Systematic analysis of bypass suppression of essential genes.

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

doi:10.15252/msb.20209828

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.

Highlights

Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring
To systematically identify suppressor mutations that can bypass the requirement of an essential yeast gene, we developed a powerful approach for generating suppressors of essential gene deletion alleles
Cells were subsequently transferred to medium that selected against the plasmid carrying the TS allele of the query gene, to assess for growth in the absence of the essential query gene (Fig 1A)

Summary

Introduction

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. 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

Methods

Results

Conclusion