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Updated: May 6, 2026
Generation of Genomic Deletions in Mammalian Cell Lines via CRISPR/Cas9
Published on: January 3, 2015
Genome-wide consequences of deleting any single gene
Xinchen Teng1, Margaret Dayhoff-Brannigan, Wen-Chih Cheng
1Department 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.
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.
Insights
Altering any single gene can trigger further genetic mutations, even in yeast. These secondary mutations impact cell functions and can involve genes similar to human tumor suppressors, highlighting broad genomic instability.
Area of Science:
- Genomics
- Molecular Biology
- Evolutionary Biology
Background:
- Chromosomal segment alterations (loss or duplication) are linked to cancer development.
- The specific genes driving these subsequent genomic changes remain largely unknown.
- Understanding gene perturbation effects is crucial for cancer research.
Purpose of the Study:
- To investigate if altering any single gene can initiate subsequent genetic changes.
- To determine the functional consequences of such secondary mutations.
- To identify potential common pathways affected by single-gene knockouts.
Main Methods:
- Analysis of the yeast knockout collection.
- Screening for secondary mutations with functional consequences (nutrient responses, heat-stress cell death).
- Genome sequencing of evolved strains.
Main Results:
- Most gene knockout strains acquired secondary mutations, unlike wild-type strains.
- These mutations affected nutrient responses and/or heat-stress-induced cell death.
- Independent knockouts of the same gene frequently evolved mutations in the same secondary gene, suggesting convergent evolution.
- Sequencing revealed mutations in homologs of human tumor suppressor genes.
Conclusions:
- Perturbation of any single gene can induce genomic imbalance sufficient to drive adaptive genetic changes.
- This phenomenon complicates genetic analysis but reflects evolutionary pressures on gene function.
- The findings suggest a widespread vulnerability of genomes to single-gene disruptions.
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