Evolution of the recombination signal sequences in the Ig heavy-chain variable region locus of mammals

The Ig and T cell receptor (TCR) loci have an exceptionally dynamic evoluti onary history, but the mechanisms responsible remain a subject of speculati on. Ig and TCR genes are unique in vertebrates in that they are assembled f rom V, D, and J segments by site-specific recombination in developing lymph ocytes. Here we examine the extent to which the V(D)J recombination in germ line cells may have been responsible for remodeling Ig and TCR loci in mamm als by asking whether gene segments have evolved as a unit, or whether, ins tead, recombination signal sequences (RSSs) and coding sequences have diffe rent phylogenies, Four distinct types of Rss have been defined in the human Ig heavy-chain variable region (VH) locus, namely H1, H2, H3, and H5, and no other RSS type has been detected in other mammalian species. There is a well-supported discrepancy between the evolutionary history of the RSSs as compared with the VH coding sequences: the RSS type HZ of one VH gene segme nt has clearly become replaced by a 855 type H3 during mammalian evolution, between 115 and 65 million years ago. Two general models might explain the 855 swap: the first involves an unequal crossing over, and the second impl icates germline activation of V(D)J recombination. The VH-H2/RSS-H3 recombi nation product has likely been selected during the evolution of mammals bec ause it provides better V(D)J recombination efficiency.