Open AccessSuboptimal Global Transcriptional Response Increases the Harmful Effects of Loss-of-Function Mutations
Author(s) -
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
Publication year - 2020
Publication title -
molecular biology and evolution
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.637
H-Index - 218
eISSN - 1537-1719
pISSN - 0737-4038
DOI - 10.1093/molbev/msaa280
Subject(s) - biology , transcriptome , gene , genetics , loss function , gene expression , function (biology) , saccharomyces cerevisiae , regulation of gene expression , genetic fitness , mutation , gene dosage , computational biology , phenotype
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.