Natural Selection on HLA-DPB1 Amino Acids Operates Primarily on DP Serologic Categories

The DPB1 locus is notable among the classical HLA loci in that allele frequencies at this locus are consistent with genetic drift, whereas the frequencies of specific DPβ amino acids are consistent with the action of balancing selection. We investigated the influence of natural selection in shaping the diversity of three functional categories of DPB1 diversity defined by specific amino acid motifs, DPB1 T-cell epitopes, DPB1 supertypes and DP1-DP4 serologic categories (SCs), via Ewens-Watterson (EW) selective neutrality and asymmetric Linkage Disequilibrium (ALD) analyses in a worldwide sample of 136 populations. These EW analyses provide strong evidence for the operation of balancing selection on DP SCs, but no evidence for balancing selection on T-cell epitopes or supertypes. We further investigated the global distribution of SCs. Each SC is common in a different region of the world, with the DP1 SC most common in Southeast Asia and Oceania, the DP2 SC in North and South America, the DP3 SC in South America, and the DP4 SC in Europe. The DP2 SC is present in all populations, while 14% of populations are missing at least one DP1, DP3, or DP4 SC. We observed consistent DPA1∼DP SC haplotype associations across 10 populations from five global regions, and found that asymmetric linkage disequilibrium (LD) between the DPB1 locus and the four most-common DPA1 alleles (DPA1*01:03, *02:01, *02:02 and *03:01) is determined by variation at DPβ AA positions 85-87. These positions are in LD with both DPα positions 31 and 50. We conclude from these EW analyses that natural selection is primarily operating to maintain population-level diversity of DP SCs, rather than DPB1 alleles or other functional categories of DPB1 diversity.