Patterns of recent natural selection on genetic loci associated with sexually differentiated human body size and shape phenotypes

Levels of sex differences for human body size and shape phenotypes are
hypothesized to have adaptively reduced following the agricultural
transition as part of an evolutionary response to relatively more equal
divisions of labor and new technology adoption. In this study, we tested
this hypothesis by studying genetic variants associated with five sexually
differentiated human phenotypes: height, body mass, hip circumference,
body fat percentage, and waist circumference. We first analyzed
genome-wide association (GWAS) results for UK Biobank individuals
(~197,000 females and ~167,000 males) to identify a total of 119,023
single nucleotide polymorphisms (SNPs) significantly associated with at
least one of the studied phenotypes in females, males, or both sexes
(P<5x10-8). From these loci we then identified 3,016 SNPs (2.5%)
with significant differences in the strength of association between the
female- and male-specific GWAS results at a low false-discovery rate
(FDR<0.001). Genes with known roles in sexual differentiation are
significantly enriched for co-localization with one or more of these SNPs
versus SNPs associated with the phenotypes generally but not with sex
differences (2.93-fold enrichment; permutation test; P=0.0041). We also
confirmed that the identified variants are disproportionately associated
with greater phenotype effect sizes in the sex with the stronger
association value. We then used the singleton density score statistic,
which quantifies recent (within the last ~3,000 years; post-agriculture
adoption in Britain) changes in the frequencies of alleles underlying
polygenic traits, to identify a signature of recent positive selection on
alleles associated with greater body fat percentage in females
(permutation test; P=0.0038; FDR=0.0380), directionally opposite to that
predicted by the sex differentiation reduction hypothesis. Otherwise, we
found no evidence of positive selection for sex difference-associated
alleles for any other trait. Overall, our results challenge the
longstanding hypothesis that sex differences adaptively decreased
following subsistence transitions from hunting and gathering to
agriculture.