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An evolutionary perspective on epistasis and the missing heritability.

Hemani G, Knott S, Haley C - PLoS Genet. (2013)

Bottom Line: We propose that one reason that the problem of the "missing heritability" arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time.We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone.Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.

View Article: PubMed Central - PubMed

Affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Science, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the "missing heritability" arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.

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Allele frequency trajectories under selection.Top row: G-P maps. 1. Independent additive effects at locus A and B; 2. Dominant pattern of canalisation; 3. Recessive pattern of canalisation; 4–6. Patterns generated by a genetic algorithm optimising for maximised additive variance and long-term survival at intermediate frequency. Middle row: Expected allele frequency trajectories for G-P maps under selection, as derived deterministically, with initial frequencies of 0.1, 0.3, 0.5, 0.7, and 0.9 enumerated over both loci. Frequencies on the -axis correspond to alleles a/b. Only one colour appears for patterns 1–3 because the trajectories of both alleles are identical. Bottom row: The path of allele frequencies as observed through stochastic simulations of populations comprising 1000 individuals and  at generation 0, with initial allele frequencies at both loci of 0.5.
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pgen-1003295-g001: Allele frequency trajectories under selection.Top row: G-P maps. 1. Independent additive effects at locus A and B; 2. Dominant pattern of canalisation; 3. Recessive pattern of canalisation; 4–6. Patterns generated by a genetic algorithm optimising for maximised additive variance and long-term survival at intermediate frequency. Middle row: Expected allele frequency trajectories for G-P maps under selection, as derived deterministically, with initial frequencies of 0.1, 0.3, 0.5, 0.7, and 0.9 enumerated over both loci. Frequencies on the -axis correspond to alleles a/b. Only one colour appears for patterns 1–3 because the trajectories of both alleles are identical. Bottom row: The path of allele frequencies as observed through stochastic simulations of populations comprising 1000 individuals and at generation 0, with initial allele frequencies at both loci of 0.5.

Mentions: Our results demonstrate that for many of the patterns of epistasis that we assayed, deleterious effects can be maintained at intermediate frequencies over long evolutionary time periods (Figure 1 patterns 1–3, and Figures S1, S2 and S3). As might be expected, a number of G-P maps that maintained genetic variation at intermediate frequencies also exhibited over-dominance, or some form of heterozygote advantage (e.g.Figure 1 patterns 4–6). However, most patterns of epistasis that we assayed (Figure S1) do not exhibit heterozygote advantage, and these can also effectively temper the rate of extinction of deleterious alleles. Conversely, some level of under-dominance is required for variation to be maintained, for example although the classic pattern of epistasis (pattern 52, Figure S1) can theoretically avoid fixation when both loci are at allele frequencies of (Figure S2), drift provides sufficient perturbation to prevent it from being maintained at equilibrium (Figure S3).


An evolutionary perspective on epistasis and the missing heritability.

Hemani G, Knott S, Haley C - PLoS Genet. (2013)

Allele frequency trajectories under selection.Top row: G-P maps. 1. Independent additive effects at locus A and B; 2. Dominant pattern of canalisation; 3. Recessive pattern of canalisation; 4–6. Patterns generated by a genetic algorithm optimising for maximised additive variance and long-term survival at intermediate frequency. Middle row: Expected allele frequency trajectories for G-P maps under selection, as derived deterministically, with initial frequencies of 0.1, 0.3, 0.5, 0.7, and 0.9 enumerated over both loci. Frequencies on the -axis correspond to alleles a/b. Only one colour appears for patterns 1–3 because the trajectories of both alleles are identical. Bottom row: The path of allele frequencies as observed through stochastic simulations of populations comprising 1000 individuals and  at generation 0, with initial allele frequencies at both loci of 0.5.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3585114&req=5

pgen-1003295-g001: Allele frequency trajectories under selection.Top row: G-P maps. 1. Independent additive effects at locus A and B; 2. Dominant pattern of canalisation; 3. Recessive pattern of canalisation; 4–6. Patterns generated by a genetic algorithm optimising for maximised additive variance and long-term survival at intermediate frequency. Middle row: Expected allele frequency trajectories for G-P maps under selection, as derived deterministically, with initial frequencies of 0.1, 0.3, 0.5, 0.7, and 0.9 enumerated over both loci. Frequencies on the -axis correspond to alleles a/b. Only one colour appears for patterns 1–3 because the trajectories of both alleles are identical. Bottom row: The path of allele frequencies as observed through stochastic simulations of populations comprising 1000 individuals and at generation 0, with initial allele frequencies at both loci of 0.5.
Mentions: Our results demonstrate that for many of the patterns of epistasis that we assayed, deleterious effects can be maintained at intermediate frequencies over long evolutionary time periods (Figure 1 patterns 1–3, and Figures S1, S2 and S3). As might be expected, a number of G-P maps that maintained genetic variation at intermediate frequencies also exhibited over-dominance, or some form of heterozygote advantage (e.g.Figure 1 patterns 4–6). However, most patterns of epistasis that we assayed (Figure S1) do not exhibit heterozygote advantage, and these can also effectively temper the rate of extinction of deleterious alleles. Conversely, some level of under-dominance is required for variation to be maintained, for example although the classic pattern of epistasis (pattern 52, Figure S1) can theoretically avoid fixation when both loci are at allele frequencies of (Figure S2), drift provides sufficient perturbation to prevent it from being maintained at equilibrium (Figure S3).

Bottom Line: We propose that one reason that the problem of the "missing heritability" arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time.We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone.Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.

View Article: PubMed Central - PubMed

Affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Science, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the "missing heritability" arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly.

Show MeSH
Related in: MedlinePlus