The Causes of Epistasis in Genetic Networks

Epistasis stands for the non-additive interactions between genes in determining phenotypes. Considerable efforts have shown that, even for a given organism, epistasis may vary both in intensity and sign. Recent comparative studies suggested that the overall sign of epistasis switches from positive to negative as the complexity of organisms increases, and it has been hypothesized that this change shall be a consequence of the underlying gene network properties. Why should this be the case? What characteristics of genetic networks determine the sign of epistasis? Here we show, by evolving genetic networks that differ in their complexity and robustness against perturbations, while still performing the same tasks, that robustness increased with complexity and that epistasis was positive for small non-robust networks but negative for large robust ones. Our results indicate that robustness and negative epistasis appear as a consequence of the existence of redundant elements in regulatory structures of genetic networks and that the correlation between complexity and epistasis seems to be a byproduct of such redundancy, allowing for a decoupling of epistasis from complexity.