ArticleNature2016
Local fitness landscape of the green fluorescent protein.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 306 papers.
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Who cites it
306 citing papers in PubMed.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Synthetic Approaches as Empirical Tools for Testing Evolutionary Theory.Genome biology and evolution · 2026Review
- Functional alignment of protein language models via reinforcement learning.Nature communications · 2026Article
- Deconstructing empirical fitness seascapes across scales of granularity.G3 (Bethesda, Md.) · 2026Article
- Article
- The limits of bio-molecular modeling with large language models: a cross-scale evaluation.Bioinformatics (Oxford, England) · 2026Article
- The adaptive landscapes of three globaleLife · 2026Article
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- 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
- Evolution-guided engineering of an ancient nitrogenase interface enhances enzyme activity and stability.bioRxiv : the preprint server for biology · 2026Article
- Limitations of the refolding pipeline for de novo protein design.Protein science : a publication of the Protein Society · 2026Article
- Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.PLoS genetics · 2026Article
- Scalable and cost-efficient custom gene library assembly from oligopools.Science advances · 2026Article
- Mount Fuji's stubby peak: the genotypic density of additive landscapes near maximal fitness.bioRxiv : the preprint server for biology · 2026Article
- Descent from a common ancestor restricts exploration of protein sequence space.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Supervised learning of protein variant effects across large-scale mutagenesis datasets.Protein science : a publication of the Protein Society · 2026Article
- Determinants of metal import and specificity in a bacterial transporter.bioRxiv : the preprint server for biology · 2026Article
- Kozak sequences regulate gene expression in Trypanosoma brucei.Nucleic acids research · 2026Article
- Functional protein design and enhancement with ontology reinforcement iteration.Nature communications · 2026Article
246 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors.
Funding
Abstract
Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here we visualize an extensive region of the local fitness landscape of the green fluorescent protein from Aequorea victoria (avGFP) by measuring the native function (fluorescence) of tens of thousands of derivative genotypes of avGFP. We show that the fitness landscape of avGFP is narrow, with 3/4 of the derivatives with a single mutation showing reduced fluorescence and half of the derivatives with four mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations and mostly occurred through the cumulative effect of slightly deleterious mutations causing a threshold-like decrease in protein stability and a concomitant loss of fluorescence. A model of orthologous sequence divergence spanning hundreds of millions of years predicted the extent of epistasis in our data, indicating congruence between the fitness landscape properties at the local and global scales. The characterization of the local fitness landscape of avGFP has important implications for several fields including molecular evolution, population genetics and protein design.
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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.