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

Károly Kovács, Zoltán Farkas, Djordje Bajić, Dorottya Kalapis, Andreea Daraba, Karola Almási, Bálint Kintses, Zoltán Bódi, Richard A. Notebaart, Juan F. Poyatos, Patrick Kemmeren, Frank C.P. Holstege, Csaba Pál, Balázs Papp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 ∼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.

Original languageEnglish
Pages (from-to)1137-1150
Number of pages14
JournalMolecular biology and evolution
Volume38
Issue number3
DOIs
Publication statusPublished - 3 Nov 2020

Keywords

  • fitness effect of mutations
  • gene deletion
  • gene expression regulation
  • genotype–phenotype map

Fingerprint Dive into the research topics of 'Suboptimal Global Transcriptional Response Increases the Harmful Effects of Loss-of-Function Mutations'. Together they form a unique fingerprint.

Cite this