ArticlePLoS genetics2014
Mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed.
- Core elements play distinct roles in promoter birth and transcriptional regulation.Nature communications · 2026Article
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- Context dependency is essential for predicting intrahost evolution.Nature ecology & evolution · 2026Article
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- HJ Muller and the Relationship Between Sex Chromosome Degeneration and the Evolution of Dosage Compensation.Genome biology and evolution · 2025Review
- Idiosyncratic evolvability among single-point ribosomal mutants towards multi-aminoglycoside resistance.PLoS genetics · 2025Article
- Evolution of pollutant biodegradation.Applied microbiology and biotechnology · 2025Review
- Enhanced catabolism of glycine betaine and derivatives provides improved osmotic stress protection inApplied and environmental microbiology · 2024Article
- Frustration can Limit the Adaptation of Promiscuous Enzymes Through Gene Duplication and Specialisation.Journal of molecular evolution · 2024Article
- A continuous epistasis model for predicting growth rate given combinatorial variation in gene expression and environment.Cell systems · 2024Article
- Metagenomic insights into the response of soil microbial communities to pathogenicFrontiers in plant science · 2024Article
- Mechanistic causes of sign epistasis and its applications.Frontiers in genetics · 2024Review
- On the incongruence of genotype-phenotype and fitness landscapes.PLoS computational biology · 2022Article
- Reversion is most likely under high mutation supply when compensatory mutations do not fully restore fitness costs.G3 (Bethesda, Md.) · 2022Article
- Mutational robustness changes during long-term adaptation in laboratory budding yeast populations.eLife · 2022Article
- A Family of Fitness Landscapes Modeled through Gene Regulatory Networks.Entropy (Basel, Switzerland) · 2022Article
- Environmental selection and epistasis in an empirical phenotype-environment-fitness landscape.Nature ecology & evolution · 2022Article
- Genetic Context Significantly Influences the Maintenance and Evolution of Degenerate Pathways.Genome biology and evolution · 2021Article
- Spurious regulatory connections dictate the expression-fitness landscape of translation factors.Molecular systems biology · 2021Article
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4 authors.
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Abstract
How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.
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