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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.

Pubmed ID: 16455487

Authors

  • Sopko R
  • Huang D
  • Preston N
  • Chua G
  • Papp B
  • Kafadar K
  • Snyder M
  • Oliver SG
  • Cyert M
  • Hughes TR
  • Boone C
  • Andrews B

Journal

Molecular cell

Publication Data

February 3, 2006

Associated Grants

  • Agency: Biotechnology and Biological Sciences Research Council, Id: BB/C505140/1

Mesh Terms

  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal
  • Genes, Fungal
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Signal Transduction