Multiplication of Mhc-DRB5 loci in the orangutan: implications for the evolution of DRB haplotypes

The β chain-encoding (B) class II genes of the primate major histocompatibility complex belong to several families. The DRB family of class II genes is distinguished by the occurrence of haplotype polymorphism-the existence of multiple chromosomal forms differing in length, gene number, and gene combinations, each form occurring at an appreciable frequency in the population. Some of the haplotypes, or fragments thereof, are shared by humans, chimpanzees, and gorillas. In an effort to follow the DRB haplotype polymorphism further back in time, we constructed DRB contig maps of the two chromosomes present in the orangutan cell line CP81. Two types of genes were found in the two haplotypes, Popy-DRB5 and Popy-DRB1^*03, the former occurring in two copies and one gene fragment in each haplotype, so that the CP81 cell line contains four complete DRB5 genes and two DRB5 fragments altogether. Since the four genes are more closely related to one another than they are to other DRB5 genes, they must have arisen from a single ancestral copy by multiple duplications. At the same time, however, the two CP81 haplotypes differ considerably in their restriction enzyme sites and in the presence of Alu elements at different positions, indicating that they have been separated for a length of time that exceeds the lifespan of a primate species. Moreover, a segment of about 100 kilobase pairs is shared between the orangutan CP81-1 and the human HLA-DR2 haplotype. These findings indicate that part of the haplotype polymorphism may have persisted for more than 13 million years, which is the estimated time of human-orangutan divergence.