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The deleterious mutation load is insensitive to recent population history


Human populations have undergone major changes in population size in the past 100,000 years, including recent rapid growth. How these demographic events have affected the burden of deleterious mutations in individuals and the frequencies of disease mutations in populations remains unclear. We use population genetic models to show that recent human demography has probably had little impact on the average burden of deleterious mutations. This prediction is supported by two exome sequence data sets showing that individuals of west African and European ancestry carry very similar burdens of damaging mutations. We further show that for many diseases, rare alleles are unlikely to contribute a large fraction of the heritable variation, and therefore the impact of recent growth is likely to be modest. However, for those diseases that have a direct impact on fitness, strongly deleterious rare mutations probably do have an important role, and recent growth will have increased their impact.

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Figure 1: Time course of load and other key aspects of variation through a bottleneck and exponential growth.
Figure 2: Changes in load due to changes in population size during the histories of European and African Americans.
Figure 3: Observed mean allele frequencies in AAs and EAs at various classes of SNVs.
Figure 4: Predicted effect of demography on the genetic architecture of disease risk.


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This work was supported by grants from the US National Institutes of Health (NIH) (MH084703 to J.K.P. and GM083228 to G.S.), the Israel Science Foundation (grant 1492/10 to G.S.) and the Howard Hughes Medical Institute (J.K.P.). M.C.T. was supported in part by NIH grant T32 GM007197. We thank D. Reich and S. Sunyaev for helpful discussions and generous input regarding the interpretation of PolyPhen-2, I. Adzhubey for human-independent PolyPhen scores, J. Akey for assistance in accessing data, J. Akey, A. Siepel, G. Coop, I. Eshel, R. Hudson and two anonymous reviewers for comments on the manuscript and M. Przeworski for many discussions and comments on the manuscript.

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J.K.P. and G.S. conceived and supervised the research. Y.B.S., G.S. and J.K.P. developed theory. Y.B.S. performed simulations. M.C.T. and J.K.P. performed data analysis. J.K.P. and G.S. wrote the manuscript with input from Y.B.S. and M.C.T.

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Correspondence to Jonathan K Pritchard or Guy Sella.

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The authors declare no competing financial interests.

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Simons, Y., Turchin, M., Pritchard, J. et al. The deleterious mutation load is insensitive to recent population history. Nat Genet 46, 220–224 (2014).

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