ArticleJournal of molecular biology2019
Pervasive Pairwise Intragenic Epistasis among Sequential Mutations in TEM-1 β-Lactamase.
Article in Journal of molecular biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Cryptic phenotypic variation emerges rapidly during the adaptive evolution of a carbapenemase.Nature ecology & evolution · 2026Article
- BEST: Basic Embedding Search Tool Enhancing Discovery of Novel Enzyme.Interdisciplinary sciences, computational life sciences · 2026Article
- Mistranslation suppresses mistranscription in eukaryotes.Nature communications · 2026Article
- ΦX174 bacteriophage viability predicted by protein biophysical modeling.bioRxiv : the preprint server for biology · 2025Article
- 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
- A protein dynamics-based deep learning model enhances predictions of fitness and epistasis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Biophysics-based protein language models for protein engineering.Nature methods · 2025Article
- Ultrahigh-Throughput Activity Engineering of Promiscuous Amidases through a Fluorescence-Activated Cell Sorting Assay.ACS catalysis · 2025Article
- Coevolutionary history of predation constrains the evolvability of antibiotic resistance in prey bacteria.npj antimicrobials and resistance · 2025Article
- Biophysics-based protein language models for protein engineering.bioRxiv : the preprint server for biology · 2025Article
- Article
- Pleiotropy, epistasis and the genetic architecture of quantitative traits.Nature reviews. Genetics · 2024Review
- Ultrahigh Throughput Evolution of Tryptophan Synthase in Droplets via an Aptamer Sensor.ACS catalysis · 2024Article
- Network of epistatic interactions in an enzyme active site revealed by large-scale deep mutational scanning.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Experimental andACS infectious diseases · 2022Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Article
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2 authors.
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Abstract
Interactions between mutations play a central role in shaping the fitness landscape, but a clear picture of intragenic epistasis has yet to emerge. To further reveal the prevalence and patterns of intragenic epistasis, we present a survey of epistatic interactions between sequential mutations in TEM-1 β-lactamase. We measured the fitness effect of ~12,000 pairs of consecutive amino acid substitutions and used our previous study of the fitness effects of single amino acid substitutions to calculate epistasis for over 8000 mutation pairs. Since sequential mutations are prone to physically interact, we postulated that our study would be surveying specific epistasis instead of nonspecific epistasis. We found widespread negative epistasis, especially in beta-strands, and a high frequency of negative sign epistasis among individually beneficial mutations. Negative epistasis (52%) occurred 7.6 times as frequently as positive epistasis (6.8%). Buried residues experienced more negative epistasis that surface-exposed residues. However, TEM-1 exhibited a couple of hotspots for positive epistasis, most notably L221/ R222 at which many combinations of mutations positively interacted. This study is the first to systematically examine pairwise epistasis throughout an entire protein performing its native function in its native host.
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