ArticlePLoS genetics2010
Pervasive cryptic epistasis in molecular evolution.
Article in PLoS genetics, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 118 papers.
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Who cites it
118 citing papers in PubMed.
- Mechanisms of Phenotypic Evolution from Molecules to Organisms: Integrating Evolutionary Biochemistry and Evolutionary Developmental Biology.Annual review of ecology, evolution, and systematics · 2026Article
- Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.PLoS genetics · 2026Article
- Multidomain DNA-Protein Mining Reveals Polymorphic Variations in RhlB Enhancing Monorhamnolipid Biosynthesis.ACS synthetic biology · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Epistasis among clustered lineage-specific adaptive amino acid substitutions in the Drosophila Trio protein.bioRxiv : the preprint server for biology · 2025Article
- Widespread epistasis shapes RNA polymerase II active site function and evolution.Nature communications · 2025Article
- The Constructive Neutral Evolution of Behaviour.Ecology and evolution · 2025Article
- Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape.Science (New York, N.Y.) · 2025Article
- Recombinant inbred line panels inform the genetic architecture and interactions of adaptive traits in Drosophila melanogaster.G3 (Bethesda, Md.) · 2025Article
- Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.Molecular biology and evolution · 2025Article
- Identification of coevolving positions by ancestral reconstruction.Communications biology · 2025Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.Nature communications · 2025Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Article
- Emergent time scales of epistasis in protein evolution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.Nature communications · 2024Article
- Higher-order epistasis within Pol II trigger loop haplotypes.bioRxiv : the preprint server for biology · 2024Article
- Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.bioRxiv : the preprint server for biology · 2024Article
58 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
3 authors.
Funding
Abstract
The functional effects of most amino acid replacements accumulated during molecular evolution are unknown, because most are not observed naturally and the possible combinations are too numerous. We created 168 single mutations in wild-type Escherichia coli isopropymalate dehydrogenase (IMDH) that match the differences found in wild-type Pseudomonas aeruginosa IMDH. 104 mutant enzymes performed similarly to E. coli wild-type IMDH, one was functionally enhanced, and 63 were functionally compromised. The transition from E. coli IMDH, or an ancestral form, to the functional wild-type P. aeruginosa IMDH requires extensive epistasis to ameliorate the combined effects of the deleterious mutations. This result stands in marked contrast with a basic assumption of molecular phylogenetics, that sites in sequences evolve independently of each other. Residues that affect function are scattered haphazardly throughout the IMDH structure. We screened for compensatory mutations at three sites, all of which lie near the active site and all of which are among the least active mutants. No compensatory mutations were found at two sites indicating that a single site may engage in compound epistatic interactions. One complete and three partial compensatory mutations of the third site are remote and lie in a different domain. This demonstrates that epistatic interactions can occur between distant (>20Å) sites. Phylogenetic analysis shows that incompatible mutations were fixed in different lineages.
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