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


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.

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Figure 1: Relative load of nonsynonymous mutations RX/Y for diverse pairs of populations.
Figure 2: The effect of demographic history on the accumulation of deleterious mutations.
Figure 3: The rise in the proportion of nonsynonymous sites in Europeans in comparison to West Africans is not due to reduced effectiveness of selection in Europeans since the population split.

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We thank J. Akey, D. Altshuler, C. Bustamante, S. Castellano, C. de Filippo, A. Keinan, A. Kondrashov, E. Lander, K. Lohmueller, S. Mallick, S. Pääbo, N. Patterson, J. Pritchard, M. Przeworski, J. Schaiber, G. Sella and M. Slatkin for valuable discussions. R.D. was supported by a Banting fellowship from the Canadian Institutes of Health Research. S.S. was supported by US National Institutes of Health grants R01GM078598 and R01MH101244. D.R. was supported by US National Institutes of Health grants GM100233 and HG006399 and US National Science Foundation grant 1032255 and is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations



R.D., D.B., H.L., I.A., S.S. and D.R. performed analyses. S.S. and D.R. supervised the research. R.D., D.B., S.S. and D.R. wrote the manuscript with the assistance of all coauthors.

Corresponding authors

Correspondence to Shamil Sunyaev or David Reich.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 RWestAfrican/European for four demographic histories (simulations).

We show the expected accumulation of deleterious mutation in West Africans compared with Europeans at the present. We explore a range of selection coefficients s and dominance coefficients h, for the four models of demographic history specified in Supplementary Table 4. We observe a greater accumulation of deleterious mutations in West Africans for recessively acting mutations (h = 0) and a greater accumulation in Europeans for additively acting mutations (h = 0.5).

Supplementary Figure 2 Our modified version of PolyPhen-2 has no reference bias.

In each of the panels, the y axis shows the fraction of nonsynonymous segregating sites in 1000 Genomes Project data that are labeled by PolyPhen-2 as being ‘possibly damaging’ or ‘probably damaging’, and the x axis shows the derived allele frequency in 1000 Genomes Project European Americans (CEU) or Yoruba Nigerians (YRI). The data are stratified into sites where the human reference sequence allele is ancestral (red) or derived (blue). (a,b) Standard PolyPhen-2. The probability of being labeled as likely to be damaging is strongly dependent on the status of the human reference sequence. (c,d) Reference-free PolyPhen-2 has no such dependence.

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Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–9 and Supplementary Note. (PDF 1968 kb)

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Do, R., Balick, D., Li, H. et al. No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nat Genet 47, 126–131 (2015).

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