MHC-DRB allelic sequences incorporate distinct intragenic trans-specific segments

The second exon of primate MHC-DRB genes encodes discrete areas of allelic hypervariability (HVR), which are used as the basis for lineage assignments to determine genetic and evolutionary relationships. Comparisons of these regions have led to the "trans-species hypothesis", which proposes that certain MHC alleles from one species are more closely related to those from other species than they are to each other; i.e., that allelic lineages are ancestral in origin. We evaluated this paradigm in an analysis of macaque and baboon MHC-DRB genes using oligotyping and sequencing of 87 new nonhuman primate DRB alleles. A remarkable conservation of sequence motifs in the HVRIII region (codon 60-79) was observed, detected both by hybridization and by sequencing; some of these motifs were found in species such as prosimians that have diverged from the human lineage 50 MYA. However, these fixed HVRIII motif sequences nevertheless occur on a background of diverse lineages suggesting that it is the segmental motif, rather than the allele per se which is trans-specific in origin. Sequences within the first hypervariable region (codons 7-14) identified lineage assignments to several DRB loci (DRB1, DRB3, DRB4, DRB5, DRB6 and DRB7), although a large number of DRB nucleotide sequences did not correspond to a defined allelic motif, suggesting that many of the nonhuman sequences lack human HVRI homologs and have accumulated additional intraspecies variation subsequent to speciation. While there are certain allelic lineages in HVRI that show trans-species conservation, other sequence motifs seem purely species-specific. These differences suggest that HVRI and HVRIII regions have distinct mechanisms for maintenance of trans-specific sequence elements, with different evolutionary histories for segmental nucleotide conservation.