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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 effect of demographic history on the accumulation of deleterious mutationsTo study the expected value of RWestAfrica/Europe stratified by selection coefficient, we simulated a previously published model of the joint history of West Africans and Europeans6, for a range of selection coefficients, assuming both additive (h=0.5) and recessive (h=0) models of selection. For the additive case, RWestAfrica/Europe dips below a confidently detectable ratio of 0.95 (given the standard errors of our empirical measurements) for s ∈ (−0.0004, −0.004). Real distributions of selection coefficients may include a large fraction of their density outside this range, and thus a true signal may be difficult to detect. We also simulated a published model of the history of Denisovans and Neanderthals15. The simulations predict similar curves for R′WestAfrica/Denisova and R′WestAfrica/Neanderthal reflecting their similar inferred demographic histories (we use a normalized R’ statistic to correct for the effects of branch shortening in these ancient genomes). The simulations show that R′WestAfrica/Denisova is expected to be below a detectable ratio of 0.95 for s ∈ (−0.00002, −0.03) and that R′WestAfrica/Neanderthal is expected to be below 0.95 for s ∈ (−0.00002, −0.09). For recessively acting alleles, the directionality of the effects are opposite.
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Figure 2: The effect of demographic history on the accumulation of deleterious mutationsTo study the expected value of RWestAfrica/Europe stratified by selection coefficient, we simulated a previously published model of the joint history of West Africans and Europeans6, for a range of selection coefficients, assuming both additive (h=0.5) and recessive (h=0) models of selection. For the additive case, RWestAfrica/Europe dips below a confidently detectable ratio of 0.95 (given the standard errors of our empirical measurements) for s ∈ (−0.0004, −0.004). Real distributions of selection coefficients may include a large fraction of their density outside this range, and thus a true signal may be difficult to detect. We also simulated a published model of the history of Denisovans and Neanderthals15. The simulations predict similar curves for R′WestAfrica/Denisova and R′WestAfrica/Neanderthal reflecting their similar inferred demographic histories (we use a normalized R’ statistic to correct for the effects of branch shortening in these ancient genomes). The simulations show that R′WestAfrica/Denisova is expected to be below a detectable ratio of 0.95 for s ∈ (−0.00002, −0.03) and that R′WestAfrica/Neanderthal is expected to be below 0.95 for s ∈ (−0.00002, −0.09). For recessively acting alleles, the directionality of the effects are opposite.

Mentions: To contextualize these findings, we carried out simulations using fitted models of the histories of West African and European populations5,6,17 (Supplementary Table 4). The simulations show that if selection acts additively and coefficients are in the range s ∈ [−0.004, −0.0004], RWestAfrica/Europe is expected to be below 0.95 and detectable given the standard errors of our measurements (Figure 2). However, if many mutations had selection coefficients outside this range, the signal could be diluted to the point of not being detectable. Indeed, when we compute the expected value of RWestAfrica/Europe integrating over a previously fitted distribution of selection coefficients18, we find that RWestAfrica/Europe(non-synonymous) is expected to be 0.987, too close to 1 to be reliably detected given the standard errors of our measurements (Table 1). This is consistent with other studies that have concluded that assuming additively acting mutations, the mutational load in West Africans and Europeans is expected to be indistinguishable measured on a per-genome basis16,19–21. We also simulated recessively acting mutations, and in this case predict a stronger difference across populations. The direction of the difference is opposite to that for additively acting mutations, however, reflecting the fact that recessively acting mutations that drift up in frequency due to the bottleneck can be efficiently purged through the action of selection as they are exposed in homozygous form22 (Figure 2; Supplementary Figure 1). The difference in direction for additively and recessively acting mutations suggests that until there is a reliable model of demographic history and the joint distribution of dominance and selection coefficients in humans, it will be impossible to make a reliable theoretical prediction about whether West Africans or Europeans carry a higher per-genome load.


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 effect of demographic history on the accumulation of deleterious mutationsTo study the expected value of RWestAfrica/Europe stratified by selection coefficient, we simulated a previously published model of the joint history of West Africans and Europeans6, for a range of selection coefficients, assuming both additive (h=0.5) and recessive (h=0) models of selection. For the additive case, RWestAfrica/Europe dips below a confidently detectable ratio of 0.95 (given the standard errors of our empirical measurements) for s ∈ (−0.0004, −0.004). Real distributions of selection coefficients may include a large fraction of their density outside this range, and thus a true signal may be difficult to detect. We also simulated a published model of the history of Denisovans and Neanderthals15. The simulations predict similar curves for R′WestAfrica/Denisova and R′WestAfrica/Neanderthal reflecting their similar inferred demographic histories (we use a normalized R’ statistic to correct for the effects of branch shortening in these ancient genomes). The simulations show that R′WestAfrica/Denisova is expected to be below a detectable ratio of 0.95 for s ∈ (−0.00002, −0.03) and that R′WestAfrica/Neanderthal is expected to be below 0.95 for s ∈ (−0.00002, −0.09). For recessively acting alleles, the directionality of the effects are opposite.
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Related In: Results  -  Collection

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Figure 2: The effect of demographic history on the accumulation of deleterious mutationsTo study the expected value of RWestAfrica/Europe stratified by selection coefficient, we simulated a previously published model of the joint history of West Africans and Europeans6, for a range of selection coefficients, assuming both additive (h=0.5) and recessive (h=0) models of selection. For the additive case, RWestAfrica/Europe dips below a confidently detectable ratio of 0.95 (given the standard errors of our empirical measurements) for s ∈ (−0.0004, −0.004). Real distributions of selection coefficients may include a large fraction of their density outside this range, and thus a true signal may be difficult to detect. We also simulated a published model of the history of Denisovans and Neanderthals15. The simulations predict similar curves for R′WestAfrica/Denisova and R′WestAfrica/Neanderthal reflecting their similar inferred demographic histories (we use a normalized R’ statistic to correct for the effects of branch shortening in these ancient genomes). The simulations show that R′WestAfrica/Denisova is expected to be below a detectable ratio of 0.95 for s ∈ (−0.00002, −0.03) and that R′WestAfrica/Neanderthal is expected to be below 0.95 for s ∈ (−0.00002, −0.09). For recessively acting alleles, the directionality of the effects are opposite.
Mentions: To contextualize these findings, we carried out simulations using fitted models of the histories of West African and European populations5,6,17 (Supplementary Table 4). The simulations show that if selection acts additively and coefficients are in the range s ∈ [−0.004, −0.0004], RWestAfrica/Europe is expected to be below 0.95 and detectable given the standard errors of our measurements (Figure 2). However, if many mutations had selection coefficients outside this range, the signal could be diluted to the point of not being detectable. Indeed, when we compute the expected value of RWestAfrica/Europe integrating over a previously fitted distribution of selection coefficients18, we find that RWestAfrica/Europe(non-synonymous) is expected to be 0.987, too close to 1 to be reliably detected given the standard errors of our measurements (Table 1). This is consistent with other studies that have concluded that assuming additively acting mutations, the mutational load in West Africans and Europeans is expected to be indistinguishable measured on a per-genome basis16,19–21. We also simulated recessively acting mutations, and in this case predict a stronger difference across populations. The direction of the difference is opposite to that for additively acting mutations, however, reflecting the fact that recessively acting mutations that drift up in frequency due to the bottleneck can be efficiently purged through the action of selection as they are exposed in homozygous form22 (Figure 2; Supplementary Figure 1). The difference in direction for additively and recessively acting mutations suggests that until there is a reliable model of demographic history and the joint distribution of dominance and selection coefficients in humans, it will be impossible to make a reliable theoretical prediction about whether West Africans or Europeans carry a higher per-genome load.

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
Related in: MedlinePlus