title: Genome-wide consequences of deleting any single gene.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
authors.forename: Xinchen
authors.initials: X
authors.lastname: Teng
authors.forename: Margaret
authors.initials: M
authors.lastname: Dayhoff-Brannigan
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Cheng
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Gilbert
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Sing
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Diny
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Wheelan
authors.forename: Maitreya J
authors.initials: MJ
authors.lastname: Dunham
authors.forename: Jef D
authors.initials: JD
authors.lastname: Boeke
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Pineda
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics; D001483:Base Sequence; D019143:Evolution, Molecular; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D018740:Genetic Heterogeneity; D016681:Genome, Fungal; D042822:Genomic Instability; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013312:Stress, Physiological / Q000235:genetics