Academic journal article Genetics

Directionality of Epistasis in a Murine Intercross Population

Academic journal article Genetics

Directionality of Epistasis in a Murine Intercross Population

Article excerpt

ABSTRACT

Directional epistasis describes a situation in which epistasis consistently increases or decreases the effect of allele substitutions, thereby affecting the amount of additive genetic variance available for selection in a given direction. This study applies a recent parameterization of directionality of epistasis to empirical data. Data stems from a QTL mapping study on an intercross between inbred mouse (Mus musculus) strains LG/J and SM/J, originally selected for large and small body mass, respectively. Results show a negative average directionality of epistasis for body-composition traits, predicting a reduction in additive allelic effects and in the response to selection for increased size. Focusing on average modification of additive effect of single loci, we find a more complex picture, whereby the effects of some loci are enhanced consistently across backgrounds, while effects of other loci are decreased, potentially contributing to either enhancement or reduction of allelic effects when selection acts at single loci. We demonstrate and discuss how the interpretation of the overall measurement of directionality depends on the complexity of the genotype-phenotype map. The measure of directionality changes with the power of scale in a predictable way; however, its expected effect with respect to the modification of additive genetic effects remains constant.

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EPISTASIS is present when the effect of a genetic substitution depends on the genotypes at other loci. At the population level, this means that average allelic effects change as allele frequencies at other loci change, and thus that gene effects can evolve. The evolutionary significance of epistasis has been recognized mainly in relation to the allele-frequency changes that are caused by genetic drift (e.g., Goodnight 1987, 1988, 1995; Cheverud and Routman 1996; Barton and Turelli 2004; De Brito et al. 2005; Turelli and Barton 2006), whereas the epistatic effects under directional selection have been treated only recently (e.g., Carter et al. 2005; Weinreich et al. 2005; Carlborg et al. 2006; Hansen et al. 2006; Yukilevich et al. 2008). Technically, the effects of epistatic interaction can be considered as having two aspects: the architecture itself (i.e., the existence of a nonadditive component, the so-called functional aspect, see below), and the effect of allele frequency on genetic variance (i.e., the statistical aspect). An additional consideration is crucial for the response to selection of a given trait, namely that the response is generated by the joint action of many epistatic interactions. Each of the interactions can either enhance or diminish the additive genetic effect in any specific phenotypic dimension. Their composite effect depends on the pattern, i.e., whether the effects accumulate or cancel each other out (Hansen and Wagner 2001a,b; Carter et al. 2005; Hansen et al. 2006). In the following we provide a brief general account of epistasis and then focus on the effect of its composite pattern, the empirical assessment of which is the goal of this study.

The traditional population-genetic approach to selection response initially emphasized additive genetic variance and treated any variance unexplained by the additive effects, including variance due to interactions within or between loci, as residual variance (Fisher 1918). Later this model was extended to account for epistasis (Cockerham 1954, Kempthorne 1954). The interaction component of this residual variance is dependent on population allele frequencies at the interacting loci. Starting with nonadditive effects within a single locus (dominance), Falconer (1960) described the effect of allele frequencies on the statistical measure of average allelic effect. Cheverud and Routman (1995) explored the analogous effect at the two-locus level, leading to distinction between allele-frequencydependent statistical epistasis (contributing to epistatic variance) on population level, and allele-frequencyindependent physiological (or functional) epistasis on the individual level, which contributes to all the genetic variance components, i. …

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