Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Charlesworth, B. Fundamental concepts in genetics: effective population size and patterns of molecular evolution and variation. Nat. Rev. Genet. 10, 195–205 (2009).

    Article  CAS  Google Scholar 

  2. Li, H. & Durbin, R. Inference of human population history from individual whole-genome sequences. Nature 475, 493–496 (2011).

    Article  CAS  Google Scholar 

  3. Keinan, A., Mullikin, J.C., Patterson, N. & Reich, D. Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans. Nat. Genet. 39, 1251–1255 (2007).

    Article  CAS  Google Scholar 

  4. Gronau, I., Hubisz, M.J., Gulko, B., Danko, C.G. & Siepel, A. Bayesian inference of ancient human demography from individual genome sequences. Nat. Genet. 43, 1031–1034 (2011).

    Article  CAS  Google Scholar 

  5. Lohmueller, K.E. et al. Proportionally more deleterious genetic variation in European than in African populations. Nature 451, 994–997 (2008).

    Article  CAS  Google Scholar 

  6. Tennessen, J.A. et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337, 64–69 (2012).

    Article  CAS  Google Scholar 

  7. Fu, W. et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493, 216–220 (2013).

    Article  CAS  Google Scholar 

  8. Casals, F. et al. Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans. PLoS Genet. 9, e1003815 (2013).

    Article  CAS  Google Scholar 

  9. Lim, E.T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

    Article  Google Scholar 

  10. Kidd, J.M. et al. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation. Am. J. Hum. Genet. 91, 660–671 (2012).

    Article  CAS  Google Scholar 

  11. Carmi, S. et al. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. Nat. Commun. 5, 4835 (2014).

    Article  CAS  Google Scholar 

  12. Kunsch, H.R. The jackknife and the bootstrap for general stationary observations. Ann. Stat. 17, 1217–1241 (1989).

    Article  Google Scholar 

  13. Abecasis, G.R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

    Article  Google Scholar 

  14. Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012).

    Article  CAS  Google Scholar 

  15. Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).

    Article  Google Scholar 

  16. Simons, Y.B., Turchin, M.C., Pritchard, J.K. & Sella, G. The deleterious mutation load is insensitive to recent population history. Nat. Genet. 46, 220–224 (2014).

    Article  CAS  Google Scholar 

  17. Gravel, S. et al. Demographic history and rare allele sharing among human populations. Proc. Natl. Acad. Sci. USA 108, 11983–11988 (2011).

    Article  CAS  Google Scholar 

  18. Boyko, A.R. et al. Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 4, e1000083 (2008).

    Article  Google Scholar 

  19. Gazave, E., Chang, D., Clark, A.G. & Keinan, A. Population growth inflates the per-individual number of deleterious mutations and reduces their mean effect. Genetics 195, 969–978 (2013).

    Article  Google Scholar 

  20. Lohmueller, K.E. The impact of population demography and selection on the genetic architecture of complex traits. PLoS Genet. 10, e1004379 (2014).

    Article  Google Scholar 

  21. Lohmueller, K.E. The distribution of deleterious genetic variation in human populations. bioRxiv 10.1101/005330 (2014).

  22. Balick, D.J., Do, R., Reich, D. & Sunyaev, S.R. Response to a population bottleneck can be used to infer recessive selection. bioRxiv 10.1101/003491 (2014).

  23. Adzhubei, I., Jordan, D.M. & Sunyaev, S.R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. Chapter 7 Unit 7.20 (2013).

  24. Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

    Article  CAS  Google Scholar 

  25. Duret, L. & Galtier, N. Biased gene conversion and the evolution of mammalian genomic landscapes. Annu. Rev. Genomics Hum. Genet. 10, 285–311 (2009).

    Article  CAS  Google Scholar 

  26. Schuster, S.C. et al. Complete Khoisan and Bantu genomes from southern Africa. Nature 463, 943–947 (2010).

    Article  CAS  Google Scholar 

  27. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat. Biotechnol. 27, 182–189 (2009).

    Article  CAS  Google Scholar 

  28. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

  29. Sunyaev, S.R. et al. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein Eng. 12, 387–394 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/ng.3186

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3186

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing