Human Genetics

, 126:255

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

Authors

    • Department of Genomics, Life and Brain CenterUniversity of Bonn
    • Genome Institute of SingaporeAgency for Science, Technology and Research (A*STAR)
    • Genome Technology and Biology GroupGenome Institute of Singapore
  • Jan Freudenberg
    • Center for Genomics and Human Genetics, Feinstein Institute for Medical ResearchNorthshore-LIJ Healthsystem
  • Sean Myles
    • Institute for Genomic DiversityCornell University
  • Stefan Herms
    • Department of Genomics, Life and Brain CenterUniversity of Bonn
  • Kun Tang
    • Department of Evolutionary GeneticsMax Planck Institute for Evolutionary Anthropology
  • David A. Hughes
    • Department of Evolutionary GeneticsMax Planck Institute for Evolutionary Anthropology
  • Felix F. Brockschmidt
    • Department of Genomics, Life and Brain CenterUniversity of Bonn
  • Yijun Ruan
    • Genome Institute of SingaporeAgency for Science, Technology and Research (A*STAR)
  • Mark Stoneking
    • Department of Evolutionary GeneticsMax Planck Institute for Evolutionary Anthropology
  • Markus M. Nöthen
    • Department of Genomics, Life and Brain CenterUniversity of Bonn
    • Institute of Human GeneticsUniversity of Bonn
Original Investigation

DOI: 10.1007/s00439-009-0668-z

Cite this article as:
Hillmer, A.M., Freudenberg, J., Myles, S. et al. Hum Genet (2009) 126: 255. doi:10.1007/s00439-009-0668-z

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 FST 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.

Supplementary material

439_2009_668_MOESM1_ESM.eps (11.9 mb)
AR promoter haplotype frequency, bifurcation, EHH and REHH in the African population. Phased HapMap data was analyzed using Sweep software. (a) Haplotypes with frequencies >5% are shown. The six core haplotypes are numbered 1-6 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 “.” and in cases where the 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 six 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. (d) Plots of decay of EHH and REHH (e) for increasing distances from AR for each common haplotype are shown (EPS 12219 kb)
439_2009_668_MOESM2_ESM.eps (2.8 mb)
AR promoter haplotype frequency, bifurcation, EHH and REHH in the East Asian 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. 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. (d) Plots of decay of EHH and REHH (e) for increasing distances from AR for each common haplotype are shown (EPS 2836 kb)
439_2009_668_MOESM3_ESM.pdf (1.5 mb)
LD plots of the AR locus of the three HapMap populations. (a) Genes are represented by horizontal black bars and transcript orientations are illustrated by arrows. (b) - (d) LD was visualized using Haploview software. LD is indicated as shades of pink and red for LOD ≥ 2 and D’ < 1, bright red for LOD ≥ 2 and D’ = 1, white for LOD < 2 and D’ < 1, and blue for LOD < 2 and D’ = 1. The haplotype block definitions of Gabriel et al. (2002) were used and haplotype blocks are indicated by black triangles (PDF 1544 kb)
439_2009_668_MOESM4_ESM.eps (1.7 mb)
Derived-allele frequencies of the AR locus for the three HapMap populations. Genotype data were downloaded from the HapMap home page and derived alleles were defined by comparison to chimpanzee alleles using Sweep software (EPS 1708 kb)
439_2009_668_MOESM5_ESM.eps (298 kb)
Distribution of recombination rates for 1 Mb windows across the human genome based on the Decode genetic map (Kong et al. 2002) (EPS 298 kb)
439_2009_668_MOESM6_ESM.doc (54 kb)
Supplementary material 6 (DOC 54 kb)

Copyright information

© The Author(s) 2009