Recent positive selection of a human androgen receptor/ectodysplasin A2 receptor haplotype and its relationship to male pattern baldness

Abstract

Genetic variants in the human androgen receptor gene (AR) are associated with male pattern baldness (androgenetic alopecia, AGA) in Europeans. Previous observations of long-range linkage disequilibrium at the AR locus are consistent with the hypothesis of recent positive selection. Here, we further investigate this signature and its relationship to the AGA risk haplotype. The haplotype homozygosity suggests that the AGA risk haplotype was driven to high frequency by positive selection in Europeans although a low meiotic recombination rate contributed to the high haplotype homozygosity. Further, we find high levels of population differentiation as measured by F(ST) and a series of fixed derived alleles along an extended region centromeric to AR in the Asian HapMap sample. The predominant AGA risk haplotype also carries the putatively functional variant 57K in the flanking ectodysplasin A2 receptor gene (EDA2R). It is therefore probable that the AGA risk haplotype rose to high frequency in combination with this EDA2R variant, possibly by hitchhiking on a positively selected 57K haplotype.

Fig. 1

AR promoter haplotype frequency, bifurcation, EHH, and REHH in the European population. Phased HapMap data was analyzed using Sweep software. a Haplotypes with frequencies >5% are shown. The three core haplotypes are numbered 1–3 and are colored to match the colors in parts b–e. The ancestral alleles were determined using the chimpanzee sequence. Positions that carry the ancestral allele are represented by dot and in cases where t he ancestral allele could not be determined, the nucleotides carried by each haplotype are indicated in light gray. Freq, frequency. b Haplotype bifurcation plots of the three core haplotypes depict recombination events, and therefore the breakdown of LD, on each common AR promoter haplotype. The thickness of the line represents the frequency of each haplotype. Bifurcation occurs when haplotype homozygosity breaks down. c Relative gene positions (boxes) and analyzed SNPs (gray vertical lines) are shown; SNPs for core haplotypes are in blue, non-synonymous SNP rs1385699 is in red. d Plots of decay of EHH and REHH (e) for increasing distances from AR for each common haplotype are shown

Fig. 2

The distribution of EHH values by allele frequency distribution across the X chromosome in Europeans. EHH was calculated at 0.5 cM distances on both sides of all possible core haplotypes from European X chromosome HapMap data. EHH of the AR core haplotype toward the centromere (EHH = 0.793; REHH = 2.751) and telomere (EHH = 0.308; REHH = 0.513) are shown. Points outside the shaded areas have EHH values within the top 5% of the empirical distribution

Fig. 3

Average F _ST values calculated from the HapMap data for 200 kb windows across the X chromosome. Population pairwise comparisons and the three way comparison are presented. 95 and 99% thresholds are indicated by dotted lines. The shaded region indicates the genomic region surrounding AR, which is shown in detail in the shaded box in the top right of each plot. In the shaded boxes, each dot represents the F _ST value for a 200 kb window. The 200 kb window containing AR is represented by a solid dot and the F _ST value for this window and its P value are given in a box in each plot