A global genetic interaction network maps a wiring diagram of cellular function

Abstract

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell.

Cellular responses to proteostasis perturbations reveal non-optimal feedback in chaperone networks

“…This suggests that there are additional cellular responses that can take care of defects arising due to jjj1Δ, but are not part of the basal response to the deletion. We checked for the negative genetic interactors of jjj1Δ and found that one of the transcription factors responsible for oxidative stress response are among the top ten ( Figure 5B) (26,33). This led us to hypothesize, that a specific branch of oxidative response work in parallel with jjj1, upregulation of this pathway should lead to abrogation of the fitness defect of jjj1Δ.…”

“…Genetic interactions as obtained through fitness epistasis scores (ε) (26) define functional relationships between pathways; we asked if cellular response is commensurate with epistatic interactions. When not peer-reviewed) is the author/funder.…”

“…We downloaded the transcriptome fold changes as provided in the supplementary files by in a recent report by Kemmeren et al, (27) and mapped the deletion from the columns in the provided data set to deletions in the epistasis score matrix (26) and extracted their epistasis profiles. 511 mutants out of the 700 mutants mapped to the epistasis score matrix.…”

“…We also thank Gopal G. Jayaraj and Satya Pandey for critically reading the manuscript. A) Transcriptional alteration of each gene (fold change in a PQC gene deletion with respect to WT strain from this study) is plotted against their epistasis score (ε) as reported (26).…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…In yeast, large-scale studies have begun to define gene interaction networks. 98,99 In mice and humans, a combination of empirical evidence and literature review has begun to define the circuitry of networks associated with disease. 100,101 In many species, modifier genes are readily identified for both simple and complex traits.…”