Journal
PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
Volume 279, Issue 1745, Pages 4156-4164Publisher
ROYAL SOC
DOI: 10.1098/rspb.2012.1449
Keywords
epistasis; benefit-cost model; evolution; pleiotropy; modularity
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Funding
- NIH [R01 GM078209, R01 GM089978]
- NASA Astrobiology Institute
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Epistasis between mutations in two genes is thought to reflect an interdependence of their functions. While sometimes epistasis is predictable using mechanistic models, its roots seem, in general, hidden in the complex architecture of biological networks. Here, we ask how epistasis can be quantified based on the mathematical dependence of a system-level trait (e.g. fitness) on lower-level traits (e.g. molecular or cellular properties). We first focus on a model in which fitness is the difference between a benefit and a cost trait, both pleiotropically affected by mutations. We show that despite its simplicity, this model can be used to analytically predict certain properties of the ensuing distribution of epistasis, such as a global negative bias, resulting in antagonism between beneficial mutations, and synergism between deleterious ones. We next extend these ideas to derive a general expression for epistasis given an arbitrary functional dependence of fitness on other traits. This expression demonstrates how epistasis relative to fitness can emerge despite the absence of epistasis relative to lower level traits, leading to a formalization of the concept of independence between biological processes. Our results suggest that epistasis may be largely shaped by the pervasiveness of pleiotropic effects and modular organization in biological networks.
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