ArticlePLoS genetics2015
Functional Constraint Profiling of a Viral Protein Reveals Discordance of Evolutionary Conservation and Functionality.
Article in PLoS genetics, 2015. 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 33 papers.
What it found
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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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed.
- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- Deep mutational scanning and CRISPR-engineered viruses: tools for evolutionary and functional genomics studies.mSphere · 2025Review
- MMRT: MultiMut Recursive Tree for predicting functional effects of high-order protein variants from low-order variants.Computational and structural biotechnology journal · 2025Article
- ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction.bioRxiv : the preprint server for biology · 2023Article
- Deep mutational scanning reveals the functional constraints and evolutionary potential of the influenza A virus PB1 protein.Journal of virology · 2023Article
- Naturally occurring substitution of an amino acid in a plant virus gene-silencing suppressor enhances viral adaptation to increasing thermal stress.PLoS pathogens · 2023Article
- The ubiquitination landscape of the influenza A virus polymerase.Nature communications · 2023Article
- Accurate prediction of functional effect of single amino acid variants with deep learning.Computational and structural biotechnology journal · 2023Article
- Phylogenetic inference of changes in amino acid propensities with single-position resolution.PLoS computational biology · 2022Article
- Applications of Deep Mutational Scanning in Virology.Viruses · 2021Review
- Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein.mSystems · 2021Article
- Article
- Prediction of Function Determining and Buried Residues Through Analysis of Saturation Mutagenesis Datasets.Frontiers in molecular biosciences · 2021Article
- Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations.Molecular systems biology · 2020Article
- MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect.Genome biology · 2019Article
- Teaching an Old Virus New Tricks: A Review on New Approaches to Study Age-Old Questions in Influenza Biology.Journal of molecular biology · 2019Review
- Evolving generalists in switching rugged landscapes.PLoS computational biology · 2019Article
- Inferring protein 3D structure from deep mutation scans.Nature genetics · 2019Article
- Deep generative models of genetic variation capture the effects of mutations.Nature methods · 2018Article
- Multiplexed assays of variant effects contribute to a growing genotype-phenotype atlas.Human genetics · 2018Review
Corrections and comments
- Erratum issued
Authors and funding
11 authors.
Funding
Abstract
Viruses often encode proteins with multiple functions due to their compact genomes. Existing approaches to identify functional residues largely rely on sequence conservation analysis. Inferring functional residues from sequence conservation can produce false positives, in which the conserved residues are functionally silent, or false negatives, where functional residues are not identified since they are species-specific and therefore non-conserved. Furthermore, the tedious process of constructing and analyzing individual mutations limits the number of residues that can be examined in a single study. Here, we developed a systematic approach to identify the functional residues of a viral protein by coupling experimental fitness profiling with protein stability prediction using the influenza virus polymerase PA subunit as the target protein. We identified a significant number of functional residues that were influenza type-specific and were evolutionarily non-conserved among different influenza types. Our results indicate that type-specific functional residues are prevalent and may not otherwise be identified by sequence conservation analysis alone. More importantly, this technique can be adapted to any viral (and potentially non-viral) protein where structural information is available.
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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.