ArticleNature ecology & evolution2022
Expression level is a major modifier of the fitness landscape of a protein coding gene.
Article in Nature ecology & evolution, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Fitness costs of mobilised colistin resistance gene 3 (mcr-3): systematic review, epidemiological study, and functional analysis.EBioMedicine · 2025Pooled it
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- Reciprocal cross-feeding between bacteria can limit the emergence of metabolic dependencies.Applied and environmental microbiology · 2026Article
- Environmental and mutational modulation of collateral fitness effects informs their mechanisms.Molecular biology and evolution · 2026Article
- Mistranslation suppresses mistranscription in eukaryotes.Nature communications · 2026Article
- A slight mismatch between a gene's codon usage and the cellular tRNA supply is beneficial.Nature communications · 2026Article
- Phenotypic dominance emerges from activity fitness functions and molecular interactions.Genetics · 2026Article
- High Gene Expression Predicts Extremely Low Segregation of Deleterious Mutations in Large Penguin Populations.Molecular biology and evolution · 2025Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.Nature communications · 2025Article
- Functional Optimization in Distinct Tissues and Conditions Constrains the Rate of Protein Evolution.Molecular biology and evolution · 2024Article
- Transcriptome-wide expression landscape and starch synthesis pathway co-expression network in sorghum.The plant genome · 2024Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.bioRxiv : the preprint server for biology · 2024Article
- Evolutionary Analyses of Gene Expression Divergence in Panicum hallii: Exploring Constitutive and Plastic Responses Using Reciprocal Transplants.Molecular biology and evolution · 2023Article
- Genome-wide probing of eukaryotic nascent RNA structure elucidates cotranscriptional folding and its antimutagenic effect.Nature communications · 2023Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Weaker selection on genes with treatment-specific expression consistent with a limit on plasticity evolution in Arabidopsis thaliana.Genetics · 2023Article
- Fitness and Functional Landscapes of the E. coli RNase III Gene rnc.Molecular biology and evolution · 2023Article
- Genes Vary Greatly in Their Propensity for Collateral Fitness Effects of Mutations.Molecular biology and evolution · 2023Article
- Epistasis between promoter activity and coding mutations shapes gene evolvability.Science advances · 2023Article
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Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phenotypic consequence of a genetic mutation depends on many factors including the expression level of a gene. However, a comprehensive quantification of this expression effect is still lacking, as is a further general mechanistic understanding of the effect. Here, we measured the fitness effect of almost all (>97.5%) single-nucleotide mutations in GFP, an exogenous gene with no physiological function, and URA3, a conditionally essential gene. Both genes were driven by two promoters whose expression levels differed by around tenfold. The resulting fitness landscapes revealed that the fitness effects of at least 42% of all single-nucleotide mutations within the genes were expression dependent. Although only a small fraction of variation in fitness effects among different mutations can be explained by biophysical properties of the protein and messenger RNA of the gene, our analyses revealed that the avoidance of stochastic molecular errors generally underlies the expression dependency of mutational effects and suggested protein misfolding as the most important type of molecular error among those examined. Our results therefore directly explained the slower evolution of highly expressed genes and highlighted cytotoxicity due to stochastic molecular errors as a non-negligible component for understanding the phenotypic consequence of mutations.
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