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.

Figure 1.—

Map of the world showing the location of sampled populations. The numbers identifying populations are given in Table 1.

Figure 2.—

Steps taken to make CDP and HLA data sets comparable.

Figure 3.—

Scatterplots of heterozygosity values for six HLA loci. The population numbers correspond to those in Table 1.

Figure 4.—

Distribution of variance components over 377 CDP microsatellite loci. Values are averages over 1000 replicate population resamplings (according to population assignments to regions as described in the Table 3 legend). (Top) Variance components for CDP data using the HLA class I composition of populations among regions, among populations within regions, and within populations; (bottom) variance components for CDP data using the HLA class II composition of populations among regions, among populations within regions, and within populations. The vertical lines indicate the values for the variance components for each of the HLA loci.

Figure 5.—

Genetic differentiation measured by D = −ln(1 − F_ST) between all pairs of populations for (a) HLA-A vs. HLA-B, (b) HLA-B vs. HLA-C, (c) HLA-A vs. HLA-C, and (d) DRB1 vs. DQB1. Solid circles are comparisons between populations from the same region; open circles are for populations from different regions. The dotted line represents the values for which D is the same for both loci; the solid and dashed lines are best-fit linear regressions for differentiation at the two loci between and within regions, respectively.

Figure 6.—

LD by geographic region. D′, W_n, and CF (the fraction of complementary haplotypes) are described in Methods. Population numbers correspond to those in Table 1.

Figure 7.—

LD [W_n* = log(W_n/(1 − W_n)] vs. geographic distance from East Africa (following the routes proposed by Prugnolle et al. 2005a). The size of the data points is proportional to the weights used in the regression model for W_n*. The dotted line in the plot for A:C in the bottom left corresponds to the regression line after removing the outlying Guarani–Nandewa population.