The evolution of the immunoglobulin heavy chain variable region (IgV H ) in Leporids: an unusual case of transspecies polymorphism

In domestic rabbit (Oryctolagus cuniculus), three serological types have been distinguished at the variable domain of the antibody H chain, the so-called V _H a allotypes a1, a2, and a3. They correspond to highly divergent allelic lineages of the V _H 1 gene, which is the gene rabbit utilizes in more than 80% of VDJ rearrangements. The sharing of serological V _H a markers between rabbit and snowshoe hare (Lepus americanus) has suggested that the large genetic distances between rabbit V _H 1 alleles (9–14% nucleotide differences) can be explained by unusually long lineage persistence times (transspecies polymorphism). Because this interpretation of the serological data is uncertain, we have determined the nucleotide sequences of V _H genes expressed in specimens of Lepus species. Two sequence groups were distinguished, one of which occurred only in hare specimen displaying serological motifs of the rabbit V _H a-a2 allotype. Sequences of this group are part of a monophyletic cluster containing the V _H 1 sequences of the rabbit a2 allotype. The fact that this “transspecies a2 cluster” did not include genes of other rabbit V _H a allotypes (a1, a3, and a4) is incompatible with the existence of a common V _H a ancestor gene within the species, and suggests that the divergence of the V _H a lineages preceded the Lepus vs Oryctolagus split. The sequence data are furthermore compatible with the hypothesis that the V _H a polymorphism can be two times older than the divergence time between the Lepus and Oryctolagus lineages, which was estimated at 16–24 million years.