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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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Deterministic change in variance components of G-P maps under selection.For (a) Genetic variance and (b) Additive variance as a proportion of genetic variation, with initial frequencies of 0.1, 0.3, 0.5, 0.7 and 0.9 enumerated over both loci. The variance decomposition was performed at the causal locus (), and at SNP pairs that were in incomplete LD with the causal loci. Boxes represent the different G-P maps from Figure 1.
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pgen-1003295-g002: Deterministic change in variance components of G-P maps under selection.For (a) Genetic variance and (b) Additive variance as a proportion of genetic variation, with initial frequencies of 0.1, 0.3, 0.5, 0.7 and 0.9 enumerated over both loci. The variance decomposition was performed at the causal locus (), and at SNP pairs that were in incomplete LD with the causal loci. Boxes represent the different G-P maps from Figure 1.

Mentions: The genetic variance of a G-P map depends on the allele frequencies of the loci involved, and selection drives these allele frequencies to minimise the directional effect of each locus. From this we can calculate the expected changes in genetic variance over time. For many of the patterns of epistasis studied they maintain genetic variance over long evolutionary periods (Figure 2a and Figure S5), as often their allele frequencies can be maintained at intermediate levels. However the majority of this variance is non-additive, with almost all of the additive variance eventually disappearing (Figure 2b and Figure S6).


An evolutionary perspective on epistasis and the missing heritability.

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

Deterministic change in variance components of G-P maps under selection.For (a) Genetic variance and (b) Additive variance as a proportion of genetic variation, with initial frequencies of 0.1, 0.3, 0.5, 0.7 and 0.9 enumerated over both loci. The variance decomposition was performed at the causal locus (), and at SNP pairs that were in incomplete LD with the causal loci. Boxes represent the different G-P maps from Figure 1.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003295-g002: Deterministic change in variance components of G-P maps under selection.For (a) Genetic variance and (b) Additive variance as a proportion of genetic variation, with initial frequencies of 0.1, 0.3, 0.5, 0.7 and 0.9 enumerated over both loci. The variance decomposition was performed at the causal locus (), and at SNP pairs that were in incomplete LD with the causal loci. Boxes represent the different G-P maps from Figure 1.
Mentions: The genetic variance of a G-P map depends on the allele frequencies of the loci involved, and selection drives these allele frequencies to minimise the directional effect of each locus. From this we can calculate the expected changes in genetic variance over time. For many of the patterns of epistasis studied they maintain genetic variance over long evolutionary periods (Figure 2a and Figure S5), as often their allele frequencies can be maintained at intermediate levels. However the majority of this variance is non-additive, with almost all of the additive variance eventually disappearing (Figure 2b and Figure S6).

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