Genome-wide detection and characterization of positive selection in human populations

Abstract

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

Figure 1. Localizing SLC24A5 and EDAR signals of selection

a–d, SLC24A5. a, Strong evidence for positive selection in CEU samples at a chromosome 15 locus: XP-EHH between CEU and JPT + CHB (blue), CEU and YRI (red), and YRI and JPT + CHB (grey). SNPs are classified as having low probability (bordered diamonds) and high probability (filled diamonds) potential for function. SNPs were filtered to identify likely targets of selection on the basis of the frequency of derived alleles (b), differences between populations (c) and differences between populations for high-frequency derived alleles (less than 20% in non-selected populations) (d). The number of SNPs that passed each filter is given in the top left corner in red. The threonine to alanine candidate polymorphism in SLC24A5 is the clear outlier. e–h, EDAR. e, Similar evidence for positive selection in JPT + CHB at a chromosome 2 locus: XP-EHH between CEU and JPT + CHB (blue), between YRI and JPT + CHB (red), and between CEU and YRI (grey); iHS in JPT + CHB (green). A valine to alanine polymorphism in EDAR passes all filters: the frequency of derived alleles (f), differences between populations (g) and differences between populations for high-frequency derived alleles (less than 20% in non-selected populations) (h). Three other functional changes, a D→E change in SULT1C2 and two SNPs associated with RANBP2 expression (Methods), have also become common in the selected population.

Figure 2. Global distribution of SLC24A5 A111T and EDAR V370A

Worldwide allele-frequency distributions for candidate polymorphisms with the strongest evidence for selection. a, SLC24A5 A111T is common in Europe, Northern Africa and Pakistan, but rare or absent elsewhere. b, EDAR V370A is common in Asia and the Americas, but absent in Europe and Africa.

Figure 3. Structural model of the EDAR death domain

Ribbon representation of a homology model of the EDAR death domain (DD), based on the alignment of the EDAR DD amino acid sequence (EDAR residues 356–431), with multiple known DD structures. The helices are labelled H1 to H6. Residues in blue (the H1–H2 and H5–H6 loops, residues 370–376 and 419–425, respectively) correspond to the homologous residues in Tube that interact with Pelle in the Tube-DD–Pelle-DD structure. These EDAR-DD residues therefore form a potential region of interaction with a DD-containing EDAR-interacting protein, such as EDARADD. The V370A polymorphic residue (red) is located prominently within this potential binding region in the H1–H2 loop. Seven of the thirteen known mis-sense mutations in EDAR that lead to hypohidrotic ectodermal dysplasia (HED) in humans are located in the EDAR-DD: the only four mutations in EDAR that lead to the dominant transmission of HED (green) and three recessive mutations (yellow). Four of these mutations, R375H, L377F, R420Q and I418T are located in the vicinity of the predicted interaction interface.