No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans

Abstract

Non-African populations have experienced size reductions in the time since their split from West Africans, leading to the hypothesis that natural selection to remove weakly deleterious mutations has been less effective in the history of non-Africans. To test this hypothesis, we measured the per-genome accumulation of nonsynonymous substitutions across diverse pairs of populations. We find no evidence for a higher load of deleterious mutations in non-Africans. However, we detect significant differences among more divergent populations, as archaic Denisovans have accumulated nonsynonymous mutations faster than either modern humans or Neanderthals. To reconcile these findings with patterns that have been interpreted as evidence of the less effective removal of deleterious mutations in non-Africans than in West Africans, we use simulations to show that the observed patterns are not likely to reflect changes in the effectiveness of selection after the populations split but are instead likely to be driven by other population genetic factors.

Figure 1. Relative load of non-synonymous mutations R_X/Y for diverse pairs of populations

Results for the deep genomes are given at the bottom left and results for 1000 Genomes Project populations are given at the top right. Ratios are based on the accumulation observed in the population in the row divided by the population in the column. ±1 standard errors (parentheses) are based on a Weighted Block Jackknife. We highlight numbers >4 standard errors from expectation. Ratios for Neanderthal and Denisova are normalized by the number of synonymous sites specific to each genome, to adjust for the expectation of fewer mutations in the ancient samples than in the present-day human samples due to less time elapsed since divergence (all other comparisons are un-normalized). Ratios involving Neanderthal and Denisova also remove C→T and G→A mutations to avoid high error rates due to ancient DNA degradation.

Figure 2. The effect of demographic history on the accumulation of deleterious mutations

To study the expected value of R_{WestAfrica/Europe} stratified by selection coefficient, we simulated a previously published model of the joint history of West Africans and Europeans, for a range of selection coefficients, assuming both additive (h=0.5) and recessive (h=0) models of selection. For the additive case, R_{WestAfrica/Europe} dips below a confidently detectable ratio of 0.95 (given the standard errors of our empirical measurements) for s ∈ (−0.0004, −0.004). Real distributions of selection coefficients may include a large fraction of their density outside this range, and thus a true signal may be difficult to detect. We also simulated a published model of the history of Denisovans and Neanderthals. The simulations predict similar curves for R′_{WestAfrica/Denisova} and R′_{WestAfrica/Neanderthal} reflecting their similar inferred demographic histories (we use a normalized R’ statistic to correct for the effects of branch shortening in these ancient genomes). The simulations show that R′_{WestAfrica/Denisova} is expected to be below a detectable ratio of 0.95 for s ∈ (−0.00002, −0.03) and that R′_{WestAfrica/Neanderthal} is expected to be below 0.95 for s ∈ (−0.00002, −0.09). For recessively acting alleles, the directionality of the effects are opposite.

Figure 3. The rise in the proportion of non-synonymous sites in Europeans compared with West Africans is not due to a reduced effectiveness of selection in Europeans since the split

(A) The West African and European diploid population sizes for the two simulated models (left, ref. , and right, a bottleneck followed by expansion), both of which specify a population split 2,040 generations ago. Subsequent panels are restricted to Europeans, as the West African population size does not fluctuate enough to cause statistics to deviate substantially from the baseline. (B) Key statistics as a fraction of the baseline. The present proportion of non-synonymous sites in Europeans is higher than in the ancestral population (black). We also show heterozygosity at unselected sites (gray), synonymous site density (red), and non-synonymous site density (yellow). (C) Partitioning of the change in the proportion of non-synonymous sites per generation into selective and others forces. For both models, the temporal dynamics are driven by the forces of mutation and stochastic changes in allele frequency (the curves are positively correlated) and not by negative selective forces (negatively correlated). We plot the per-generation change in the proportion of non-synonymous mutations due to selection minus its value prior to the West African / European population split used as a baseline. A positive value does not mean that selection is working to increase the proportion of non-synonymous mutations, just that the decrease per generation due to this quantity is less than in the past.