Evolutionary relationship of HLA-DRB genes inferred from intron sequences

The major histocompatibility complex (Mhc) consists of class I and class II genes. In the human Mhc (HLA) class II genes, nine DRB loci have been identified. To elucidate the origin of these duplicated loci and allelic divergences at the most polymorphic DRB1 locus, introns 4 and 5 as well as the 3' untranslated region (altogether approximately 1,000 base pairs) of seven HLA-DRB loci, three HLA-DRB1 alleles, and nine nonhuman primate DRB genes were examined. It is shown that there were two major diversification events in HLA-DRB genes, each involving gene duplications and allelic divergences. Approximately 50 million years (my) ago, DRB1 *04 and an ancestor of the DRB1 *03 cluster (DRB1*03, DRB1*15, and DRB3) diverged from each other and DRB5, DRB7, DRB8, and an ancestor of the DRB2 cluster (DRB2, DRB4, and DRB6) arose by gene duplication. Later, about 25 my ago, DRB1*15 diverged from DRB1*03, and DRB3 was duplicated from DRB1*03. Then, some 20 my ago, the lineage leading to the DRB2 cluster produced two new loci, DRB4 and DRB6. The DRB1*03 and DRB1*04 allelic lineages are extraordinarily old and have persisted longer than some duplicated genes. The orthologous relationships of DRB genes between human and Old World monkeys are apparent, but those between Catarrhini and New World monkeys are equivocal because of a rather rapid expansion and contraction of primate DRB genes by duplication and deletion.