Transgenic mouse homozygous for chimeric IgH locus

A transgenic mouse whose genome comprises a homozygous chimeric immunoglobulin heavy chain (IgH) locus comprising unrearranged human IgH variable region gene segments positioned within an endogenous mouse heavy chain IgH locus upstream of an enhancer and a constant (C) region comprising an endogenous CH gene segment;nwherein said human variable region gene segments in said chimeric IgH locus are operably linked to said C region at a human/mouse chimeric junction;wherein said homozygous chimeric IgH locus comprises in 5⬲ to 3⬲ transcriptional orientation:n(i) unrearranged human immunoglobulin heavy chain (IgH) variable region (VH) DNA comprising one or more human IgH V gene segments, one or more human D gene segments DH and human JH gene segments comprising a human JH6 gene segment,(ii) a chimeric J/C intron comprising human JC intronic DNA contiguous with said human JH6 gene segment and mouse JC intronic DNA, and wherein said human DNA joins said mouse JC intronic DNA at said human/mouse chimeric junction upstream of the enhancer, and(iii) said enhancer and said C region,wherein said human JH6 is less than 1 kb upstream of said chimeric junction,wherein DNA between said chimeric junction and said enhancer comprises mouse 129 strain JC intronic DNA;wherein said enhancer is a mouse 129 strain μ enhancer;wherein said transgenic mouse is functional to form rearranged human VH DH and JH gene segments and to express mRNA transcripts encoding chimeric immunoglobulin heavy chain polypeptide comprising a human VH region and a mouse C region, and wherein said transgenic mouse is capable, upon stimulation with antigen, of producing an antibody comprising a chimeric Ig heavy chain comprising a human IgH variable region and said C region; andwherein the genome of said transgenic mouse comprises all or part of the endogenous mouse IgH variable region, and is capable of breeding to produce subsequent generation mice having in their germline an IgH locus comprising unrearranged human IgH variable region gene segments positioned upstream of an IgH constant (C) region comprising an endogenous C gene segment of an IgH locus.