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

The fitness impact of loss-of-function mutations is generally assumed to reflect the loss of specific molecular functions associated with the perturbed gene. Here, we propose that rewiring of the transcriptome upon deleterious gene inactivation is frequently nonspecific and mimics stereotypic responses to external environmental change. Consequently, transcriptional response to gene deletion could be suboptimal and incur an extra fitness cost. Analysis of the transcriptomes of similar to 1,500 single-gene deletion Saccharomyces cerevisiae strains supported this scenario. First, most transcriptomic changes are not specific to the deleted gene but are rather triggered by perturbations in functionally diverse genes. Second, gene deletions that alter the expression of dosage-sensitive genes are especially harmful. Third, by elevating the expression level of downregulated genes, we could experimentally mitigate the fitness defect of gene deletions. Our work shows that rewiring of genomic expression upon gene inactivation shapes the harmful effects of mutations.

Automated summary

The rewiring of the transcriptome upon gene inactivation is often nonspecific and mimics stereotypic responses to external environmental changes. Most transcriptomic changes after gene deletion are not specific to the deleted gene, but rather triggered by perturbations in functionally diverse genes. Additionally, gene deletions that alter the expression of dosage-sensitive genes can be particularly harmful.