Gene function prediction from congruent synthetic lethal interactions in yeast.
We predicted gene function using synthetic lethal genetic interactions between null alleles in Saccharomyces cerevisiae. Phenotypic and protein interaction data indicate that synthetic lethal gene pairs function in parallel or compensating pathways. Congruent gene pairs, defined as sharing synthetic lethal partners, are in single pathway branches. We predicted benomyl sensitivity and nuclear migration defects using congruence; these phenotypes were uncorrelated with direct synthetic lethality. We also predicted YLL049W as a new member of the dynein-dynactin pathway and provided new supporting experimental evidence. We performed synthetic lethal screens of the parallel mitotic exit network (MEN) and Cdc14 early anaphase release pathways required for late cell cycle. Synthetic lethal interactions bridged genes in these pathways, and high congruence linked genes within each pathway. Synthetic lethal interactions between MEN and all components of the Sin3/Rpd3 histone deacetylase revealed a novel function for Sin3/Rpd3 in promoting mitotic exit in parallel to MEN. These in silico methods can predict phenotypes and gene functions and are applicable to genomic synthetic lethality screens in yeast and analogous RNA interference screens in metazoans.
Ye
Ping
P
Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Peyser
Brian D
BD
Pan
Xuewen
X
Boeke
Jef D
JD
Spencer
Forrest A
FA
Bader
Joel S
JS
D000483:Alleles; D001542:Benomyl / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D025141:Drug Resistance, Fungal; D005800:Genes, Fungal / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology; D008870:Microtubules / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological; D010641:Phenotype; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
C074860:CDC14 protein, S cerevisiae; D018797:Cell Cycle Proteins; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C512379:YLL049W protein, S cerevisiae; D017027:Protein Tyrosine Phosphatases; C071665:RPD3 protein, S cerevisiae; D006655:Histone Deacetylases; D001542:Benomyl