Systematic analysis of bypass suppression of essential genes

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.

Diverse natural variants suppress mutations in hundreds of essential genes

“…We next sought to identify the causal suppressor genes. As each of the mapped suppressor regions harbors tens of plausible candidate genes, we computationally prioritised them based on their functional connection to the query gene (Data S6, Methods, (van Leeuwen et al 2020)). We also included known general modifiers, such as MKT1 and HAP1 , that each affect the expression of thousands of genes (Fay 2013; Parts et al 2014; Albert et al 2014, 2018).…”

“…However, this subcomplex would not assemble in the absence of the NSE3 gene, and the NSE1 mutant allele does not rescue a nse3Δ deletion mutant (Figure S6). Comparison of our suppressors with a systematic survey of bypass suppression of essential gene deletion mutants (van Leeuwen et al 2020), showed little overlap in the identified suppressable essential genes, suggesting that the vast majority of standing variation suppressors will depend on the presence of the TS allele.…”

“…This could indicate that the suppressor allele complements an independent deficiency in the reference strain (consistent suppression of GAB1 in all wild strains by the same GPI8 allele), or that the suppressor has co-evolved with the complex or pathway within (SMC5/6 complex and TORC2 pathway). Further, the vast majority of validated suppressor alleles likely conferred a gain-of-function phenotype compared to the reference allele (Data S7), whereas many of the spontaneous suppressor mutations isolated in the reference background had a loss-of-function effect (van Leeuwen et al 2016, 2020). Loss-of-function alleles are more likely to arise spontaneously as the underlying mutation events are more common, but may have a higher chance to be subjected to negative selection in natural population compared to gain-of-function variants.…”

“…For the allele swaps (see section “suppressor candidate validation”) we used strains from either the BY4741 deletion mutant collection ( MAT a xxxΔ::kanMX4 his3Δ1 leu2Δ0 ura3Δ0 met15Δ0 ; Euroscarf), or the TS-allele-on-plasmid collection ( MAT a xxxΔ::natR_kanR(Cterm) his3Δ1 leu2Δ0 ura3Δ0 [xxx-ts_kanR(Nterm), AgMFA2pr-hphR, URA3] ; (van Leeuwen et al 2020)).…”

“…Systematic identification of spontaneous mutations that can suppress fitness defects of “query” mutant alleles in a reference yeast strain has illuminated mechanisms of suppression (van Leeuwen et al 2016, 2017, 2020). These studies have shown that although deletion mutants are mainly suppressed by genes with a role in the same functional module, partial loss-of-function alleles are frequently suppressed by more general mechanisms affecting query protein expression or stability.…”