Genome-wide Consequences of Deleting Any Single Gene

TLDR

Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. The study aims to determine whether perturbing any single gene can drive subsequent genetic changes. The authors examined the yeast knockout collection for secondary mutations of functional consequence. Most gene knockouts acquired a secondary mutation affecting nutrient response or heat‑stress cell death, often targeting the same gene across independent knockouts, and sequencing revealed mutations in human tumor suppressor homologs, indicating that loss of any single gene can trigger genomic imbalance and adaptive changes.

Abstract

Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known whether only a select subset of genes is responsible for driving further changes. To determine whether perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild-type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance, with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses but is a logical consequence of losing a functional unit originally acquired under pressure during evolution.