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 (~194,000 females and ~167,000 males) to identify a total of 114,199 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 (2.6%) 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 (2.73-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 differences 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.
Digital Object Identifier (DOI)
This work was funded by the National Institutes of Health (NIH) grant R01-GM115656 (to G.H.P.); NIH grant F32-GM123634 (to K.E.G.); Deutsche Forschungsgemeinschaft (DFG) grant FOR-22337 (to A.M.A, M.G, H.R.C., and G.H.P.); and Erickson Discovery (https://urfm.psu.edu/research/erickson-discovery-grant), Presidential Leadership Academy Enrichment (https://academy.psu.edu/current/grants/), and Liberal Arts Enrichment grants (https://la.psu.edu/current-students/undergraduate-students/scholarships-and-funding/enrichment-funding) from Penn State University (to A.M.A).
All data files are available in the Dryad Digital Repository: https://doi.org/10.5061/dryad.nzs7h44rc.
Arner, Audrey M.; Grogan, Kathleen E.; Grabowski, Mark; Reyes-Centeno, Hugo; and Perry, George H., "Patterns of Recent Natural Selection on Genetic Loci Associated with Sexually Differentiated Human Body Size and Shape Phenotypes" (2021). Anthropology Faculty Publications. 26.
S1 Fig. Permutation enrichment distribution at each FDR threshold. https://doi.org/10.1371/journal.pgen.1009562.s001
pgen.1009562.s002.tif (9194 kB)
S2 Fig. Sex-specific iHS scores for anthropometric SexDiff and phenotype-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s002
pgen.1009562.s003.docx (16 kB)
S1 Table. Observed number of SexDiff-associated SNPs at each FDR threshold for every phenotype. aRatio of SexDiff-associated SNPs at the FDR threshold of 0.001 to the number of phenotype-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s003
pgen.1009562.s004.docx (17 kB)
S2 Table. Observed unique sexual differentiation genes (SDG) and total number of genes for SexDiff-associated SNPs and Non SexDiff-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s004
pgen.1009562.s005.docx (17 kB)
S3 Table. Observed log2 ratio of female to male beta values and p-values for each set of Female SexDiff-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s005
pgen.1009562.s006.docx (17 kB)
S4 Table. Observed log2 ratio of female to male beta values and p-values for each set of Male SexDiff-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s006
pgen.1009562.s007.docx (17 kB)
S5 Table. Observed trait-SDS and permutation P-values for each set of Female SexDiff-associated SNPs and Male SexDiff-associated SNPs permuted against phenotype-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s007
pgen.1009562.s008.docx (17 kB)
S6 Table. Observed trait-SDS and permutation P-values for each set of Female SexDiff-associated SNPs and Male SexDiff-associated SNPs permuted against phenotype-associated SNPs matched for minor allele frequency. https://doi.org/10.1371/journal.pgen.1009562.s008
pgen.1009562.s009.docx (17 kB)
S7 Table. Observed average |iHS| scores and permutation P-values for each set of Female SexDiff-associated SNPs and Male SexDiff-associated SNPs permuted against phenotype-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s009
pgen.1009562.s010.docx (17 kB)
S8 Table. Observed number of intergenic SNPs and permutation P-values for each set of Female SexDiff-associated SNPs and Male SexDiff-associated SNPs permuted against phenotype-associated SNPs. https://doi.org/10.1371/journal.pgen.1009562.s010
pgen.1009562.s011.docx (16 kB)
S9 Table. Phenotype information. https://doi.org/10.1371/journal.pgen.1009562.s011
pgen.1009562.s012.docx (16 kB)
S10 Table. Observed trait-SDS for each set of pruned phenotype-associated SNP groups. https://doi.org/10.1371/journal.pgen.1009562.s012