Fifty-million-year-old polymorphism at an immunoglobulin variable region gene locus in the rabbit evolutionary lineage

The Ig heavy chain variable region (V-H) genes encode the antigen binding r egions of antibodies, The rabbit genome contains more than 100 V-H genes, b ut only one (V(H)1) is preferentially used in the VDJ gene rearrangement, T hree highly divergent alleles occur at this V(H)1 locus in most rabbit popu lations. These three VH alleles are also present in snowshoe hare populatio ns, indicating that the polymorphism of the V(H)1 alleles is trans-specific . Here we report the results of a phylogenetic analysis of rabbit Ig germ-l ine V-H genes (alleles) together with VH genes from humans and mice. We hav e found that all rabbit VII genes belong to one mammalian VN group (group C ), which also includes various human and mouse VH genes. Using the rate of nucleotide substitution obtained from human and mouse V-H sequences, we hav e estimated that the V(H)1 polymorphism in the rabbit lineage has been main tained for about 50 million years. This extremely long persistence of VH1 p olymorphism is apparently caused by overdominant selection, though the real mechanism is unclear.