Genome-wide consequences of deleting any single gene

Xinchen Teng, Margaret Dayhoff-Brannigan, Wen Chih Cheng, Catherine E. Gilbert, Cierra N. Sing, Nicola L. Diny, Sarah J. Wheelan, Maitreya J. Dunham, Jef D. Boeke, Fernando J. Pineda, J. Marie Hardwick

Research output: Contribution to journalArticlepeer-review

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. •Knockouts of the same gene evolve similarly without applied environmental pressure•Yeast knockouts harbor meaningful second mutations that challenge genetic analyses•Common assumptions about problems with yeast knockout collections are unlikely•First (engineered) and evolved yeast mutations also co-occur in human tumors.

Original languageEnglish (US)
Pages (from-to)485-494
Number of pages10
JournalMolecular cell
Volume52
Issue number4
DOIs
StatePublished - Nov 21 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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