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Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks

Nature Genetics volume 42, pages 272–276 (2010)Cite this article

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Abstract

Epistasis refers to the interaction between genes. Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks1,2,3, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear4,5,6. 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.

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Figure 1: Functions of E. coli metabolic reactions in glucose minimal medium.
Figure 2: Pairwise epistasis and functional association among 255 important reactions in E. coli.
Figure 3: Pairwise epistasis and functional association among 212 important reactions in yeast.
Figure 4: Epistasis (ε) and scaled epistasis (ε̃) among 17 yeast genes.

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Acknowledgements

We thank N. Bharucha, G. Kalay, A. Kumar, J. Ma and B. Williams for advice and assistance in yeast experiments, B. Palsson and his group for instruction on FBA, B.-Y. Liao for drawing Supplementary Figure 2 and M. Bakewell, S. Cho, W. Grus, B.-Y. Liao, and C. Maclean for valuable comments. This work was supported by research grants from the US National Institutes of Health and University of Michigan Center for Computational Medicine and Biology to J.Z.

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Author notes

  1. Xionglei He

    Present address: Present address: State Key Laboratory of Bio-control, College of Life Sciences, Sun Yat-Sen University, Guangzhou, China.,

  2. Xionglei He, Wenfeng Qian and Zhi Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ecology and Evolutionary Biology, Ann Arbor, Michigan, USA

    Xionglei He, Wenfeng Qian, Zhi Wang, Ying Li & Jianzhi Zhang

  2. Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Ying Li

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  1. Xionglei He
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Contributions

X.H. and J.Z. conceived the research; X.H., Z.W., W.Q. and J.Z. designed the experiments; X.H., W.Q., Z.W., Y.L. and J.Z. conducted the experiments; X.H., W.Q., Z.W. and J.Z. analyzed the data; X.H. and J.Z. drafted the manuscript and all authors contributed to the final manuscript writing and its revisions.

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Correspondence to Jianzhi Zhang.

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Supplementary Figures 1–5, Supplementary Tables 1–5 and Supplementary Note (PDF 3352 kb)

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He, X., Qian, W., Wang, Z. et al. Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks. Nat Genet 42, 272–276 (2010). https://doi.org/10.1038/ng.524

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