Suboptimal Global Transcriptional Response Increases the Harmful Effects of Loss-of-Function Mutations

Area of Science:

• Molecular Biology
• Genetics
• Systems Biology

Background:

• Loss-of-function mutations are typically assumed to impact fitness by losing specific gene functions.
• The resulting changes in gene expression (transcriptome) after gene inactivation are often considered specific to the deleted gene.

Purpose of the Study:

• To investigate whether the transcriptomic response to gene deletion is specific or nonspecific.
• To determine if nonspecific transcriptomic rewiring contributes to the fitness cost of mutations.
• To explore strategies for mitigating the fitness defects caused by gene deletions.

Main Methods:

• Analysis of transcriptomes from approximately 1,500 single-gene deletion strains of Saccharomyces cerevisiae.
• Experimental manipulation to elevate expression levels of downregulated genes in deletion mutants.

Main Results:

• Most transcriptomic changes observed were not specific to the deleted gene but were general responses to cellular perturbation.
• Gene deletions affecting the expression of dosage-sensitive genes resulted in particularly severe fitness defects.
• Increasing the expression of downregulated genes partially rescued the fitness defects associated with gene deletions.

Conclusions:

• The transcriptomic response to gene inactivation is often nonspecific, mimicking responses to environmental stress.
• This nonspecific rewiring of gene expression contributes to the fitness cost of loss-of-function mutations.
• Targeting these widespread transcriptional changes offers a potential therapeutic strategy for mitigating mutation effects.