Nature Biotechnology
23, 561 - 566 (2005)
Published online: 5 May 2005; | doi:10.1038/nbt1096
Systematic interpretation of genetic interactions using protein networksRyan Kelley1, 2
& Trey Ideker1, 21
Program in Bioinformatics, University of California, San Diego, 9500 Gilman Dr., San Diego, California 92093-0412, USA. 2
Department of Bioengineering, University of California, San Diego, 9500 Gilman Dr., San Diego, California 92093-0412, USA.
Correspondence should be addressed to Trey Ideker trey@bioeng.ucsd.eduGenetic interaction analysis,in which two mutations have a combined effect not exhibited by either mutation alone, is a powerful and widespread tool for establishing functional linkages between genes. In the yeast Saccharomyces cerevisiae, ongoing screens have generated >4,800 such genetic interaction data. We demonstrate that by combining these data with information on protein-protein, prote in-DNA or metabolic networks, it is possible to uncover physical mechanisms behind many of the observed genetic effects. Using a probabilistic model, we found that 1,922 genetic interactions are significantly associated with either between- or within-pathway explanations encoded in the physical networks, covering  40% of known genetic interactions. These models predict new functions for 343 proteins and suggest that between-pathway explanations are better than within-pathway explanations at interpreting genetic interactions identified in systematic screens. This study provides a road map for how genetic and physical interactions can be integrated to reveal pathway organization and function.
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