An Evolutionary Perspective on Epistasis and the Missing Heritability

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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. In this study we have shown that two independent problems may have a common cause. Why do traits under selection exhibit additive genetic variance, and why is the proportion of the heritability explained by additive effects much smaller than the total heritability estimated to exist? Our results indicate that epistatic interactions can allow deleterious mutations to persist under selection and that these interactions can abate the depletion of additive genetic variation. Furthermore, a much larger element of non-additive genetic variance is maintained, which supports the notion that the heritability estimated from family studies could be a mixture of both additive and non-additive components. We show that searching directly for epistatic effects greatly improves the discovery of variants under selection, despite the multiple testing penalty being much larger. Finally, we demonstrate that common practices in genome-wide association studies could lead to both an ascertainment bias in detecting additive effects and a confirmation bias in perceiving that most of the genetic variance is additive.

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