Systematic analysis of bypass suppression of essential genes

Jolanda van Leeuwen, Carles Pons, Guihong Tan, Jason Zi Wang, Jing Hou, Jochen Weile, Marinella Gebbia, Wendy Liang, Ermira Shuteriqi, Zhijian Li, Maykel Lopes, Matej Ušaj, Andreia Dos Santos Lopes, Natascha van Lieshout, Chad L. Myers, Frederick P. Roth, Patrick Aloy, Brenda J. Andrews, Charles Boone

Research output: Contribution to journalArticlepeer-review

Abstract

Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane-associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line-specific essentiality in the Cancer Dependency Map (DepMap) project.

Original languageEnglish (US)
Article numbere9828
JournalMolecular Systems Biology
Volume16
Issue number9
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
We thank M. Costanzo, A. Batté, B. Ünlü, T. Sing, M. Hung, C. Ross, the Donnelly Sequencing Centre, and the Faculty of Medicine Flow Cytometry Facility for critical reading of the manuscript and technical assistance. We also thank J. Rine and A. Warren for discussion of bypass suppressor mechanisms. This work was supported by grants from the Canadian Institutes of Health Research (FDN‐143264 and FDN‐143265) (C.B., B.J.A.), the National Institutes of Health (R01HG005853) (C.B., B.J.A., C.L.M.), the Swiss National Science Foundation (PCEGP3_181242) (J.v.L.), and a Ramon y Cajal fellowship (RYC‐2017‐22959) (C.P.). C.B., B.J.A., F.P.R., and C.L.M. are Senior Fellows in the Canadian Institute for Advanced Research, Genetic Networks Program.

Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

  • compensatory evolution
  • gene essentiality
  • genetic interactions
  • genetic networks
  • genetic suppression

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