ArticleNucleic acids research2019
funtrp: identifying protein positions for variation driven functional tuning.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Predicting Functional Effects of Synonymous Variants: A Systematic Review and Perspectives.Frontiers in genetics · 2019Pooled it
- Identification of positions in human aldolase a that are neutral for apparent KArchives of biochemistry and biophysics · 2024Article
- Dynamics-based protein network features accurately discriminate neutral and rheostat positions.Biophysical journal · 2024Article
- Variant Effect Prediction in the Age of Machine Learning.Cold Spring Harbor perspectives in biology · 2024Review
- Rheostatic contributions to protein stability can obscure a position's functional role.Protein science : a publication of the Protein Society · 2024Article
- Broken silence: 22,841 predicted deleterious synonymous variants identified in the human exome through computational analysis.Genetics and molecular biology · 2024Article
- Evolutionary history of MEK1 illuminates the nature of deleterious mutations.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation.Archives of biochemistry and biophysics · 2023Article
- VariBench, new variation benchmark categories and data sets.Frontiers in bioinformatics · 2023Article
- Using mechanism similarity to understand enzyme evolution.Biophysical reviews · 2022Review
- Evaluating the relevance of sequence conservation in the prediction of pathogenic missense variants.Human genetics · 2022Article
- mebipred: identifying metal-binding potential in protein sequence.Bioinformatics (Oxford, England) · 2022Article
- Odd one out? Functional tuning of Zymomonas mobilis pyruvate kinase is narrower than its allosteric, human counterpart.Protein science : a publication of the Protein Society · 2022Article
- Structural Plasticity Is a Feature of Rheostat Positions in the Human NaInternational journal of molecular sciences · 2022Article
- Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.Protein science : a publication of the Protein Society · 2022Article
- Evolution-Based Protein Engineering for Antifungal Peptide Improvement.Molecular biology and evolution · 2021Article
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
- Substitutions at Nonconserved Rheostat Positions Modulate Function by Rewiring Long-Range, Dynamic Interactions.Molecular biology and evolution · 2021Article
- Article
- Low Diversity of Human Variation Despite Mostly Mild Functional Impact of De Novo Variants.Frontiers in molecular biosciences · 2021Article
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Authors and funding
5 authors.
Funding
Abstract
Evaluating the impact of non-synonymous genetic variants is essential for uncovering disease associations and mechanisms of evolution. An in-depth understanding of sequence changes is also fundamental for synthetic protein design and stability assessments. However, the variant effect predictor performance gain observed in recent years has not kept up with the increased complexity of new methods. One likely reason for this might be that most approaches use similar sets of gene and protein features for modeling variant effects, often emphasizing sequence conservation. While high levels of conservation highlight residues essential for protein activity, much of the variation observable in vivo is arguably weaker in its impact, thus requiring evaluation at a higher level of resolution. Here, we describe functionNeutral/Toggle/Rheostatpredictor (funtrp), a novel computational method that categorizes protein positions based on the position-specific expected range of mutational impacts: Neutral (weak/no effects), Rheostat (function-tuning positions), or Toggle (on/off switches). We show that position types do not correlate strongly with familiar protein features such as conservation or protein disorder. We also find that position type distribution varies across different protein functions. Finally, we demonstrate that position types can improve performance of existing variant effect predictors and suggest a way forward for the development of new ones.
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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.