Changes in life history and population size can explain the relative neutral diversity levels on X and autosomes in extant human populations

Abstract

In human populations, the relative levels of neutral diversity on the X and autosomes differ markedly from each other and from the naïve theoretical expectation of 3/4. Here we propose an explanation for these differences based on new theory about the effects of sex-specific life history and given pedigree-based estimates of the dependence of human mutation rates on sex and age. We demonstrate that life history effects, particularly longer generation times in males than in females, are expected to have had multiple effects on human X-to-autosome (X:A) diversity ratios, as a result of male-biased mutation rates, the equilibrium X:A ratio of effective population sizes, and the differential responses to changes in population size. We also show that the standard approach of using divergence between species to correct for male mutation bias results in biased estimates of X:A effective population size ratios. We obtain alternative estimates using pedigree-based estimates of the male mutation bias, which reveal that X:A ratios of effective population sizes are considerably greater than previously appreciated. Finally, we find that the joint effects of historical changes in life history and population size can explain the observed X:A diversity ratios in extant human populations. Our results suggest that ancestral human populations were highly polygynous, that non-African populations experienced a substantial reduction in polygyny and/or increase in the male-to-female ratio of generation times around the Out-of-Africa bottleneck, and that current diversity levels were affected by fairly recent changes in sex-specific life history.

Keywords: autosomes; human; life history; polymorphism; sex chromosomes.

Fig. 1.

Life history and mutational effects on the human X:A diversity ratio assuming a constant population size. Ratios of reproductive variances $\left(\left({\gamma }_M{V}_M+{\gamma }_F/{\gamma }_M\right)/\left({\gamma }_F{V}_F+{\gamma }_M/{\gamma }_F\right)\right)$ and generation times are varied within a range corresponding to estimates in extant hunter-gatherers (see text and refs. , , and 33). The male mutation bias dependence on the ratio of generation times is based on human pedigree studies (see text, Fig. 3, and ref. 37); this bias causes the diversity ratio to differ from 3/4 even when life history parameters are equal in both sexes. Note that these predictions are not directly comparable with most X:A diversity ratios reported in the literature, which are normalized by the X:A ratio of divergence to an outgroup.

Fig. 2.

The effect of a population bottleneck on the X:A diversity ratio is modulated by sex-specific life history. Bottleneck parameters were chosen to roughly correspond to autosomal estimates for the OoA bottleneck in humans (right y axis), with the population size dropping from $2\cdot {10}^4$ to $2\cdot {10}^3$ between 50 and 100 kya. We show the change in X:A diversity ratios, measured relative to their values at demographic equilibrium (left y axis), assuming an autosomal generation time of 30 y and four combinations of generation times and reproductive variances ratios. When both life history ratios have the same value, the ratio of $N_e$ at equilibrium is 3/4 (as is the case for black and dashed blue-red curves); when $G_M/G_F=1.25$, there are more generations on the X than on the autosomes per unit time $\left(G_X/G_A=0.72\right)$. See SI Appendix, Fig. S1 for the absolute rather than relative changes in diversity and $N_e$ ratios.

Fig. 3.

Substantial differences between estimates of male mutation bias ($\alpha )$ in humans based on X:A ratios of divergence to an outgroup (SI Appendix, section 2.3 and Table S3) and on pedigree studies in contemporary humans (SI Appendix, section 1 and ref. 27). Pedigree-based estimates strongly depend on (and are therefore shown as a function of) the generation time ratio, $G_M/G_F$ (SI Appendix, section 1 and ref. 37). They depend only weakly on the average generation time, $G_A$, as shown by the (cyan) range corresponding to $G_A$ between 25 and 35 y. The divergence-based estimates were calculated using Miyata’s formula $\left({\widehat{\alpha }}_D=f^{-1}\left(d_X/d_A\right)\right)$ and the divergence of humans from orangutans and rhesus macaques (SI Appendix, section 2.3).

Fig. 4.

The X:A $N_e$ ratios in human populations are greater than previously appreciated. We rely on genome-wide polymorphism data from the 1000 Genomes Project (phase 3) to estimate neutral $N_e$ ratios in the absence of selection at linked sites, as described in the text and detailed in SI Appendix, section 2. Specifically, we estimate the ratios for the following six ancestry groups, as labeled by the 1000 Genomes (40): Yoruba (YRI), Mexican (MXL), Tuscan (TSI), Northern and Western European (CEU), Han Chinese (CHB), and Japanese (JPT). For the “old estimates” we rely on divergence from rhesus macaque to correct for male biased mutation, and for the “new estimates” we rely on a pedigree-based estimate of the male mutation bias ($\alpha =4.25$; see text for details). Confidence intervals are based on bootstrapping, in which we resample 1-Mb windows with replacement, excluding windows without any putatively neutral sites.

Fig. 5.

The combinations of ratios of generation times and reproductive variances in the two sexes that are consistent with estimates of the X:A diversity ratio in YRI. Solid curves correspond to parameter values that would yield the point estimate of the diversity ratio, and shaded areas correspond to values that would yield ratios within the 95% CI of the diversity ratio estimate.

Fig. 6.

The expected reduction in X:A diversity ratios in CEU vs. YRI given previously inferred historical changes in population size (Fig. 7A) and different models of life history (see text for details). (i) Without life history effects: $G_M/G_F=\left({\gamma }_M{V}_M+{\gamma }_F/{\gamma }_M\right)/\left({\gamma }_F{V}_F+{\gamma }_M/{\gamma }_F\right)=1$. (ii–iv) The ratios $G_M/G_F$ and $\left({\gamma }_M{V}_M+{\gamma }_F/{\gamma }_M\right)/\left({\gamma }_F{V}_F+{\gamma }_M/{\gamma }_F\right)$ are allowed to vary within the ranges detailed in the text and are chosen to maximize the current reduction in diversity ratios in CEU relative to YRI given: (ii) life history ratios that are constant over time and populations; (iii) life history ratios that can differ before and after the populations split but are the same in both populations; and (iv) life history ratios that are the same before the populations split but different after. The observed reduction in the X:A diversity ratio in CEU relative to YRI is shown for comparison.

Fig. 7.

Together, variation in sex-specific life history traits over time and across populations and changes in population sizes can explain the X:A diversity ratios observed in six human populations. (A) Changes in population sizes in six human populations inferred by pairwise MSMC (41). Split times among populations were determined visually and are marked by stars: blue for (YRI, non-African populations), black for ((CEU, TSI), (CHB, JPT), MXL), purple for (CEU, TSI), and red for (CHB, JPT). (B) Comparison of estimates of the X:A diversity ratios with those predicted under the historical changes in population size shown in A, assuming 1) no life history effects (black), 2) sex-specific life history parameters that vary within the ranges specified in the text and were chosen to best fit observations (red), and 3) the best fit further allowing sex-specific life history parameters to vary among populations after they split (blue). See text and SI Appendix, section 3 for details.