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

Do R, Balick D, Li H, Adzhubei I, Sunyaev S, Reich D - Nat. Genet. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

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.

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Relative load of non-synonymous mutations RX/Y for diverse pairs of populationsResults 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.
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Figure 1: Relative load of non-synonymous mutations RX/Y for diverse pairs of populationsResults 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.

Mentions: We measured RWestAfrica/Europe in four sequencing datasets: (1) coding regions of genes (exomes) in 15 African Americans and 20 European Americans5; (2) exomes from 1,089 individuals in the 1000 Genomes Project (1KG)13; (3) exomes from 1,088 African Americans and 1,351 European Americans6, and (4) 24 whole genomes sequenced to high coverage14,15 (Supplementary Table 1). We inferred the ancestral allele based on comparison to chimpanzee. As expected for sites unaffected by selection and for indistinguishable differences in mutation rates in the history of the two populations, RWestAfrica/Europe(synonymous) is within two standard errors of 1 (Table 1 and Supplementary Table 2). However, RWestAfrica/Europe(non-synonymous) is also indistinguishable from 1. Thus, our data provide no evidence that purging of weakly deleterious mutations has been less effective in Europeans than in West-Africans, similar to the finding of ref. 16 for similar population comparisons. To extend these results to a more diverse set of populations, we computed RX/Y between all possible pairs of 11 populations each represented by two deep genome sequences15, and all pairwise comparisons of 14 populations from the 1000 Genomes Project13. We observe no significant differences for any population pair despite sometimes profound differences in demographic history (Figure 1 and Supplementary Table 3).


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

Do R, Balick D, Li H, Adzhubei I, Sunyaev S, Reich D - Nat. Genet. (2015)

Relative load of non-synonymous mutations RX/Y for diverse pairs of populationsResults 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4310772&req=5

Figure 1: Relative load of non-synonymous mutations RX/Y for diverse pairs of populationsResults 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.
Mentions: We measured RWestAfrica/Europe in four sequencing datasets: (1) coding regions of genes (exomes) in 15 African Americans and 20 European Americans5; (2) exomes from 1,089 individuals in the 1000 Genomes Project (1KG)13; (3) exomes from 1,088 African Americans and 1,351 European Americans6, and (4) 24 whole genomes sequenced to high coverage14,15 (Supplementary Table 1). We inferred the ancestral allele based on comparison to chimpanzee. As expected for sites unaffected by selection and for indistinguishable differences in mutation rates in the history of the two populations, RWestAfrica/Europe(synonymous) is within two standard errors of 1 (Table 1 and Supplementary Table 2). However, RWestAfrica/Europe(non-synonymous) is also indistinguishable from 1. Thus, our data provide no evidence that purging of weakly deleterious mutations has been less effective in Europeans than in West-Africans, similar to the finding of ref. 16 for similar population comparisons. To extend these results to a more diverse set of populations, we computed RX/Y between all possible pairs of 11 populations each represented by two deep genome sequences15, and all pairwise comparisons of 14 populations from the 1000 Genomes Project13. We observe no significant differences for any population pair despite sometimes profound differences in demographic history (Figure 1 and Supplementary Table 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

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.

Show MeSH