Signatures of Demographic History and Natural Selection in the Human Major Histocompatibility Complex Loci

Abstract

Many lines of evidence show that several HLA loci have experienced balancing selection. However, distinguishing among demographic and selective explanations for patterns of variation observed with HLA genes remains a challenge. In this study we address this issue using data from a diverse set of human populations at six classical HLA loci and, employing a comparative genomics approach, contrast results for HLA loci to those for non-HLA markers. Using a variety of analytic methods, we confirm and extend evidence for selection acting on several HLA loci. We find that allele frequency distributions for four of the six HLA loci deviate from neutral expectations and show that this is unlikely to be explained solely by demographic factors. Other features of HLA variation are explained in part by demographic history, including decreased heterozygosity and increased LD for populations at greater distances from Africa and a similar apportionment of genetic variation for HLA loci compared to putatively neutral non-HLA loci. On the basis of contrasts among different HLA loci and between HLA and non-HLA loci, we conclude that HLA loci bear detectable signatures of both natural selection and demographic history.

Balancing selection and heterogeneity across the classical human leukocyte antigen loci: A meta-analytic review of 497 population studies

“…The EW homozygosity test of neutrality has proven to be a useful tool for detecting selection at HLA loci [3,7,209,218,219,[222][223][224][225][226][227][228][229][230][231], making it an appropriate method for these metaanalyses. This meta analysis reveals an extremely strong signal of balancing selection at DQA1, HLA-C, and DQB1.…”

“…The 497 population samples were carefully screened for duplications (i.e., the same individuals represented in two datasets), but some populations are represented by more than one sample (e.g., at the HLA-B locus, there are five different samples of the Japanese population.) Each population data file was annotated with a three-letter abbreviation assigning it to one of the 10 world regions shown in Figure 1 [3,13]: Sub-Saharan Africa (SSA), North Africa (NAF), Europe (EUR), Southwest Asia (SWA), Southeast Asia (SEA), Oceania (OCE), Australia (AUS), Northeast Asia (NEA), North America (NAM), South America (SAM) . These regional assignments were based on the origin of the population, in effect ignoring the last 1000 years of known human migration (e.g., people of European descent in the United States are assigned to the region EUR).…”

“…Population-level studies of HLA allelic diversity have provided insight into the selective forces that have acted to generate and maintain polymorphism in the human species [2,3]. Historical and evolutionary relationships among modern human populations have been inferred from comparisons of HLA allele and haplotype frequency distributions [4][5][6][7].…”

“…Historical and evolutionary relationships among modern human populations have been inferred from comparisons of HLA allele and haplotype frequency distributions [4][5][6][7]. Further, variation in the allelic diversity between populations, as well as comparisons of linkage disequilibrium (LD) patterns across the HLA region, have been used to infer demographic events such as bottlenecks and founder events [3,8]. Finally, differences in allele and haplotype frequencies between populations belonging to different ethnic groups have been used to better understand associations between HLA and disease, in some cases illuminating mechanisms of disease progression and resistance [9,10] and in other cases identifying the actual disease-predisposing locus due to high LD [11,12].…”

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype

“…The difference in allele distribution among different ethnic groups may be shaped by selective and demographic history. 5 It is well known that there is a strong linkage disequilibrium (LD) among alleles of genes in HLA locus, and combination of these alleles in LD form specific haplotypes. 6 Owing to the functional significance of classical HLA genes, the MHC haplotypes have been defined by using classical HLA alleles as highly polymorphic markers, and the HLA haplotypes served as a model system for high-resolution mapping of disease susceptibility genes, 7 evolution 8 and population structure.…”