ArticleeLife2019
Cryptic genetic variation shapes the adaptive evolutionary potential of enzymes.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- The bacterial phosphotransferase system-mediated rifampicin phosphorylation: ancestral links to rifampicin-inactivating enzyme.Frontiers in microbiology · 2026Article
- Time-Resolved Crystallography Reveals the Mechanisms of GTP hydrolysis for N-RAS and the Oncogenic Mutants G12C, G12V and Q61L.bioRxiv : the preprint server for biology · 2025Article
- A direct experimental test of Ohno's hypothesis.eLife · 2025Article
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System.ACS catalysis · 2025Article
- Continuous evolution of user-defined genes at 1 million times the genomic mutation rate.Science (New York, N.Y.) · 2024Article
- Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network.bioRxiv : the preprint server for biology · 2024Article
- Loop dynamics and the evolution of enzyme activity.Nature reviews. Chemistry · 2023Review
- Ribonuclease D Processes a Small RNA Regulator of Multicellular Development in Myxobacteria.Genes · 2023Article
- Robustness and innovation in synthetic genotype networks.Nature communications · 2023Article
- Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Logistic Regression-Guided Identification of Cofactor Specificity-Contributing Residues in Enzyme with Sequence Datasets Partitioned by Catalytic Properties.ACS synthetic biology · 2022Article
- The role of oligomerization in the optimization of cyclohexadienyl dehydratase conformational dynamics and catalytic activity.Protein science : a publication of the Protein Society · 2022Article
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- In vivo hypermutation and continuous evolution.Nature reviews. Methods primers · 2022Article
- Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- The adaptive landscape of a metallo-enzyme is shaped by environment-dependent epistasis.Nature communications · 2021Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Genetic variation among orthologous proteins can cause cryptic phenotypic properties that only manifest in changing environments. Such variation may impact the evolvability of proteins, but the underlying molecular basis remains unclear. Here, we performed comparative directed evolution of four orthologous metallo-β-lactamases toward a new function and found that different starting genotypes evolved to distinct evolutionary outcomes. Despite a low initial fitness, one ortholog reached a significantly higher fitness plateau than its counterparts, via increasing catalytic activity. By contrast, the ortholog with the highest initial activity evolved to a less-optimal and phenotypically distinct outcome through changes in expression, oligomerization and activity. We show how cryptic molecular properties and conformational variation of active site residues in the initial genotypes cause epistasis, that could lead to distinct evolutionary outcomes. Our work highlights the importance of understanding the molecular details that connect genetic variation to protein function to improve the prediction of protein evolution.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.