PMID- 23065702 OWN - NLM STAT- MEDLINE DCOM- 20130617 LR - 20211021 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 22 IP - 2 DP - 2013 Jan 15 TI - A sequence-based approach demonstrates that balancing selection in classical human leukocyte antigen (HLA) loci is asymmetric. PG - 252-61 LID - 10.1093/hmg/dds424 [doi] AB - Balancing selection has maintained human leukocyte antigen (HLA) allele diversity, but it is unclear whether this selection is symmetric (all heterozygotes are comparable and all homozygotes are comparable in terms of fitness) or asymmetric (distinct heterozygote genotypes display greater fitness than others). We tested the hypothesis that HLA is under asymmetric balancing selection in populations by estimating allelic branch lengths from genetic sequence data encoding peptide-binding domains. Significant deviations indicated changes in the ratio of terminal to internal branch lengths. Such deviations could arise even if no individual alleles present a strikingly altered branch length (e.g. if there is an overall distortion, with all or many terminal branches being longer than expected). DQ and DP loci were also analyzed as haplotypes. Using allele frequencies for 419 distinct populations in 10 geographical regions, we examined population differentiation in alleles within and between regions, and the relationship between allelic branch length and frequency. The strongest evidence for asymmetrical balancing selection was observed for HLA-DRB1, HLA-B and HLA-DPA1, with significant deviation (P