MHC-DRB ALLELIC SEQUENCES INCORPORATE DISTINCT INTRAGENIC TRANS-SPECIFIC SEGMENTS

The second exon of primate MHC-DRB genes encodes discrete areas of all elic hypervariability (HVR), which are used as the basis for lineage a ssignments to determine genetic and evolutionary relationships. Compar isons of these regions have led to the ''trans-species hypothesis'', w hich proposes that certain MHC alleles from one species are more close ly related to those from other species than they are to each other; i. e., that allelic lineages are ancestral in origin. We evaluated this p aradigm in an analysis of macaque and baboon MHC-DRB genes using oligo typing and sequencing of 87 new nonhuman primate DRB alleles. A remark able 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 di verged from the human lineage 50 MYA. However, these fixed HVRIII moti f sequences nevertheless occur on a background of diverse lineages sug gesting that it is the segmental motif, rather than the allele per se which is trans-specific in origin. Sequences within the first hypervar iable region (codons 7-14) identified lineage assignments to several D RB loci (DRB1, DRB3, DRB4, DRB5, DRB6 and DRB7), although a large numb er 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 subse quent to speciation. While there are certain allelic lineages in HVRI that show trans-species conservation, other sequence motifs seem purel y species-specific. These differences suggest that HVRI and HVRIII reg ions have distinct mechanisms for maintenance of trans-specific sequen ce elements, with different evolutionary histories for segmental nucle otide conservation.