Abstract
BackgroundGenetic interactions pervade every aspect of biology, from evolutionary theory, where they determine the accessibility of evolutionary paths, to medicine, where they can contribute to complex genetic diseases. Until very recently, studies on epistatic interactions have been based on a handful of mutations, providing at best anecdotal evidence about the frequency and the typical strength of genetic interactions. In this study, we analyze a publicly available dataset that contains the growth rates of over five million double knockout mutants of the yeast Saccharomyces cerevisiae.ResultsWe discuss a geometric definition of epistasis that reveals a simple and surprisingly weak scaling law for the characteristic strength of genetic interactions as a function of the effects of the mutations being combined. We then utilized this scaling to quantify the roughness of naturally occurring fitness landscapes. Finally, we show how the observed roughness differs from what is predicted by Fisher's geometric model of epistasis, and discuss the consequences for evolutionary dynamics.ConclusionsAlthough epistatic interactions between specific genes remain largely unpredictable, the statistical properties of an ensemble of interactions can display conspicuous regularities and be described by simple mathematical laws. By exploiting the amount of data produced by modern high-throughput techniques, it is now possible to thoroughly test the predictions of theoretical models of genetic interactions and to build informed computational models of evolution on realistic fitness landscapes.
Highlights
Genetic interactions pervade every aspect of biology, from evolutionary theory, where they determine the accessibility of evolutionary paths, to medicine, where they can contribute to complex genetic diseases
Genetic interactions [1] have shaped the evolutionary history of life on earth
Study, we consider growth rate in yeast as an example of a complex trait modulated by genetic interactions
Summary
Genetic interactions pervade every aspect of biology, from evolutionary theory, where they determine the accessibility of evolutionary paths, to medicine, where they can contribute to complex genetic diseases. Genetic interactions [1] have shaped the evolutionary history of life on earth. They have been found to limit the accessibility of evolutionary paths [2], to confine populations to suboptimal evolutionary states and, on larger time scales, to control the rate of speciation [3]. Complex traits and diseases are determined by a multiplicity of genomic loci [5], whose independent effects and interactions [6] are often necessary to understand the phenotype of interest. We consider growth rate in yeast as an example of a complex trait modulated by genetic interactions
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