Synthetic genetic interactions reveal buffering mechanisms in the cell against genetic perturbations. These interactions have also been used to predict functional similarity of gene pairs. In this study, we perform a comprehensive evaluation of various methods for predicting co-pathway membership of genes. We identify shortcomings in known methods and use them to motivate a rigorous statistical framework for quantifying the contribution of each pathway to the functional similarity of gene pairs. We then use our model to infer interdependencies among KEGG pathways. The resulting KEGG crosstalk map yields significant insights into the high-level organization of the genetic network and is used to explain the effective scope of genetic interactions for predicting co-pathway membership of gene pairs. A direct byproduct of this e ort is that we are able to identify subsets of genes in each pathway that act as `ports' for interaction across pathways.

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