Improved functional overview of protein complexes using inferred epistatic relationships

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.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.The representation of genetic interactions as networks emerges from continuing studies aimed at characterizing the functions of individual genes, and anticipates systems biology analyses that focus on dynamic network behavior. An important testing ground for such approaches is the single cell eukaryote Saccharomyces cerevisiae, for which a more extensive knowledge of individual gene function has been established than for any other organism, and for which by far the largest set of gene-gene and protein-protein interactions has been assembled [1].For instance, the publication of the S. cerevisiae DNA sequence in 1996[2] allowed a set of yeast strains to be generated that each contained a disruption in a single gene [3]. This, and other strain sets, facilitated a wide range of systematic studies aimed at establishing the function of the genes, e.g. [4-8]. At the same time, a number of genetic [9,10] and biochemical methods [11,12] allow