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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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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. 6, 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.
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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. 6, 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.

Mentions: Previous suggestions that weakly deleterious mutations have been removed less effectively in Europeans than in West Africans were largely based on study of an alternative statistic: the proportion of polymorphic sites in the exome that are non-synonymous. This is significantly higher in Europeans than in West Africans5. We investigated the population genetic forces shaping this statistic by carrying out simulations that allowed us to study the dynamics of the change in this statistic over time. While our simulations show qualitative patterns that are consistent with those reported previously5, they also provide new insight due to a modification to the program that allows us, in every generation, to dissect how selection (versus mutation and genetic drift) contributes to the expected change in the proportion of non-synonymous sites in that generation. The simulations show that during and after a population bottleneck, the per generation change in the proportion of segregating sites that are non-synonymous is not driven by selection being less effective at reducing this ratio than it was in the ancestral population. Instead, following a short period at the start of the bottleneck when selection’s effectiveness in changing this statistic is reduced, selection begins to be more effective at reducing the proportion of non-synonymous sites per generation than it was prior to the bottleneck (Figure 3). Thus, the rate at which selection reduces the value of this statistic per generation is enhanced rather than diminished by the bottleneck, which pushes the statistic in the direction opposite to that in which it actually moves. We can conclude from this that it is primarily non-selective forces that drove the dynamics of this statistic since West African and European population separation.


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)

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. 6, 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.
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Related In: Results  -  Collection

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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. 6, 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.
Mentions: Previous suggestions that weakly deleterious mutations have been removed less effectively in Europeans than in West Africans were largely based on study of an alternative statistic: the proportion of polymorphic sites in the exome that are non-synonymous. This is significantly higher in Europeans than in West Africans5. We investigated the population genetic forces shaping this statistic by carrying out simulations that allowed us to study the dynamics of the change in this statistic over time. While our simulations show qualitative patterns that are consistent with those reported previously5, they also provide new insight due to a modification to the program that allows us, in every generation, to dissect how selection (versus mutation and genetic drift) contributes to the expected change in the proportion of non-synonymous sites in that generation. The simulations show that during and after a population bottleneck, the per generation change in the proportion of segregating sites that are non-synonymous is not driven by selection being less effective at reducing this ratio than it was in the ancestral population. Instead, following a short period at the start of the bottleneck when selection’s effectiveness in changing this statistic is reduced, selection begins to be more effective at reducing the proportion of non-synonymous sites per generation than it was prior to the bottleneck (Figure 3). Thus, the rate at which selection reduces the value of this statistic per generation is enhanced rather than diminished by the bottleneck, which pushes the statistic in the direction opposite to that in which it actually moves. We can conclude from this that it is primarily non-selective forces that drove the dynamics of this statistic since West African and European population separation.

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