Prevalent positive epistasis in E. coli and S. cerevisiae metabolic networks

Epistasis refers to the interaction between genes. Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks1-3, to what extent genetic epistasis reflects biologically meaningful interactions remains unclear4-6. We address this question by in silico mapping of positive and negative epistatic interactions amongst biochemical reactions within the metabolic networks of E. coli and S. cerevisiae using flux balance analysis. We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant, and surprisingly, often occurs between reactions without overlapping functions. We offered mechanistic explanations of these findings and experimentally validated them for 61 S. cerevisiae gene pairs.