Evaluating human autosomal loci for sexually antagonistic viability selection in two large biobanks

Abstract

Sex and sexual differentiation are pervasive across the tree of life. Because females and males often have substantially different functional requirements, we expect selection to differ between the sexes. Recent studies in diverse species, including humans, suggest that sexually antagonistic viability selection creates allele frequency differences between the sexes at many different loci. However, theory and population-level simulations indicate that sex-specific differences in viability would need to be very large to produce and maintain reported levels of between-sex allelic differentiation. We address this contradiction between theoretical predictions and empirical observations by evaluating evidence for sexually antagonistic viability selection on autosomal loci in humans using the largest cohort to date (UK Biobank, n = 487,999) along with a second large, independent cohort (BioVU, n = 93,864). We performed association tests between genetically ascertained sex and autosomal loci. Although we found dozens of genome-wide significant associations, none replicated across cohorts. Moreover, closer inspection revealed that all associations are likely due to cross-hybridization with sex chromosome regions during genotyping. We report loci with potential for mis-hybridization found on commonly used genotyping platforms that should be carefully considered in future genetic studies of sex-specific differences. Despite being well powered to detect allele frequency differences of up to 0.8% between the sexes, we do not detect clear evidence for this signature of sexually antagonistic viability selection on autosomal variation. These findings suggest a lack of strong ongoing sexually antagonistic viability selection acting on single locus autosomal variation in humans.

Keywords: association study; biobank; male–female FST; probe mapping; sexually antagonistic selection.

Figure 1

Genome-wide association tests for genetic sex reveal candidate variants for sexually antagonistic selection. To identify candidate variants for sexually antagonistic selection, we performed genome-wide association tests between females (cases) and males (controls) in two large biobank cohorts: (A) BioVU (females = 34,269, males = 27,491) and (B) UK Biobank (females = 264,813, males = 223,478). After standard quality control and sex-specific missingness filters (“Materials and methods” section), we identified five variants with genome-wide statistically significant associations (P < 5⁻⁸, solid red line) in BioVU and eight in the UK Biobank. None of the significant variants in BioVU and UK Biobank replicated at genome-wide or nominal significance (P < 0.05) across the two cohorts (Table 1). The probe sequence for each associated variant (except rs11032483) had >90% sequence identity to at least one sequence on a sex chromosome (Table 2). Each point represents one variant. Each variant is colored by whether the best match of its probe sequence to a sex chromosome (according to BLAT score) is on X (pink) or Y (green). If it has no strong match to either sex chromosome, it is colored black. The size of each point indicates the degree of sequence similarity.

Figure 2

Probes for autosomal variants associated with genetic sex show high sequence similarity to sex chromosomes. We searched probe sequences used to genotype autosomal variants in the BioVU (798,051 autosomal probes) and UK Biobank (620,040 autosomal probes) cohorts for high sequence similarity to sex chromosome regions using BLAT (“Materials and methods” section). (A) More than 80% of BioVU autosomal probes do not have any sequence similarity (BLAT score ≤20) to a sex chromosome region; these are plotted at 0. Among the 83,083 BioVU probes with similarity to a sex chromosome sequence (inset), the probes for the variants with genome-wide significant associations with sex (blue triangles) are all in the tail of the distribution beyond the 99th percentile of the BLAT match score. (B) Patterns are similar for the UK Biobank probes; however, a higher fraction (20%, 128,090) has detectable similarity to a sex chromosome, likely due to their greater length than the BioVU probes.

Figure 3

Statistical power was sufficient to detect small allelic divergence between the sexes. (A) The power to detect different levels of allelic divergence between the sexes was calculated for the BioVU (orange) and UK Biobank (green) cohorts. The dashed line shows the 95% power threshold. (B) Statistical power for the analyzed cohorts (same as in A) compared to previous analysis of human sequences (Lucotte et al. 2016) based on approximately 100 individuals per HapMap population (gray).