Article abstract
Nature Genetics 39, 199 - 206 (2007)
Published online: 7 January 2007 | doi:10.1038/ng1948
Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions
Robert P St Onge1, Ramamurthy Mani2, Julia Oh1, Michael Proctor1, Eula Fung1, Ronald W Davis1, Corey Nislow3, Frederick P Roth2,4 & Guri Giaever3
Abstract
Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination–derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.
- Department of Biochemistry, Stanford University, Stanford, California 94305, USA.
- Biological Chemistry and Molecular Pharmacology Department, Harvard, Boston, Massachusetts 02115, USA.
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S3E1, Canada.
- Center for Cancer Systems Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Correspondence to: Frederick P Roth2,4 e-mail: froth@hms.harvard.edu
Correspondence to: Guri Giaever3 e-mail: guri.giaever@utoronto.ca
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