phe Cys Met Gly

450 455 460

Met Tyr Leu Leu Leu Ile Ala Ser Val Asp Leu Tyr Thr His Ser Glu

465 470 475 480

Tyr Tyr Asn His Ala Ile Asp Trp Gln Thr Gly Pro Gly Cys Asn Thr

485 490 495

Ala Gly Phe Phe Thr Val Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu

500 505 510

Thr Val Ile Thr Leu Glu Arg Trp Tyr Ala Ile Thr Phe Ala Met Arg

515 520 525

Leu Asp Arg Lys Met Arg Leu Arg His Ala Cys Ala Ile Met Val Gly

530 535 540

Gly Trp Val Cys Cys Phe Leu Leu Ala Leu Leu Pro Leu Val Gly Ile

545 550 555 560

Ser Ser Tyr Ala Lys Val Ser Ile Cys Leu Pro Met Asp Thr Glu Thr

565 570 575

Pro Leu Ala Leu Ala Tyr Ile Val Phe Val Leu Thr Leu Asn Ile Val

580 585 590

Ala Phe Val Ile Val Cys Cys Cys Tyr Val Lys Ile Tyr Ile Thr Val

595 600 605

Arg Asn Pro Gln Tyr Asn Pro Gly Asp Lys Asp Thr Lys Ile Ala Lys

610 615 620

Arg Met Ala Val Leu Ile Phe Thr Asp Phe Ile Cys Met Ala Pro Ile

625 630 635 640

Ser Phe Tyr Ala Leu Ser Ala Ile Leu Asn Lys Pro Leu Ile Thr Val

645 650 655

Ser Asn Ser Lys Ile Leu Leu Val Leu Phe Tyr Pro Leu Asn Ser Cys

660 665 670

Ala Asn Pro Phe Leu Tyr Ala Ile Phe Thr Lys Glu Phe Gln Arg Asp

675 680 685

Val Phe Ile Leu Leu Ser Lys Phe Gly Ile Cys Lys Arg Gln Ala Gln

690 695 700

Ala Tyr Arg Gly Gln Arg Val Pro Pro Lys Asn Ser Thr Asp Ile Gln

705 710 715 720

Val Gln Lys Val Thr His Glu Met Arg Gln Gly Leu His Asn Met Glu

725 730 735

Asp Val Tyr Glu Leu Ile Glu Lys Ser His Leu Thr Pro Lys Lys Gln

740 745 750

Gly Gln Ile Ser Glu Glu Tyr Met Gln Thr Val Leu

755 760

6

692

Rattus sp.

6

Met Ala Leu Leu Leu Val Ser Leu Leu Ala Phe Leu Gly Thr Gly Ser

1 5 10 15

Gly Cys His His Trp Leu Cys His Cys Ser Asn Arg Val Phe Leu Cys

20 25 30

Gln Asp Ser Lys Val Thr Glu Ile Pro Thr Asp Leu Pro Arg Asn Ala

35 40 45

Ile Glu Leu Arg Phe Val Leu Thr Lys Leu Arg Val Ile Pro Lys Gly

50 55 60

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

65 70 75 80

Asp Val Leu Glu Val Ile Glu Ala Asp Val Phe Ser Asn Leu Pro Lys

85 90 95

Leu His Glu Ile Arg Ile Glu Lys Ala Asn Asn Leu Leu Tyr Ile Asn

100 105 110

Pro Glu Ala Phe Gln Asn Leu Pro Ser Leu Arg Tyr Leu Leu Ile Ser

115 120 125

Asn Thr Gly Ile Lys His Leu Pro Ala Val His Lys Ile Gln Ser Leu

130 135 140

Gln Lys Val Leu Leu Asp Ile Gln Asp Asn Ile Asn Ile His Ile Val

145 150 155 160

Ala Arg Asn Ser Phe Met Gly Leu Ser Phe Glu Ser Val Ile Leu Trp

165 170 175

Leu Ser Lys Asn Gly Ile Glu Glu Ile His Asn Cys Ala Phe Asn Gly

180 185 190

Thr Gln Leu Asp Glu Leu Asn Leu Ser Asp Asn Asn Asn Leu Glu Glu

195 200 205

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

210 215 220

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

225 230 235 240

Leu Lys Lys Leu Arg Ala Arg Ser Thr Tyr Arg Leu Lys Lys Leu Pro

245 250 255

Asn Leu Asp Lys Phe Val Thr Leu Met Glu Ala Ser Leu Thr Tyr Pro

260 265 270

Ser His Cys Cys Ala Phe Ala Asn Leu Lys Arg Gln Ile Ser Glu Leu

275 280 285

His Pro Ile Cys Asn Lys Ser Ile Leu Arg Gln Asp Ile Asp Asp Met

290 295 300

Thr Gln Ile Gly Asp Gln Arg Val Ser Leu Ile Asp Asp Glu Pro Ser

305 310 315 320

Tyr Gly Lys Gly Ser Asp Met Met Tyr Asn Glu Phe Asp Tyr Asp Leu

325 330 335

Cys Asn Glu Val Val Asp Val Thr Cys Ser Pro Lys Pro Asp Ala Phe

340 345 350

Asn Pro Cys Glu Asp Ile Met Gly Tyr Asn Ile Leu Arg Val Leu Ile

355 360 365

Trp Phe Ile Ser Ile Leu Ala Ile Thr Gly Asn Thr Thr Val Leu Val

370 375 380

Val Leu Thr Thr Ser Gln Tyr Lys Leu Thr Val Pro Arg Phe Leu Met

385 390 395 400

Cys Asn Leu Ala Phe Ala Asp Leu Cys Ile Gly Ile Tyr Leu Leu Leu

405 410 415

Ile Ala Ser Val Asp Ile His Thr Lys Ser Gln Tyr His Asn Tyr Ala

420 425 430

Ile Asp Trp Gln Thr Gly Ala Gly Cys Asp Ala Ala Gly Phe Phe Thr

435 440 445

Val Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu Thr Ala Ile Thr Leu

450 455 460

Glu Arg Trp His Thr Ile Thr His Ala Met Gln Leu Glu Cys Lys Val

465 470 475 480

Gln Leu Arg His Ala Ala Ser Val Met Val Leu Gly Trp Thr Phe Ala

485 490 495

Phe Ala Ala Ala Leu Phe Pro Ile Phe Gly Ile Ser Ser Tyr Met Lys

500 505 510

Val Ser Ile Cys Leu Pro Met Asp Ile Asp Ser Pro Leu Ser Gln Leu

515 520 525

Tyr Val Met Ala Leu Leu Val Leu Asn Val Leu Ala Phe Val Val Ile

530 535 540

Cys Gly Cys Tyr Thr His Ile Tyr Leu Thr Val Arg Asn Pro Thr Ile

545 550 555 560

Val Ser Ser Ser Ser Asp Thr Lys Ile Ala Lys Arg Met Ala Thr Leu

565 570 575

Ile Phe Thr Asp Phe Leu Cys Met Ala Pro Ile Ser Phe Phe Ala Ile

580 585 590

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

595 600 605

Leu Leu Val Leu Phe Tyr Pro Ile Asn Ser Cys Ala Asn Pro Phe Leu

610 615 620

Tyr Ala Ile Phe Thr Lys Asn Phe Arg Arg Asp Phe Phe Ile Leu Leu

625 630 635 640

Ser Lys Phe Gly Cys Tyr Glu Met Gln Ala Gln Ile Tyr Arg Thr Glu

645 650 655

Thr Ser Ser Ala Thr His Asn Phe His Ala Arg Lys Ser His Cys Ser

660 665 670

Ser Ala Pro Arg Val Thr Asn Ser Tyr Val Leu Val Pro Leu Asn His

675 680 685

Ser Ser Gln Asn

690

7

636

Homo sapiens

7

Met Lys Gln Arg Phe Ser Ala Leu Gln Leu Leu Lys Leu Leu Leu Leu

1 5 10 15

Leu Gln Pro Pro Leu Pro Arg Ala Leu Arg Glu Ala Leu Cys Pro Glu

20 25 30

Pro Cys Asn Cys Val Pro Asp Gly Ala Leu Arg Cys Pro Gly Pro Thr

35 40 45

Ala Gly Leu Thr Arg Leu Ser Leu Ala Tyr Leu Pro Val Lys Val Ile

50 55 60

Pro Ser Gln Ala Phe Arg Gly Leu Asn Glu Val Ile Lys Ile Glu Ile

65 70 75 80

Ser Gln Ile Asp Ser Leu Glu Arg Ile Glu Ala Asn Ala Phe Asp Asn

85 90 95

Leu Leu Asn Leu Ser Glu Ile Leu Ile Gln Asn Thr Lys Asn Leu Arg

100 105 110

Tyr Ile Glu Pro Gly Ala Phe Ile Asn Leu Pro Gly Leu Lys Tyr Leu

115 120 125

Ser Ile Cys Asn Thr Gly Ile Arg Lys Phe Pro Asp Val Thr Lys Val

130 135 140

Phe Ser Ser Glu Ser Asn Phe Ile Leu Glu Ile Cys Asp Asn Leu His

145 150 155 160

Ile Thr Thr Ile Pro Gly Asn Ala Phe Gln Gly Met Asn Asn Glu Ser

165 170 175

Val Thr Leu Lys Leu Tyr Gly Asn Gly Phe Glu Glu Val Gln Ser His

180 185 190

Ala Phe Asn Gly Thr Thr Leu Thr Ser Leu Glu Leu Lys Glu Asn Val

195 200 205

His Leu Glu Lys Met His Asn Gly Ala Phe Arg Gly Ala Thr Gly Pro

210 215 220

Lys Thr Gln Asn Phe Ser His Ser Ile Ser Glu Asn Phe Ser Lys Gln

225 230 235 240

Cys Glu Ser Thr Val Arg Lys Val Ser Asn Lys Thr Leu Tyr Ser Ser

245 250 255

Met Leu Ala Glu Ser Glu Leu Ser Gly Trp Asp Tyr Glu Tyr Gly Phe

260 265 270

Cys Leu Pro Lys Thr Pro Arg Cys Ala Pro Glu Pro Asp Ala Phe Asn

275 280 285

Pro Cys Glu Asp Ile Met Gly Tyr Asp Phe Leu Arg Val Leu Ile Trp

290 295 300

Leu Ile Asn Ile Leu Ala Ile Met Gly Asn Met Thr Val Leu Phe Val

305 310 315 320

Leu Leu Thr Ser Arg Tyr Lys Leu Thr Val Pro Arg Phe Leu Met Cys

325 330 335

Asn Leu Ser Phe Ala Asp Phe Cys Met Gly Leu Tyr Leu Leu Leu Ile

340 345 350

Ala Ser Val Asp Ser Gln Thr Lys Gly Gln Tyr Tyr Asn His Ala Ile

355 360 365

Asp Trp Gln Thr Gly Ser Gly Cys Ser Thr Ala Gly Phe Phe Thr Val

370 375 380

Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu Thr Val Ile Thr Leu Glu

385 390 395 400

Arg Trp His Thr Ile Thr Tyr Ala Ile His Leu Asp Gln Lys Leu Arg

405 410 415

Leu Arg His Ala Ile Leu Ile Met Leu Gly Gly Trp Leu Phe Ser Ser

420 425 430

Leu Ile Ala Met Leu Pro Leu Val Gly Val Ser Asn Tyr Met Lys Val

435 440 445

Ser Ile Cys Phe Pro Met Asp Val Glu Thr Thr Leu Ser Gln Val Tyr

450 455 460

Ile Leu Thr Ile Leu Ile Leu Asn Val Val Ala Phe Phe Ile Ile Cys

465 470 475 480

Ala Cys Tyr Ile Lys Ile Tyr Phe Ala Val Arg Asn Pro Glu Leu Met

485 490 495

Ala Thr Asn Lys Asp Thr Lys Ile Ala Lys Lys Met Ala Ile Leu Ile

500 505 510

Phe Thr Asp Phe Thr Cys Met Ala Pro Ile Ser Phe Phe Ala Ile Ser

515 520 525

Ala Ala Phe Lys Val Pro Leu Ile Thr Val Thr Asn Ser Lys Val Leu

530 535 540

Leu Val Leu Phe Tyr Pro Ile Asn Ser Cys Ala Asn Pro Phe Leu Tyr

545 550 555 560

Ala Ile Phe Thr Lys Thr Phe Gln Arg Asp Phe Phe Leu Leu Leu Ser

565 570 575

Lys Phe Gly Cys Cys Lys Arg Arg Ala Glu Leu Tyr Arg Arg Lys Asp

580 585 590

Phe Ser Ala Tyr Thr Ser Asn Cys Lys Asn Gly Phe Thr Gly Ser Asn

595 600 605

Lys Pro Ser Gln Ser Thr Leu Lys Leu Ser Thr Leu His Cys Gln Gly

610 615 620

Thr Ala Leu Leu Asp Lys Thr Arg Tyr Thr Glu Cys

625 630 635

8

611

Homo sapiens

8

Arg Glu Ala Leu Cys Pro Glu Pro Cys Asn Cys Val Pro Asp Gly Ala

1 5 10 15

Leu Arg Cys Pro Gly Pro Thr Ala Gly Leu Thr Arg Leu Ser Leu Ala

20 25 30

Tyr Leu Pro Val Lys Val Ile Pro Ser Gln Ala Phe Arg Gly Leu Asn

35 40 45

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

50 55 60

Glu Ala Asn Ala Phe Asp Asn Leu Leu Asn Leu Ser Glu Ile Leu Ile

65 70 75 80

Gln Asn Thr Lys Asn Leu Arg Tyr Ile Glu Pro Gly Ala Phe Ile Asn

85 90 95

Leu Pro Gly Leu Lys Tyr Leu Ser Ile Cys Asn Thr Gly Ile Arg Lys

100 105 110

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

115 120 125

Glu Ile Cys Asp Asn Leu His Ile Thr Thr Ile Pro Gly Asn Ala Phe

130 135 140

Gln Gly Met Asn Asn Glu Ser Val Thr Leu Lys Leu Tyr Gly Asn Gly

145 150 155 160

Phe Glu Glu Val Gln Ser His Ala Phe Asn Gly Thr Thr Leu Thr Ser

165 170 175

Leu Glu Leu Lys Glu Asn Val His Leu Glu Lys Met His Asn Gly Ala

180 185 190

Phe Arg Gly Ala Thr Gly Pro Lys Thr Gln Asn Phe Ser His Ser Ile

195 200 205

Ser Glu Asn Phe Ser Lys Gln Cys Glu Ser Thr Val Arg Lys Val Ser

210 215 220

Asn Lys Thr Leu Tyr Ser Ser Met Leu Ala Glu Ser Glu Leu Ser Gly

225 230 235 240

Trp Asp Tyr Glu Tyr Gly Phe Cys Leu Pro Lys Thr Pro Arg Cys Ala

245 250 255

Pro Glu Pro Asp Ala Phe Asn Pro Cys Glu Asp Ile Met Gly Tyr Asp

260 265 270

Phe Leu Arg Val Leu Ile Trp Leu Ile Asn Ile Leu Ala Ile Met Gly

275 280 285

Asn Met Thr Val Leu Phe Val Leu Leu Thr Ser Arg Tyr Lys Leu Thr

290 295 300

Val Pro Arg Phe Leu Met Cys Asn Leu Ser Phe Ala Asp Phe Cys Met

305 310 315 320

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

325 330 335

Gln Tyr Tyr Asn His Ala Ile Asp Trp Gln Thr Gly Ser Gly Cys Ser

340 345 350

Thr Ala Gly Phe Phe Thr Val Phe Ala Ser Glu Leu Ser Val Tyr Thr

355 360 365

Leu Thr Val Ile Thr Leu Glu Arg Trp His Thr Ile Thr Tyr Ala Ile

370 375 380

His Leu Asp Gln Lys Leu Arg Leu Arg His Ala Ile Leu Ile Met Leu

385 390 395 400

Gly Gly Trp Leu Phe Ser Ser Leu Ile Ala Met Leu Pro Leu Val Gly

405 410 415

Val Ser Asn Tyr Met Lys Val Ser Ile Cys Phe Pro Met Asp Val Glu

420 425 430

Thr Thr Leu Ser Gln Val Tyr Ile Leu Thr Ile Leu Ile Leu Asn Val

435 440 445

Val Ala Phe Phe Ile Ile Cys Ala Cys Tyr Ile Lys Ile Tyr Phe Ala

450 455 460

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

465 470 475 480

Lys Lys Met Ala Ile Leu Ile Phe Thr Asp Phe Thr Cys Met Ala Pro

485 490 495

Ile Ser Phe Phe Ala Ile Ser Ala Ala Phe Lys Val Pro Leu Ile Thr

500 505 510

Val Thr Asn Ser Lys Val Leu Leu Val Leu Phe Tyr Pro Ile Asn Ser

515 520 525

Cys Ala Asn Pro Phe Leu Tyr Ala Ile Phe Thr Lys Thr Phe Gln Arg

530 535 540

Asp Phe Phe Leu Leu Leu Ser Lys Phe Gly Cys Cys Lys Arg Arg Ala

545 550 555 560

Glu Leu Tyr Arg Arg Lys Asp Phe Ser Ala Tyr Thr Ser Asn Cys Lys

565 570 575

Asn Gly Phe Thr Gly Ser Asn Lys Pro Ser Gln Ser Thr Leu Lys Leu

580 585 590

Ser Thr Leu His Cys Gln Gly Thr Ala Leu Leu Asp Lys Thr Arg Tyr

595 600 605

Thr Glu Cys

610

9

cgc gag gcg ctc tgc cct gag ccc tgc aac tgc gtg ccc gac ggc gcc 48

Arg Glu Ala Leu Cys Pro Glu Pro Cys Asn Cys Val Pro Asp Gly Ala

1 5 10 15

ctg cgc tgc ccc ggc ccc acg gcc ggt ctc act cga cta tca ctt gcc 96

Leu Arg Cys Pro Gly Pro Thr Ala Gly Leu Thr Arg Leu Ser Leu Ala

20 25 30

tac ctc cct gtc aaa gtg atc cca tct caa gct ttc aga gga ctt aat 144

Tyr Leu Pro Val Lys Val Ile Pro Ser Gln Ala Phe Arg Gly Leu Asn

35 40 45

gag gtc ata aaa att gaa atc tct cag att gat tcc ctg gaa agg ata 192

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

50 55 60

gaa gct aat gcc ttt gac aac ctc ctc aat ttg tct gaa ata ctg atc 240

Glu Ala Asn Ala Phe Asp Asn Leu Leu Asn Leu Ser Glu Ile Leu Ile

65 70 75 80

cag aac acc aaa aat ctg aga tac att gag ccc gga gca ttt ata aat 288

Gln Asn Thr Lys Asn Leu Arg Tyr Ile Glu Pro Gly Ala Phe Ile Asn

85 90 95

ctt ccc gga tta aaa tac ttg agc atc tgt aac aca ggc atc aga aag 336

Leu Pro Gly Leu Lys Tyr Leu Ser Ile Cys Asn Thr Gly Ile Arg Lys

100 105 110

ttt cca gat gtt acg aag gtc ttc tcc tct gaa tca aat ttc att ctg 384

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

115 120 125

gaa att tgt gat aac tta cac ata acc acc ata cca gga aat gct ttt 432

Glu Ile Cys Asp Asn Leu His Ile Thr Thr Ile Pro Gly Asn Ala Phe

130 135 140

caa ggg atg aat aat gaa tct gta aca ctc aaa cta tat gga aat gga 480

Gln Gly Met Asn Asn Glu Ser Val Thr Leu Lys Leu Tyr Gly Asn Gly

145 150 155 160

ttt gaa gaa gta caa agt cat gca ttc aat ggg acg aca ctg act tca 528

Phe Glu Glu Val Gln Ser His Ala Phe Asn Gly Thr Thr Leu Thr Ser

165 170 175

ctg gag cta aag gaa aac gta cat ctg gag aag atg cac aat gga gcc 576

Leu Glu Leu Lys Glu Asn Val His Leu Glu Lys Met His Asn Gly Ala

180 185 190

ttc cgt ggg gcc aca ggg ccg aaa acc ttg gat att tct tcc acc aaa 624

Phe Arg Gly Ala Thr Gly Pro Lys Thr Leu Asp Ile Ser Ser Thr Lys

195 200 205

ttg cag gcc ctg ccg agc tat ggc cta gag tcc att cag agg cta att 672

Leu Gln Ala Leu Pro Ser Tyr Gly Leu Glu Ser Ile Gln Arg Leu Ile

210 215 220

gcc acg tca tcc tat tct cta aaa aaa ttg cca tca aga gaa aca ttt 720

Ala Thr Ser Ser Tyr Ser Leu Lys Lys Leu Pro Ser Arg Glu Thr Phe

225 230 235 240

gtc aat ctc ctg gag gcc acg ttg act tac ccc agc cac tgc tgt gct 768

Val Asn Leu Leu Glu Ala Thr Leu Thr Tyr Pro Ser His Cys Cys Ala

245 250 255

ttt aga aac ttg cca aca aaa gaa cag aat ttt tca cat tcc att tct 816

Phe Arg Asn Leu Pro Thr Lys Glu Gln Asn Phe Ser His Ser Ile Ser

260 265 270

gaa aac ttt tcc aaa caa tgt gaa agc aca gta agg aaa gtg agt aac 864

Glu Asn Phe Ser Lys Gln Cys Glu Ser Thr Val Arg Lys Val Ser Asn

275 280 285

aaa aca ctt tat tct tcc atg ctt gct gag agt gaa ctg agt ggc tgg 912

Lys Thr Leu Tyr Ser Ser Met Leu Ala Glu Ser Glu Leu Ser Gly Trp

290 295 300

gac tat gaa tat ggt ttc tgc tta ccc aag aca ccc cga tgt gct cct 960

Asp Tyr Glu Tyr Gly Phe Cys Leu Pro Lys Thr Pro Arg Cys Ala Pro

305 310 315 320

gaa cca gat gct ttt aat ccc tgt gaa gac att atg ggc tat gac ttc 1008

Glu Pro Asp Ala Phe Asn Pro Cys Glu Asp Ile Met Gly Tyr Asp Phe

325 330 335

ctt agg gtc ctg att tgg ctg att aat att cta gcc atc atg gga aac 1056

Leu Arg Val Leu Ile Trp Leu Ile Asn Ile Leu Ala Ile Met Gly Asn

340 345 350

atg act gtt ctt ttt gtt ctc ctg aca agt cgt tac aaa ctt aca gtg 1104

Met Thr Val Leu Phe Val Leu Leu Thr Ser Arg Tyr Lys Leu Thr Val

355 360 365

cct cgt ttt ctc atg tgc aat ctc tcc ttt gca gac ttt tgc atg ggg 1152

Pro Arg Phe Leu Met Cys Asn Leu Ser Phe Ala Asp Phe Cys Met Gly

370 375 380

ctc tat ctg ctg ctc ata gcc tca gtt gat tcc caa acc aag ggc cag 1200

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

385 390 395 400

tac tat aac cat gcc ata gac tgg cag aca ggg agt ggg tgc agc act 1248

Tyr Tyr Asn His Ala Ile Asp Trp Gln Thr Gly Ser Gly Cys Ser Thr

405 410 415

gct ggc ttt ttc act gta ttc gca agt gaa ctt tct gtc tac acc ctc 1296

Ala Gly Phe Phe Thr Val Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu

420 425 430

acc gtc atc act cta gaa aga tgg cac acc atc acc tat gct att cac 1344

Thr Val Ile Thr Leu Glu Arg Trp His Thr Ile Thr Tyr Ala Ile His

435 440 445

ctg gac caa aag ctg cga tta aga cat gcc att ctg att atg ctt gga 1392

Leu Asp Gln Lys Leu Arg Leu Arg His Ala Ile Leu Ile Met Leu Gly

450 455 460

gga tgg ctc ttt tct tct cta att gct atg ttg ccc ctt gtc ggt gtc 1440

Gly Trp Leu Phe Ser Ser Leu Ile Ala Met Leu Pro Leu Val Gly Val

465 470 475 480

agc aat tac atg aag gtc agt att tgc ttc ccc atg gat gtg gaa acc 1488

Ser Asn Tyr Met Lys Val Ser Ile Cys Phe Pro Met Asp Val Glu Thr

485 490 495

act ctc tca caa gtc tat ata tta acc atc ctg att ctc aat gtg gtg 1536

Thr Leu Ser Gln Val Tyr Ile Leu Thr Ile Leu Ile Leu Asn Val Val

500 505 510

gcc ttc ttc ata att tgt gct tgc tac att aaa att tat ttt gca gtt 1584

Ala Phe Phe Ile Ile Cys Ala Cys Tyr Ile Lys Ile Tyr Phe Ala Val

515 520 525

cga aac cca gaa tta atg gct acc aat aaa gat aca aag att gct aag 1632

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

530 535 540

aaa atg gca atc ctc atc ttc acc gat ttc acc tgc atg gca cct atc 1680

Lys Met Ala Ile Leu Ile Phe Thr Asp Phe Thr Cys Met Ala Pro Ile

545 550 555 560

tct ttt ttt gcc atc tca gct gcc ttc aaa gta cct ctt atc aca gta 1728

Ser Phe Phe Ala Ile Ser Ala Ala Phe Lys Val Pro Leu Ile Thr Val

565 570 575

acc aac tct aaa gtt tta ctg gtt ctt ttt tat ccc atc aat tct tgt 1776

Thr Asn Ser Lys Val Leu Leu Val Leu Phe Tyr Pro Ile Asn Ser Cys

580 585 590

gcc aat cca ttt ctg tat gca ata ttc act aag aca ttc caa aga gat 1824

Ala Asn Pro Phe Leu Tyr Ala Ile Phe Thr Lys Thr Phe Gln Arg Asp

595 600 605

ttc ttt ctt ttg ctg agc aaa ttt ggc tgc tgt aaa cgt cgg gct gaa 1872

Phe Phe Leu Leu Leu Ser Lys Phe Gly Cys Cys Lys Arg Arg Ala Glu

610 615 620

ctt tat aga agg aaa gat ttt tca gct tac acc tcc aac tgc aaa aat 1920

Leu Tyr Arg Arg Lys Asp Phe Ser Ala Tyr Thr Ser Asn Cys Lys Asn

625 630 635 640

ggc ttc act gga tca aat aag cct tct caa tcc acc ttg aag ttg tcc 1968

Gly Phe Thr Gly Ser Asn Lys Pro Ser Gln Ser Thr Leu Lys Leu Ser

645 650 655

aca ttg cac tgt caa ggt aca gct ctc cta gac aag act cgc tac aca 2016

Thr Leu His Cys Gln Gly Thr Ala Leu Leu Asp Lys Thr Arg Tyr Thr

660 665 670

gag tgt 2022

Glu Cys

10

674

Homo sapiens

10

Arg Glu Ala Leu Cys Pro Glu Pro Cys Asn Cys Val Pro Asp Gly Ala

1 5 10 15

Leu Arg Cys Pro Gly Pro Thr Ala Gly Leu Thr Arg Leu Ser Leu Ala

20 25 30

Tyr Leu Pro Val Lys Val Ile Pro Ser Gln Ala Phe Arg Gly Leu Asn

35 40 45

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

50 55 60

Glu Ala Asn Ala Phe Asp Asn Leu Leu Asn Leu Ser Glu Ile Leu Ile

65 70 75 80

Gln Asn Thr Lys Asn Leu Arg Tyr Ile Glu Pro Gly Ala Phe Ile Asn

85 90 95

Leu Pro Gly Leu Lys Tyr Leu Ser Ile Cys Asn Thr Gly Ile Arg Lys

100 105 110

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

115 120 125

Glu Ile Cys Asp Asn Leu His Ile Thr Thr Ile Pro Gly Asn Ala Phe

130 135 140

Gln Gly Met Asn Asn Glu Ser Val Thr Leu Lys Leu Tyr Gly Asn Gly

145 150 155 160

Phe Glu Glu Val Gln Ser His Ala Phe Asn Gly Thr Thr Leu Thr Ser

165 170 175

Leu Glu Leu Lys Glu Asn Val His Leu Glu Lys Met His Asn Gly Ala

180 185 190

Phe Arg Gly Ala Thr Gly Pro Lys Thr Leu Asp Ile Ser Ser Thr Lys

195 200 205

Leu Gln Ala Leu Pro Ser Tyr Gly Leu Glu Ser Ile Gln Arg Leu Ile

210 215 220

Ala Thr Ser Ser Tyr Ser Leu Lys Lys Leu Pro Ser Arg Glu Thr Phe

225 230 235 240

Val Asn Leu Leu Glu Ala Thr Leu Thr Tyr Pro Ser His Cys Cys Ala

245 250 255

Phe Arg Asn Leu Pro Thr Lys Glu Gln Asn Phe Ser His Ser Ile Ser

260 265 270

Glu Asn Phe Ser Lys Gln Cys Glu Ser Thr Val Arg Lys Val Ser Asn

275 280 285

Lys Thr Leu Tyr Ser Ser Met Leu Ala Glu Ser Glu Leu Ser Gly Trp

290 295 300

Asp Tyr Glu Tyr Gly Phe Cys Leu Pro Lys Thr Pro Arg Cys Ala Pro

305 310 315 320

Glu Pro Asp Ala Phe Asn Pro Cys Glu Asp Ile Met Gly Tyr Asp Phe

325 330 335

Leu Arg Val Leu Ile Trp Leu Ile Asn Ile Leu Ala Ile Met Gly Asn

340 345 350

Met Thr Val Leu Phe Val Leu Leu Thr Ser Arg Tyr Lys Leu Thr Val

355 360 365

Pro Arg Phe Leu Met Cys Asn Leu Ser Phe Ala Asp Phe Cys Met Gly

370 375 380

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

385 390 395 400

Tyr Tyr Asn His Ala Ile Asp Trp Gln Thr Gly Ser Gly Cys Ser Thr

405 410 415

Ala Gly Phe Phe Thr Val Phe Ala Ser Glu Leu Ser Val Tyr Thr Leu

420 425 430

Thr Val Ile Thr Leu Glu Arg Trp His Thr Ile Thr Tyr Ala Ile His

435 440 445

Leu Asp Gln Lys Leu Arg Leu Arg His Ala Ile Leu Ile Met Leu Gly

450 455 460

Gly Trp Leu Phe Ser Ser Leu Ile Ala Met Leu Pro Leu Val Gly Val

465 470 475 480

Ser Asn Tyr Met Lys Val Ser Ile Cys Phe Pro Met Asp Val Glu Thr

485 490 495

Thr Leu Ser Gln Val Tyr Ile Leu Thr Ile Leu Ile Leu Asn Val Val

500 505 510

Ala Phe Phe Ile Ile Cys Ala Cys Tyr Ile Lys Ile Tyr Phe Ala Val

515 520 525

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

530 535 540

Lys Met Ala Ile Leu Ile Phe Thr Asp Phe Thr Cys Met Ala Pro Ile

545 550 555 560

Ser Phe Phe Ala Ile Ser Ala Ala Phe Lys Val Pro Leu Ile Thr Val

565 570 575

Thr Asn Ser Lys Val Leu Leu Val Leu Phe Tyr Pro Ile Asn Ser Cys

580 585 590

Ala Asn Pro Phe Leu Tyr Ala Ile Phe Thr Lys Thr Phe Gln Arg Asp

595 600 605

Phe Phe Leu Leu Leu Ser Lys Phe Gly Cys Cys Lys Arg Arg Ala Glu

610 615 620

Leu Tyr Arg Arg Lys Asp Phe Ser Ala Tyr Thr Ser Asn Cys Lys Asn

625 630 635 640

Gly Phe Thr Gly Ser Asn Lys Pro Ser Gln Ser Thr Leu Lys Leu Ser

645 650 655

Thr Leu His Cys Gln Gly Thr Ala Leu Leu Asp Lys Thr Arg Tyr Thr

660 665 670

Glu Cys

11

2799

Homo sapiens

11

atgaagcagc ggttctcggc gctgcagctg ctgaagctgc tgctgctgct gcagccgccg 60

ctgccacgag cgctgcgcga ggcgctctgc cctgagccct gcaactgcgt gcccgacggc 120

gccctgcgct gccccggccc cacggccggt ctcactcgac tatcacttgc ctacctccct 180

gtcaaagtga tcccatctca agctttcaga ggacttaatg aggtcataaa aattgaaatc 240

tctcagattg attccctgga aaggatagaa gctaatgcct ttgacaacct cctcaatttg 300

tctgaaatac tgatccagaa caccaaaaat ctgagataca ttgagcccgg agcatttata 360

aatcttcccg gattaaaata cttgagcatc tgtaacacag gcatcagaaa gtttccagat 420

gttacgaagg tcttctcctc tgaatcaaat ttcattctgg aaatttgtga taacttacac 480

ataaccacca taccaggaaa tgcttttcaa gggatgaata atgaatctgt aacactcaaa 540

ctatatggaa atggatttga agaagtacaa agtcatgcat tcaatgggac gacactgact 600

tcactggagc taaaggaaaa cgtacatctg gagaagatgc acaatggagc cttccgtggg 660

gccacagggc cgaaaaccac agaatttttc acattccatt tctgaaaact tttccaaaca 720

atgtgaaagc acagtaagga aagtgagtaa caaaacactt tattcttcca tgcttgctga 780

gagtgaactg agtggctggg actatgaata tggtttctgc ttacccaaga caccccgatg 840

tgctcctgaa ccagatgctt ttaatccctg tgaagacatt atgggctatg acttccttag 900

ggtcctgatt tggctgatta atattctagc catcatggga aacatgactg ttctttttgt 960

tctcctgaca agtcgttaca aacttacagt gcctcgtttt ctcatgtgca atctctcctt 1020

tgcagacttt tgcatggggc tctatctgct gctcatagcc tcagttgatt cccaaaccaa 1080

gggccagtac tataaccatg ccatagactg gcagacaggg agtgggtgca gcactgctgg 1140

ctttttcact gtattcgcaa gtgaactttc tgtctacacc ctcaccgtca tcactctaga 1200

aagatggcac accatcacct atgctattca cctggaccaa aagctgcgat taagacatgc 1260

cattctgatt atgcttggag gatggctctt ttcttctcta attgctatgt tgccccttgt 1320

cggtgtcagc aattacatga aggtcagtat ttgcttcccc atggatgtgg aaaccactct 1380

ctcacaagtc tatatattaa ccatcctgat tctcaatgtg gtggccttct tcataatttg 1440

tgcttgctac attaaaattt attttgcagt tcgaaaccca gaattaatgg ctaccaataa 1500

agatacaaag attgctaaga aaatggcaat cctcatcttc accgatttca cctgcatggc 1560

acctatctct ttttttgcca tctcagctgc cttcaaagta cctcttatca cagtaaccaa 1620

ctctaaagtt ttactggttc ttttttatcc catcaattct tgtgccaatc catttctgta 1680

tgcaatattc actaagacat tccaaagaga tttctttctt ttgctgagca aatttggctg 1740

ctgtaaacgt cgggctgaac tttatagaag gaaagatttt tcagcttaca cctccaactg 1800

caaaaatggc ttcactggat caaataagcc ttctcaatcc accttgaagt tgtccacatt 1860

gcactgtcaa ggtacagctc tcctagacaa gactcgctac acagagtgtt aactgttaca 1920

tcagtaactg cattattgaa ttgttcttaa acctgtaaaa aaaaattacc tgtaccagta 1980

attttaacat aaagggttgg atttaggaaa ttatttattt ttaggtacat taggcaagag 2040

acctctacct agtagaaagt gtagtctatg accactgcca cacgtaaaaa ctatttgtca 2100

ttgttacatg gcataaatat gaagttgaga gtgtttagaa atttttatag aaattttgac 2160

acagtaattt tgtttgatga atcttttaaa aaacagagga ggtattttgc atatcttttt 2220

ttcattttcg taatttgtat tgcattctat aaaaatatta gttcataaca gatcagaaat 2280

ttaaaataag gggctttttc ctcaggtagt ttgaaaaaca cactctagag atgcactgtt 2340

caattcggta cgcactagcc acatgtggct aaattaaaat taaataaaat gagaaatgta 2400

gtttctcagt tgcactacgt ttcaagttct caatggctac gtcaagttct caatggctac 2460

gtgtgactag tgcttaccat actggacagc acagacacag aatattttca tcaccacaga 2520

aagttctatc tgttctatta tagagacttt tatgtatgcc ctatctggat tctacttatt 2580

tataatttaa ggtaaacatc tgaaagcaca tttcagccta tttgcttagt gaaacattaa 2640

gctgtagact gtaaactcct cgtgagtagg aaccctgtct cagtgcattt tgttttcctg 2700

cttcctacct caagatcttg gcaatggtac actacaaatg tgctgagtta gaattactct 2760

gaagttatga aacatataat gaaaacaatt tttccggcc 2799

12

2912

Homo sapiens

12

cgcgaggcgc tctgccctga gccctgcaac tgcgtgcccg acggcgccct gcgctgcccc 60

ggccccacgg ccggtctcac tcgactatca cttgcctacc tccctgtcaa agtgatccca 120

tctcaagctt tcagaggact taatgaggtc ataaaaattg aaatctctca gattgattcc 180

ctggaaagga tagaagctaa tgcctttgac aacctcctca atttgtctga aatactgatc 240

cagaacacca aaaatctgag atacattgag cccggagcat ttataaatct tcccggatta 300

aaatacttga gcatctgtaa cacaggcatc agaaagtttc cagatgttac gaaggtcttc 360

tcctctgaat caaatttcat tctggaaatt tgtgataact tacacataac caccatacca 420

ggaaatgctt ttcaagggat gaataatgaa tctgtaacac tcaaactata tggaaatgga 480

tttgaagaag tacaaagtca tgcattcaat gggacgacac tgacttcact ggagctaaag 540

gaaaacgtac atctggagaa gatgcacaat ggagccttcc gtggggccac agggccgaaa 600

accttggata tttcttccac caaattgcag gccctgccga gctatggcct agagtccatt 660

cagaggctaa ttgccacgtc atcctattct ctaaaaaaat tgccatcaag agaaacattt 720

gtcaatctcc tggaggccac gttgacttac cccagccact gctgtgcttt tagaaacttg 780

ccaacaaaag aacagaattt ttcacattcc atttctgaaa acttttccaa acaatgtgaa 840

agcacagtaa ggaaagtgag taacaaaaca ctttattctt ccatgcttgc tgagagtgaa 900

ctgagtggct gggactatga atatggtttc tgcttaccca agacaccccg atgtgctcct 960

gaaccagatg cttttaatcc ctgtgaagac attatgggct atgacttcct tagggtcctg 1020

atttggctga ttaatattct agccatcatg ggaaacatga ctgttctttt tgttctcctg 1080

acaagtcgtt acaaacttac agtgcctcgt tttctcatgt gcaatctctc ctttgcagac 1140

ttttgcatgg ggctctatct gctgctcata gcctcagttg attcccaaac caagggccag 1200

tactataacc atgccataga ctggcagaca gggagtgggt gcagcactgc tggctttttc 1260

actgtattcg caagtgaact ttctgtctac accctcaccg tcatcactct agaaagatgg 1320

cacaccatca cctatgctat tcacctggac caaaagctgc gattaagaca tgccattctg 1380

attatgcttg gaggatggct cttttcttct ctaattgcta tgttgcccct tgtcggtgtc 1440

agcaattaca tgaaggtcag tatttgcttc cccatggatg tggaaaccac tctctcacaa 1500

gtctatatat taaccatcct gattctcaat gtggtggcct tcttcataat ttgtgcttgc 1560

tacattaaaa tttattttgc agttcgaaac ccagaattaa tggctaccaa taaagataca 1620

aagattgcta agaaaatggc aatcctcatc ttcaccgatt tcacctgcat ggcacctatc 1680

tctttttttg ccatctcagc tgccttcaaa gtacctctta tcacagtaac caactctaaa 1740

gttttactgg ttctttttta tcccatcaat tcttgtgcca atccatttct gtatgcaata 1800

ttcactaaga cattccaaag agatttcttt cttttgctga gcaaatttgg ctgctgtaaa 1860

cgtcgggctg aactttatag aaggaaagat ttttcagctt acacctccaa ctgcaaaaat 1920

ggcttcactg gatcaaataa gccttctcaa tccaccttga agttgtccac attgcactgt 1980

caaggtacag ctctcctaga caagactcgc tacacagagt gttaactgtt acatcagtaa 2040

ctgcattatt gaattgttct taaacctgta aaaaaaaatt acctgtacca gtaattttaa 2100

cataaagggt tggatttagg aaattattta tttttaggta cattaggcaa gagacctcta 2160

cctagtagaa agtgtagtct atgaccactg ccacacgtaa aaactatttg tcattgttac 2220

atggcataaa tatgaagttg agagtgttta gaaattttta tagaaatttt gacacagtaa 2280

ttttgtttga tgaatctttt aaaaaacaga ggaggtattt tgcatatctt tttttcattt 2340

tcgtaatttg tattgcattc tataaaaata ttagttcata acagatcaga aatttaaaat 2400

aaggggcttt ttcctcaggt agtttgaaaa acacactcta gagatgcact gttcaattcg 2460

gtacgcacta gccacatgtg gctaaattaa aattaaataa aatgagaaat gtagtttctc 2520

agttgcacta cgtttcaagt tctcaatggc tacgtcaagt tctcaatggc tacgtgtgac 2580

tagtgcttac catactggac agcacagaca cagaatattt tcatcaccac agaaagttct 2640

atctgttcta ttatagagac ttttatgtat gccctatctg gattctactt atttataatt 2700

taaggtaaac atctgaaagc acatttcagc ctatttgctt agtgaaacat taagctgtag 2760

actgtaaact cctcgtgagt aggaaccctg tctcagtgca ttttgttttc ctgcttccta 2820

cctcaagatc ttggcaatgg tacactacaa atgtgctgag ttagaattac tctgaagtta 2880

tgaaacatat aatgaaaaca atttttccgg cc 2912

13

2724

Homo sapiens

13

cgcgaggcgc tctgccctga gccctgcaac tgcgtgcccg acggcgccct gcgctgcccc 60

ggccccacgg ccggtctcac tcgactatca cttgcctacc tccctgtcaa agtgatccca 120

tctcaagctt tcagaggact taatgaggtc ataaaaattg aaatctctca gattgattcc 180

ctggaaagga tagaagctaa tgcctttgac aacctcctca atttgtctga aatactgatc 240

cagaacacca aaaatctgag atacattgag cccggagcat ttataaatct tcccggatta 300

aaatacttga gcatctgtaa cacaggcatc agaaagtttc cagatgttac gaaggtcttc 360

tcctctgaat caaatttcat tctggaaatt tgtgataact tacacataac caccatacca 420

ggaaatgctt ttcaagggat gaataatgaa tctgtaacac tcaaactata tggaaatgga 480

tttgaagaag tacaaagtca tgcattcaat gggacgacac tgacttcact ggagctaaag 540

gaaaacgtac atctggagaa gatgcacaat ggagccttcc gtggggccac agggccgaaa 600

accacagaat ttttcacatt ccatttctga aaacttttcc aaacaatgtg aaagcacagt 660

aaggaaagtg agtaacaaaa cactttattc ttccatgctt gctgagagtg aactgagtgg 720

ctgggactat gaatatggtt tctgcttacc caagacaccc cgatgtgctc ctgaaccaga 780

tgcttttaat ccctgtgaag acattatggg ctatgacttc cttagggtcc tgatttggct 840

gattaatatt ctagccatca tgggaaacat gactgttctt tttgttctcc tgacaagtcg 900

ttacaaactt acagtgcctc gttttctcat gtgcaatctc tcctttgcag acttttgcat 960

ggggctctat ctgctgctca tagcctcagt tgattcccaa accaagggcc agtactataa 1020

ccatgccata gactggcaga cagggagtgg gtgcagcact gctggctttt tcactgtatt 1080

cgcaagtgaa ctttctgtct acaccctcac cgtcatcact ctagaaagat ggcacaccat 1140

cacctatgct attcacctgg accaaaagct gcgattaaga catgccattc tgattatgct 1200

tggaggatgg ctcttttctt ctctaattgc tatgttgccc cttgtcggtg tcagcaatta 1260

catgaaggtc agtatttgct tccccatgga tgtggaaacc actctctcac aagtctatat 1320

attaaccatc ctgattctca atgtggtggc cttcttcata atttgtgctt gctacattaa 1380

aatttatttt gcagttcgaa acccagaatt aatggctacc aataaagata caaagattgc 1440

taagaaaatg gcaatcctca tcttcaccga tttcacctgc atggcaccta tctctttttt 1500

tgccatctca gctgccttca aagtacctct tatcacagta accaactcta aagttttact 1560

ggttcttttt tatcccatca attcttgtgc caatccattt ctgtatgcaa tattcactaa 1620

gacattccaa agagatttct ttcttttgct gagcaaattt ggctgctgta aacgtcgggc 1680

tgaactttat agaaggaaag atttttcagc ttacacctcc aactgcaaaa atggcttcac 1740

tggatcaaat aagccttctc aatccacctt gaagttgtcc acattgcact gtcaaggtac 1800

agctctccta gacaagactc gctacacaga gtgttaactg ttacatcagt aactgcatta 1860

ttgaattgtt cttaaacctg taaaaaaaaa ttacctgtac cagtaatttt aacataaagg 1920

gttggattta ggaaattatt tatttttagg tacattaggc aagagacctc tacctagtag 1980

aaagtgtagt ctatgaccac tgccacacgt aaaaactatt tgtcattgtt acatggcata 2040

aatatgaagt tgagagtgtt tagaaatttt tatagaaatt ttgacacagt aattttgttt 2100

gatgaatctt ttaaaaaaca gaggaggtat tttgcatatc tttttttcat tttcgtaatt 2160

tgtattgcat tctataaaaa tattagttca taacagatca gaaatttaaa ataaggggct 2220

ttttcctcag gtagtttgaa aaacacactc tagagatgca ctgttcaatt cggtacgcac 2280

tagccacatg tggctaaatt aaaattaaat aaaatgagaa atgtagtttc tcagttgcac 2340

tacgtttcaa gttctcaatg gctacgtcaa gttctcaatg gctacgtgtg actagtgctt 2400

accatactgg acagcacaga cacagaatat tttcatcacc acagaaagtt ctatctgttc 2460

tattatagag acttttatgt atgccctatc tggattctac ttatttataa tttaaggtaa 2520

acatctgaaa gcacatttca gcctatttgc ttagtgaaac attaagctgt agactgtaaa 2580

ctcctcgtga gtaggaaccc tgtctcagtg cattttgttt tcctgcttcc tacctcaaga 2640

tcttggcaat ggtacactac aaatgtgctg agttagaatt actctgaagt tatgaaacat 2700

ataatgaaaa caatttttcc ggcc 2724

14

2097

Homo sapiens

14

atgaagcagc ggttctcggc gctgcagctg ctgaagctgc tgctgctgct gcagccgccg 60

ctgccacgag cgctgcgcga ggcgctctgc cctgagccct gcaactgcgt gcccgacggc 120

gccctgcgct gccccggccc cacggccggt ctcactcgac tatcacttgc ctacctccct 180

gtcaaagtga tcccatctca agctttcaga ggacttaatg aggtcataaa aattgaaatc 240

tctcagattg attccctgga aaggatagaa gctaatgcct ttgacaacct cctcaatttg 300

tctgaaatac tgatccagaa caccaaaaat ctgagataca ttgagcccgg agcatttata 360

aatcttcccg gattaaaata cttgagcatc tgtaacacag gcatcagaaa gtttccagat 420

gttacgaagg tcttctcctc tgaatcaaat ttcattctgg aaatttgtga taacttacac 480

ataaccacca taccaggaaa tgcttttcaa gggatgaata atgaatctgt aacactcaaa 540

ctatatggaa atggatttga agaagtacaa agtcatgcat tcaatgggac gacactgact 600

tcactggagc taaaggaaaa cgtacatctg gagaagatgc acaatggagc cttccgtggg 660

gccacagggc cgaaaacctt ggatatttct tccaccaaat tgcaggccct gccgagctat 720

ggcctagagt ccattcagag gctaattgcc acgtcatcct attctctaaa aaaattgcca 780

tcaagagaaa catttgtcaa tctcctggag gccacgttga cttaccccag ccactgctgt 840

gcttttagaa acttgccaac aaaagaacag aatttttcac attccatttc tgaaaacttt 900

tccaaacaat gtgaaagcac agtaaggaaa gtgagtaaca aaacacttta ttcttccatg 960

cttgctgaga gtgaactgag tggctgggac tatgaatatg gtttctgctt acccaagaca 1020

ccccgatgtg ctcctgaacc agatgctttt aatccctgtg aagacattat gggctatgac 1080

ttccttaggg tcctgatttg gctgattaat attctagcca tcatgggaaa catgactgtt 1140

ctttttgttc tcctgacaag tcgttacaaa cttacagtgc ctcgttttct catgtgcaat 1200

ctctcctttg cagacttttg catggggctc tatctgctgc tcatagcctc agttgattcc 1260

caaaccaagg gccagtacta taaccatgcc atagactggc agacagggag tgggtgcagc 1320

actgctggct ttttcactgt attcgcaagt gaactttctg tctacaccct caccgtcatc 1380

actctagaaa gatggcacac catcacctat gctattcacc tggaccaaaa gctgcgatta 1440

agacatgcca ttctgattat gcttggagga tggctctttt cttctctaat tgctatgttg 1500

ccccttgtcg gtgtcagcaa ttacatgaag gtcagtattt gcttccccat ggatgtggaa 1560

accactctct cacaagtcta tatattaacc atcctgattc tcaatgtggt ggccttcttc 1620

ataatttgtg cttgctacat taaaatttat tttgcagttc gaaacccaga attaatggct 1680

accaataaag atacaaagat tgctaagaaa atggcaatcc tcatcttcac cgatttcacc 1740

tgcatggcac ctatctcttt ttttgccatc tcagctgcct tcaaagtacc tcttatcaca 1800

gtaaccaact ctaaagtttt actggttctt ttttatccca tcaattcttg tgccaatcca 1860

tttctgtatg caatattcac taagacattc caaagagatt tctttctttt gctgagcaaa 1920

tttggctgct gtaaacgtcg ggctgaactt tatagaagga aagatttttc agcttacacc 1980

tccaactgca aaaatggctt cactggatca aataagcctt ctcaatccac cttgaagttg 2040

tccacattgc actgtcaagg tacagctctc ctagacaaga ctcgctacac agagtgt 2097

15

2022

Homo sapiens

15

cgcgaggcgc tctgccctga gccctgcaac tgcgtgcccg acggcgccct gcgctgcccc 60

ggccccacgg ccggtctcac tcgactatca cttgcctacc tccctgtcaa agtgatccca 120

tctcaagctt tcagaggact taatgaggtc ataaaaattg aaatctctca gattgattcc 180

ctggaaagga tagaagctaa tgcctttgac aacctcctca atttgtctga aatactgatc 240

cagaacacca aaaatctgag atacattgag cccggagcat ttataaatct tcccggatta 300

aaatacttga gcatctgtaa cacaggcatc agaaagtttc cagatgttac gaaggtcttc 360

tcctctgaat caaatttcat tctggaaatt tgtgataact tacacataac caccatacca 420

ggaaatgctt ttcaagggat gaataatgaa tctgtaacac tcaaactata tggaaatgga 480

tttgaagaag tacaaagtca tgcattcaat gggacgacac tgacttcact ggagctaaag 540

gaaaacgtac atctggagaa gatgcacaat ggagccttcc gtggggccac agggccgaaa 600

accttggata tttcttccac caaattgcag gccctgccga gctatggcct agagtccatt 660

cagaggctaa ttgccacgtc atcctattct ctaaaaaaat tgccatcaag agaaacattt 720

gtcaatctcc tggaggccac gttgacttac cccagccact gctgtgcttt tagaaacttg 780

ccaacaaaag aacagaattt ttcacattcc atttctgaaa acttttccaa acaatgtgaa 840

agcacagtaa ggaaagtgag taacaaaaca ctttattctt ccatgcttgc tgagagtgaa 900

ctgagtggct gggactatga atatggtttc tgcttaccca agacaccccg atgtgctcct 960

gaaccagatg cttttaatcc ctgtgaagac attatgggct atgacttcct tagggtcctg 1020

atttggctga ttaatattct agccatcatg ggaaacatga ctgttctttt tgttctcctg 1080

acaagtcgtt acaaacttac agtgcctcgt tttctcatgt gcaatctctc ctttgcagac 1140

ttttgcatgg ggctctatct gctgctcata gcctcagttg attcccaaac caagggccag 1200

tactataacc atgccataga ctggcagaca gggagtgggt gcagcactgc tggctttttc 1260

actgtattcg caagtgaact ttctgtctac accctcaccg tcatcactct agaaagatgg 1320

cacaccatca cctatgctat tcacctggac caaaagctgc gattaagaca tgccattctg 1380

attatgcttg gaggatggct cttttcttct ctaattgcta tgttgcccct tgtcggtgtc 1440

agcaattaca tgaaggtcag tatttgcttc cccatggatg tggaaaccac tctctcacaa 1500

gtctatatat taaccatcct gattctcaat gtggtggcct tcttcataat ttgtgcttgc 1560

tacattaaaa tttattttgc agttcgaaac ccagaattaa tggctaccaa taaagataca 1620

aagattgcta agaaaatggc aatcctcatc ttcaccgatt tcacctgcat ggcacctatc 1680

tctttttttg ccatctcagc tgccttcaaa gtacctctta tcacagtaac caactctaaa 1740

gttttactgg ttctttttta tcccatcaat tcttgtgcca atccatttct gtatgcaata 1800

ttcactaaga cattccaaag agatttcttt cttttgctga gcaaatttgg ctgctgtaaa 1860

cgtcgggctg aactttatag aaggaaagat ttttcagctt acacctccaa ctgcaaaaat 1920

ggcttcactg gatcaaataa gccttctcaa tccaccttga agttgtccac attgcactgt 1980

caaggtacag ctctcctaga caagactcgc tacacagagt gt 2022

16

1909

Homo sapiens

16

atgaagcagc ggttctcggc gctgcagctg ctgaagctgc tgctgctgct gcagccgccg 60

ctgccacgag cgctgcgcga ggcgctctgc cctgagccct gcaactgcgt gcccgacggc 120

gccctgcgct gccccggccc cacggccggt ctcactcgac tatcacttgc ctacctccct 180

gtcaaagtga tcccatctca agctttcaga ggacttaatg aggtcataaa aattgaaatc 240

tctcagattg attccctgga aaggatagaa gctaatgcct ttgacaacct cctcaatttg 300

tctgaaatac tgatccagaa caccaaaaat ctgagataca ttgagcccgg agcatttata 360

aatcttcccg gattaaaata cttgagcatc tgtaacacag gcatcagaaa gtttccagat 420

gttacgaagg tcttctcctc tgaatcaaat ttcattctgg aaatttgtga taacttacac 480

ataaccacca taccaggaaa tgcttttcaa gggatgaata atgaatctgt aacactcaaa 540

ctatatggaa atggatttga agaagtacaa agtcatgcat tcaatgggac gacactgact 600

tcactggagc taaaggaaaa cgtacatctg gagaagatgc acaatggagc cttccgtggg 660

gccacagggc cgaaaaccac agaatttttc acattccatt tctgaaaact tttccaaaca 720

atgtgaaagc acagtaagga aagtgagtaa caaaacactt tattcttcca tgcttgctga 780

gagtgaactg agtggctggg actatgaata tggtttctgc ttacccaaga caccccgatg 840

tgctcctgaa ccagatgctt ttaatccctg tgaagacatt atgggctatg acttccttag 900

ggtcctgatt tggctgatta atattctagc catcatggga aacatgactg ttctttttgt 960

tctcctgaca agtcgttaca aacttacagt gcctcgtttt ctcatgtgca atctctcctt 1020

tgcagacttt tgcatggggc tctatctgct gctcatagcc tcagttgatt cccaaaccaa 1080

gggccagtac tataaccatg ccatagactg gcagacaggg agtgggtgca gcactgctgg 1140

ctttttcact gtattcgcaa gtgaactttc tgtctacacc ctcaccgtca tcactctaga 1200

aagatggcac accatcacct atgctattca cctggaccaa aagctgcgat taagacatgc 1260

cattctgatt atgcttggag gatggctctt ttcttctcta attgctatgt tgccccttgt 1320

cggtgtcagc aattacatga aggtcagtat ttgcttcccc atggatgtgg aaaccactct 1380

ctcacaagtc tatatattaa ccatcctgat tctcaatgtg gtggccttct tcataatttg 1440

tgcttgctac attaaaattt attttgcagt tcgaaaccca gaattaatgg ctaccaataa 1500

agatacaaag attgctaaga aaatggcaat cctcatcttc accgatttca cctgcatggc 1560

acctatctct ttttttgcca tctcagctgc cttcaaagta cctcttatca cagtaaccaa 1620

ctctaaagtt ttactggttc ttttttatcc catcaattct tgtgccaatc catttctgta 1680

tgcaatattc actaagacat tccaaagaga tttctttctt ttgctgagca aatttggctg 1740

ctgtaaacgt cgggctgaac tttatagaag gaaagatttt tcagcttaca cctccaactg 1800

caaaaatggc ttcactggat caaataagcc ttctcaatcc accttgaagt tgtccacatt 1860

gcactgtcaa ggtacagctc tcctagacaa gactcgctac acagagtgt 1909

17

1834

Homo sapiens

17

cgcgaggcgc tctgccctga gccctgcaac tgcgtgcccg acggcgccct gcgctgcccc 60

ggccccacgg ccggtctcac tcgactatca cttgcctacc tccctgtcaa agtgatccca 120

tctcaagctt tcagaggact taatgaggtc ataaaaattg aaatctctca gattgattcc 180

ctggaaagga tagaagctaa tgcctttgac aacctcctca atttgtctga aatactgatc 240

cagaacacca aaaatctgag atacattgag cccggagcat ttataaatct tcccggatta 300

aaatacttga gcatctgtaa cacaggcatc agaaagtttc cagatgttac gaaggtcttc 360

tcctctgaat caaatttcat tctggaaatt tgtgataact tacacataac caccatacca 420

ggaaatgctt ttcaagggat gaataatgaa tctgtaacac tcaaactata tggaaatgga 480

tttgaagaag tacaaagtca tgcattcaat gggacgacac tgacttcact ggagctaaag 540

gaaaacgtac atctggagaa gatgcacaat ggagccttcc gtggggccac agggccgaaa 600

accacagaat ttttcacatt ccatttctga aaacttttcc aaacaatgtg aaagcacagt 660

aaggaaagtg agtaacaaaa cactttattc ttccatgctt gctgagagtg aactgagtgg 720

ctgggactat gaatatggtt tctgcttacc caagacaccc cgatgtgctc ctgaaccaga 780

tgcttttaat ccctgtgaag acattatggg ctatgacttc cttagggtcc tgatttggct 840

gattaatatt ctagccatca tgggaaacat gactgttctt tttgttctcc tgacaagtcg 900

ttacaaactt acagtgcctc gttttctcat gtgcaatctc tcctttgcag acttttgcat 960

ggggctctat ctgctgctca tagcctcagt tgattcccaa accaagggcc agtactataa 1020

ccatgccata gactggcaga cagggagtgg gtgcagcact gctggctttt tcactgtatt 1080

cgcaagtgaa ctttctgtct acaccctcac cgtcatcact ctagaaagat ggcacaccat 1140

cacctatgct attcacctgg accaaaagct gcgattaaga catgccattc tgattatgct 1200

tggaggatgg ctcttttctt ctctaattgc tatgttgccc cttgtcggtg tcagcaatta 1260

catgaaggtc agtatttgct tccccatgga tgtggaaacc actctctcac aagtctatat 1320

attaaccatc ctgattctca atgtggtggc cttcttcata atttgtgctt gctacattaa 1380

aatttatttt gcagttcgaa acccagaatt aatggctacc aataaagata caaagattgc 1440

taagaaaatg gcaatcctca tcttcaccga tttcacctgc atggcaccta tctctttttt 1500

tgccatctca gctgccttca aagtacctct tatcacagta accaactcta aagttttact 1560

ggttcttttt tatcccatca attcttgtgc caatccattt ctgtatgcaa tattcactaa 1620

gacattccaa agagatttct ttcttttgct gagcaaattt ggctgctgta aacgtcgggc 1680

tgaactttat agaaggaaag atttttcagc ttacacctcc aactgcaaaa atggcttcac 1740

tggatcaaat aagccttctc aatccacctt gaagttgtcc acattgcact gtcaaggtac 1800

agctctccta gacaagactc gctacacaga gtgt 1834