ArticleScientific reports2022
Extracting phylogenetic dimensions of coevolution reveals hidden functional signals.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- RoBep: a region-oriented deep learning model for B-cell epitope prediction.Bioinformatics (Oxford, England) · 2026Article
- Co-Var, a Measure to Determine Intra-protein, Inter-protein, Protein-DNA, or Protein-RNA Coevolution.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Phylogenetic corrections and higher-order sequence statistics in protein families: Potts vs multiple sequence alignment transformer machine learning models.Physical review research · 2025Article
- Shannon Entropy and Informational Redundancy in Minimally Monophyletic Bryophyte Genera.Plants (Basel, Switzerland) · 2025Article
- Article
- Identification of coevolving positions by ancestral reconstruction.Communications biology · 2025Article
- Efficient epistasis inference via higher-order covariance matrix factorization.bioRxiv : the preprint server for biology · 2024Article
- Impact of phylogeny on the inference of functional sectors from protein sequence data.PLoS computational biology · 2024Article
- Article
- Impact of phylogeny on structural contact inference from protein sequence data.Journal of the Royal Society, Interface · 2023Article
- Binding and Functional Folding (BFF): A Physiological Framework for Studying Biomolecular Interactions and Allostery.Journal of molecular biology · 2022Review
- Protein language models trained on multiple sequence alignments learn phylogenetic relationships.Nature communications · 2022Article
- Computational Docking Reveals Co-Evolution of C4 Carbon Delivery Enzymes in Diverse Plants.International journal of molecular sciences · 2022Article
- Correlations from structure and phylogeny combine constructively in the inference of protein partners from sequences.PLoS computational biology · 2022Article
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Authors and funding
4 authors at 2 institutions in 3 countries.
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Abstract
Despite the structural and functional information contained in the statistical coupling between pairs of residues in a protein, coevolution associated with function is often obscured by artifactual signals such as genetic drift, which shapes a protein's phylogenetic history and gives rise to concurrent variation between protein sequences that is not driven by selection for function. Here, we introduce a background model for phylogenetic contributions of statistical coupling that separates the coevolution signal due to inter-clade and intra-clade sequence comparisons and demonstrate that coevolution can be measured on multiple phylogenetic timescales within a single protein. Our method, nested coevolution (NC), can be applied as an extension to any coevolution metric. We use NC to demonstrate that poorly conserved residues can nonetheless have important roles in protein function. Moreover, NC improved the structural-contact predictions of several coevolution-based methods, particularly in subsampled alignments with fewer sequences. NC also lowered the noise in detecting functional sectors of collectively coevolving residues. Sectors of coevolving residues identified after application of NC were more spatially compact and phylogenetically distinct from the rest of the protein, and strongly enriched for mutations that disrupt protein activity. Thus, our conceptualization of the phylogenetic separation of coevolution provides the potential to further elucidate relationships among protein evolution, function, and genetic diseases.
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