Evolution of HLA class II molecules: Allelic and amino acid site variability across populations

Analysis of the highly polymorphic beta 1 domains of the HLA class II molec ules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele f requency distributions, based on Watterson's homozygosity statistic F, reve al distinct evolutionary patterns for these loci in ethnically diverse samp les (26 populations for DQB1 and DRB2 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balance d polymorphism (P < 10(-4)), DRB1 shows some evidence of balancing selectio n (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over po lymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutr ality expectations, and both exhibit more balanced polymorphic amino acid s ites than DRB1. Across ethnic groups, polymorphisms at many codons show evi dence for balancing selection, yet data consistent with directional selecti on were observed at other codons. Both antigen-binding pocket- and non-pock et-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference bet ween pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic ami no acid residues, and that in many cases this selection is consistent acros s populations.