title: Mapping pathways and phenotypes by systematic gene overexpression.
abstract: Many disease states result from gene overexpression, often in a specific genetic context. To explore gene overexpression phenotypes systematically, we assembled an array of 5280 yeast strains, each containing an inducible copy of an S. cerevisiae gene, covering >80% of the genome. Approximately 15% of the overexpressed genes (769) reduced growth rate. This gene set was enriched for cell cycle-regulated genes, signaling molecules, and transcription factors. Overexpression of most toxic genes resulted in phenotypes different from known deletion mutant phenotypes, suggesting that overexpression phenotypes usually reflect a specific regulatory imbalance rather than disruption of protein complex stoichiometry. Global overexpression effects were also assayed in the context of a cyclin-dependent kinase mutant (pho85Delta). The resultant gene set was enriched for Pho85p targets and identified the yeast calcineurin-responsive transcription factor Crz1p as a substrate. Large-scale application of this approach should provide a strategy for identifying target molecules regulated by specific signaling pathways.
authors.affiliation: Department of Medical Genetics and Microbiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Richelle
authors.initials: R
authors.lastname: Sopko
authors.forename: Dongqing
authors.initials: D
authors.lastname: Huang
authors.forename: Nicolle
authors.initials: N
authors.lastname: Preston
authors.forename: Gordon
authors.initials: G
authors.lastname: Chua
authors.forename: Balázs
authors.initials: B
authors.lastname: Papp
authors.forename: Kimberly
authors.initials: K
authors.lastname: Kafadar
authors.forename: Mike
authors.initials: M
authors.lastname: Snyder
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Oliver
authors.forename: Martha
authors.initials: M
authors.lastname: Cyert
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Charles
authors.initials: C
authors.lastname: Boone
authors.forename: Brenda
authors.initials: B
authors.lastname: Andrews
mesh_terms: D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D029701:Saccharomyces cerevisiae Proteins