An Evolutionary Perspective on Epistasis and the Missing Heritability

PLoS Genetics, Feb 2013

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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An Evolutionary Perspective on Epistasis and the Missing Heritability

Citation: Hemani G, Knott S, Haley C ( An Evolutionary Perspective on Epistasis and the Missing Heritability Gibran Hemani 0 Sara Knott 0 Chris Haley 0 Trudy F. C. Mackay, North Carolina State University, United States of America 0 1 The Roslin Institute and Royal (Dick) School of Veterinary Science, University of Edinburgh , Edinburgh , United Kingdom , 2 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital , Edinburgh , United Kingdom , 3 Institute for Evolutionary Biology, University of Edinburgh , Edinburgh , United Kingdom 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. - Funding: GH would like to thank the BBSRC, Biosciences KTN, and Newsham Choice Genetics for the funding provided for his PhD. SK acknowledges funding from the BBSRC. CH is grateful for funding from the BBSRC and the MRC. This work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). The ECDF is partially supported by the eDIKT initiative ( http://www.edikt.org.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. There exists a paradox in evolutionary biology. Despite a nearubiquitous abundance of genetic variation [1] traits under selection often evolve more slowly than expected and, contrary to expectation, genetic variation is maintained under selection. This problem is known as stasis [2,3], and it is particularly evident in fitness-related traits where the genetic variation tends to be highest [4] yet there is commonly no observed response to selection at all [57]. There are a number of mechanisms by which this might arise, amongst which the most commonly cited are various forms of constraints [8,9] or stabilising selection [10]. Because stasis is widespread its properties may reveal insights into the genetic architecture of complex traits related to fitness and thus inform the strategies that are employed to detect their underlying genetic variants. After hundreds of genome-wide association (GWA) studies [11] a picture is emerging where the total genetic variation explained by variants that have been individually mapped to complex traits is vastly lower than the amount of genetic variation expected to exist as estimated from pedigreebased studies, a phenomenon that has come to be known as the problem of the missing heritability [12]. Again, there are probably numerous contributing factors, and ostensibly the most parsimonious explanation is that complex traits comprise many small effects that GWA studies are underpowered to detect [13,14], but whether this is the complete story deserves exploration. With respect to the fields of both the aforementioned issues, it is typical to model genetic variation using an additive framework, such that each allele affecting a trait acts in an independent, linear, cumulative manner. For many practical applications this is a very useful approach (e.g. [15,16]), but there does exist a popular school of thought that suggests that the mechanisms of gene action, and the architecture of complex traits, are actually much more complex than the additive model allows (e.g. [1720]). Epistasis, defined in functional terms as the event whereby the effect of one locus depends on the genotype at another locus, is one source of non-additive genetic variation. How it contributes to both the paradox of stasis and the problem of the missing heritability will be the focus of this study. The impo (...truncated)


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Gibran Hemani, Sara Knott, Chris Haley. An Evolutionary Perspective on Epistasis and the Missing Heritability, PLoS Genetics, 2013, Volume 9, Issue 2, DOI: 10.1371/journal.pgen.1003295