Prevalent positive epistasis in Escherichia coli and Saccharomyces 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 networks(1-3), the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear(4-6). We have addressed this question through in silico mapping of positive and negative epistatic interactions amongst biochemical reactions within the metabolic networks of Escherichia coli and Saccharomyces 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, unexpectedly, often occurs between reactions without overlapping functions. We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

This project was supported financially by file NSFC (No. 20802082) and 30830115) and funds from the Chinese Academy of Sciences ("Xibuzhiguang" to W.-L.X and No. KSCX1-YW-R-24), the Major State Basic Research Development program of China (Nos. 2009CB522303 and 2009CB940900), the Young Academic and Technical Leader Rising Foundation of Yunnan province (2006PY0147), and the Natural Science Foundation of Yunnan Province (2005XY04 and 2006B0042Q).