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Gene function prediction from congruent synthetic lethal interactions in yeast
Ping Ye1, Brian D Peyser, Xuewen Pan
1Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
Abstract:
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.
Insights
Synthetic lethal genetic interactions in yeast predict gene function and pathway relationships. This approach identified novel gene roles and functions in cell cycle regulation, applicable to broader genomic screens.
Area of Science:
- Genetics
- Molecular Biology
- Systems Biology
Background:
- Synthetic lethal genetic interactions reveal functional relationships between genes.
- Genes in synthetic lethal pairs often function in parallel or compensating pathways.
- Congruent gene pairs, sharing synthetic lethal partners, indicate genes within the same pathway branch.
Purpose of the Study:
- To predict gene function and cellular phenotypes using synthetic lethality data.
- To elucidate the roles of genes in parallel pathways, specifically the mitotic exit network (MEN) and Cdc14 early anaphase release pathways.
- To identify novel gene functions and pathway memberships, such as YLL049W in the dynein-dynactin pathway and Sin3/Rpd3 in mitotic exit.
Main Methods:
- Analysis of synthetic lethal genetic interactions in Saccharomyces cerevisiae.
- Integration of phenotypic and protein interaction data to define gene relationships.
- Application of congruence analysis to predict pathway membership and phenotypes.
- Performing synthetic lethal screens to investigate parallel pathways and their interactions with regulatory complexes.
Main Results:
- Synthetic lethal interactions and congruence effectively predict gene function and pathway organization.
- Predicted phenotypes like benomyl sensitivity and nuclear migration defects were correlated with congruence, not direct synthetic lethality.
- YLL049W was identified as a novel component of the dynein-dynactin pathway.
- A novel function for the Sin3/Rpd3 histone deacetylase in promoting mitotic exit, parallel to the MEN pathway, was uncovered.
Conclusions:
- In silico prediction of gene function and phenotypes using synthetic lethality is a powerful approach.
- This methodology can map genes to specific pathway branches and identify novel pathway components.
- The findings are broadly applicable to large-scale genomic synthetic lethality screens in yeast and RNA interference screens in metazoans.
