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Open Access Methodology article

Improved functional overview of protein complexes using inferred epistatic relationships

Colm Ryan13*, Derek Greene1, Aude Guénolé2, Haico van Attikum2, Nevan J Krogan3, Pádraig Cunningham1 and Gerard Cagney4*

Author Affiliations

1 School of Computer Science and Informatics, University College Dublin, Ireland

2 Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands

3 Department of Cellular and Molecular Pharmacology and California Institute of Quantitative Biosciences, University of California, San Francisco, CA 94158, USA

4 School of Biomolecular and Biomedical Science, University College Dublin, Ireland

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BMC Systems Biology 2011, 5:80  doi:10.1186/1752-0509-5-80

Published: 23 May 2011

Abstract

Background

Epistatic Miniarray Profiling(E-MAP) quantifies the net effect on growth rate of disrupting pairs of genes, often producing phenotypes that may be more (negative epistasis) or less (positive epistasis) severe than the phenotype predicted based on single gene disruptions. Epistatic interactions are important for understanding cell biology because they define relationships between individual genes, and between sets of genes involved in biochemical pathways and protein complexes. Each E-MAP screen quantifies the interactions between a logically selected subset of genes (e.g. genes whose products share a common function). Interactions that occur between genes involved in different cellular processes are not as frequently measured, yet these interactions are important for providing an overview of cellular organization.

Results

We introduce a method for combining overlapping E-MAP screens and inferring new interactions between them. We use this method to infer with high confidence 2,240 new strongly epistatic interactions and 34,469 weakly epistatic or neutral interactions. We show that accuracy of the predicted interactions approaches that of replicate experiments and that, like measured interactions, they are enriched for features such as shared biochemical pathways and knockout phenotypes. We constructed an expanded epistasis map for yeast cell protein complexes and show that our new interactions increase the evidence for previously proposed inter-complex connections, and predict many new links. We validated a number of these in the laboratory, including new interactions linking the SWR-C chromatin modifying complex and the nuclear transport apparatus.

Conclusion

Overall, our data support a modular model of yeast cell protein network organization and show how prediction methods can considerably extend the information that can be extracted from overlapping E-MAP screens.