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

Citation

Arner, Audrey M. et al. (2021), Patterns of recent natural selection on genetic loci associated with sexually differentiated human body size and shape phenotypes, Dryad, Dataset, https://doi.org/10.5061/dryad.nzs7h44rc

Abstract

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. 

Usage Notes

AllPhenotypeSNPs.txt
This file contains information on all phenotype-associated SNPs. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) ancestral allele, 6) derived allele,  7) male-specific beta value, 8) male-specific p-value, 9) male-specific trait-SDS, 10) female-specific beta value, 11) female-specific p-value, 12) female-specific trait-SDS, 13) t-SexDiff statistic, 14) p-value calculated from t-SexDiff, 15) false discovery rate of p-value calculated from t-SexDiff. 

PrunedPhenotypeSNPs.txt
This file contains information on each of the pruned phenotype-associated SNPs. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) ancestral allele, 6) derived allele,  7) male-specific beta value, 8) male-specific p-value, 9) male-specific trait-SDS, 10) female-specific beta value, 11) female-specific p-value, 12) female-specific trait-SDS, 13) t-SexDiff statistic, 14) p-value calculated from t-SexDiff, 15) false discovery rate of p-value calculated from t-SexDiff. 

AllSexDiffSNPs.txt
This file contains information on all SexDiff-associated SNPs. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) ancestral allele, 6) derived allele,  7) male-specific beta value, 8) male-specific p-value, 9) male-specific trait-SDS, 10) female-specific beta value, 11) female-specific p-value, 12) female-specific trait-SDS, 13) t-SexDiff statistic, 14) p-value calculated from t-SexDiff, 15) false discovery rate of p-value calculated from t-SexDiff. 

PrunedSexDiffSNPs.txt
This file contains information on each of the pruned SexDiff-associated SNPs. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) ancestral allele, 6) derived allele,  7) male-specific beta value, 8) male-specific p-value, 9) male-specific trait-SDS, 10) female-specific beta value, 11) female-specific p-value, 12) female-specific trait-SDS, 13) t-SexDiff statistic, 14) p-value calculated from t-SexDiff, 15) false discovery rate of p-value calculated from t-SexDiff. 

FemaleBodyFatPercentSexDiffSNPs.txt
Information on pruned female body fat percentage SexDiff-associated SNPs. This file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) ancestral allele, 5) derived allele, 6) male-specific beta value, 7) male-specific p-value, 8) male-specific trait-SDS, 9) female-specific beta value, 10) female-specific p-value, 11) female-specific trait-SDS, 12) t-SexDiff statistic, 13) p-value calculated from t-SexDiff, 14) false discovery rate of p-value calculated from t-SexDiff.

AllGenesGRCh37.txt
This file contains the genes with GO terms we used in our enrichment analysis. The file is tab delimited. The first row is a header, with columns corresponding to 1) chromosome, 2) base pair position of the start of the gene, 3) base pair position of the end of the gene, 4) gene name, 5) ten thousand base pairs before the start of the gene, 6) ten thousand base pairs before then end of the gene.

GOSexDifferenceGRCh37.txt
This file contains the sexual differentiation GO term genes we used in our enrichment analysis. The file is tab delimited. The first row is a header, with columns corresponding to 1) chromosome, 2) base pair position of the start of the gene, 3) base pair position of the end of the gene, 4) gene name, 5) ten thousand base pairs before the start of the gene, 6) ten thousand base pairs before then end of the gene.

SexDiffGOGenes.txt
This file contains the genes with at least one SexDiff-associated SNP at a t-SexDiff FDR of 0.001. The file is tab delimited. The first row is a header, with columns corresponding to 1) chromosome, 2) base pair position of the start of the gene, 3) base pair position of the end of the gene, 4) gene name, 5) ten thousand base pairs before the start of the gene, 6) ten thousand base pairs before then end of the gen, 7) category of the gene (represented by SD if in GO:0007548, O if in a GO term but not GO:0007548).

LDBlocks.txt
This file contains the list of LD blocks we used from Pickrell et al. The file is tab delimited. The first row is a header, with columns corresponding to 1) chromosome, 2) base pair position of the start of the block, 3) base pair position of the end of the block, 4) unique identifier for each block.

SexDiffSNPsPleiotropy.txt
This file contains the list of SexDiff-associated SNPs along with the phenotypes queried from the GWAS Catalog that each SNP is associated with. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) sex the SNP is disproportionately associated with, 6) GWAS Catalog phenotype(s) the SNP is associated with, where NA means the SNP was not associated with any GWAS Catalog phenotype.

PhenotypeSNPsPleiotropy.txt
This file contains the list of phenotype-associated SNPs along with the phenotypes queried from the GWAS Catalog that each SNP is associated with. The file is tab delimited. The first row is a header, with columns corresponding to 1) rsid, 2) chromosome, 3) base pair position (hg19), 4) sexually differentiated phenotype the SNP is associated with, 5) GWAS Catalog phenotype(s) the SNP is associated with, where NA means the SNP was not associated with any GWAS Catalog phenotype.

Funding

National Institutes of Health, Award: R01-GM115656 (to GHP)

Deutsche Forschungsgemeinschaft, Award: FOR-22337 (to GHP, MG, HRC, AMA)

National Institutes of Health, Award: F32-GM123634 (to KEG)