Evidence for increased levels of positive and negative selection on the X chromosome versus autosomes in humans

Abstract

Partially recessive variants under positive selection are expected to go to fixation more quickly on the X chromosome as a result of hemizygosity, an effect known as faster-X. Conversely, purifying selection is expected to reduce substitution rates more effectively on the X chromosome. Previous work in humans contrasted divergence on the autosomes and X chromosome, with results tending to support the faster-X effect. However, no study has yet incorporated both divergence and polymorphism to quantify the effects of both purifying and positive selection, which are opposing forces with respect to divergence. In this study, we develop a framework that integrates previously developed theory addressing differential rates of X and autosomal evolution with methods that jointly estimate the level of purifying and positive selection via modeling of the distribution of fitness effects (DFE). We then utilize this framework to estimate the proportion of nonsynonymous substitutions fixed by positive selection (α) using exome sequence data from a West African population. We find that varying the female to male breeding ratio (β) has minimal impact on the DFE for the X chromosome, especially when compared with the effect of varying the dominance coefficient of deleterious alleles (h). Estimates of α range from 46% to 51% and from 4% to 24% for the X chromosome and autosomes, respectively. While dependent on h, the magnitude of the difference between α values estimated for these two systems is highly statistically significant over a range of biologically realistic parameter values, suggesting faster-X has been operating in humans.

Keywords: X chromosome; autosomes; distribution of fitness effects; humans; positive selection; purifying selection.

Fig. 1.

Folded AFS for 44 Yoruba females for the autosomes and X chromosome at 4-fold and 0-fold sites both including (A) and excluding (B) CpG sites. The minor allele counts from 11 to 44 are not shown to aid interpretation. The full AFS are shown in supplementary figures S1 and S2, Supplementary Material online.

Fig. 2.

Estimates of parameters of selection under various combinations of β and h for 44 Yoruba females. (A) 2N_e,As, the scale parameter of the gamma distribution for the DFE, (B) a, the shape parameter of the gamma distribution for the DFE, and (C) α, the proportion of substitutions along the human lineage since divergence from a human–chimpanzee ancestor that fixed as a result of adaptive selection. Solid lines are when including CpG sites and dashed lines are when excluding CpG sites.

Fig. 3.

Comparison of gene expression tissue specificity for X chromosome and autosomes based on RNA-Seq data from 16 human tissue generated as part of the Illumina Body Map 2.0.