Mapping pathways and phenotypes by systematic gene overexpression.
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.
Sopko
Richelle
R
Department of Medical Genetics and Microbiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Huang
Dongqing
D
Preston
Nicolle
N
Chua
Gordon
G
Papp
Balázs
B
Kafadar
Kimberly
K
Snyder
Mike
M
Oliver
Stephen G
SG
Cyert
Martha
M
Hughes
Timothy R
TR
Boone
Charles
C
Andrews
Brenda
B
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*
D029701:Saccharomyces cerevisiae Proteins