ArticleMolecular biology and evolution2015
Covariation Is a Poor Measure of Molecular Coevolution.
Article in Molecular biology and evolution, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Exploring cooperation among social pathogens: a computational perspective.FEMS microbiology reviews · 2026Review
- Developing and Applying RNA Empirical Models With Secondary Structure Insights for Orthoptera Phylogenetics.Ecology and evolution · 2025Article
- Protein Structural Phylogenetics.Genome biology and evolution · 2025Review
- PHACE: Phylogeny-Aware Detection of Molecular Coevolution.Molecular biology and evolution · 2025Article
- Identification of coevolving positions by ancestral reconstruction.Communications biology · 2025Article
- General strategies for using amino acid sequence data to guide biochemical investigation of protein function.Biochemical Society transactions · 2022Review
- Genomic Signatures of Mitonuclear Coevolution in Mammals.Molecular biology and evolution · 2022Article
- The Structural Determinants of Intra-Protein Compensatory Substitutions.Molecular biology and evolution · 2022Article
- Combined Theoretical, Bioinformatic, and Biochemical Analyses of RNA Editing by Adenine Base Editors.The CRISPR journal · 2022Article
- Covariance predicts conserved protein residue interactions important to the emergence and continued evolution of SARS-CoV-2 as a human pathogen.bioRxiv : the preprint server for biology · 2022Article
- Article
- Statistical characteristics of amino acid covariance as possible descriptors of viral genomic complexity.Scientific reports · 2019Article
- A multi-scale coevolutionary approach to predict interactions between protein domains.PLoS computational biology · 2019Article
- Accurate Classification of Biological and non-Biological Interfaces in Protein Crystal Structures using Subtle Covariation Signals.Scientific reports · 2019Article
- Simultaneous Bayesian inference of phylogeny and molecular coevolution.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- CoevDB: a database of intramolecular coevolution among protein-coding genes of the bony vertebrates.Nucleic acids research · 2019Article
- Pathogenicity of the H1N1 influenza virus enhanced by functional synergy between the NPV100I and NAD248N pair.PloS one · 2019Article
- Numerical Encodings of Amino Acids in Multivariate Gaussian Modeling of Protein Multiple Sequence Alignments.Molecules (Basel, Switzerland) · 2018Article
- Article
- Applications of sequence coevolution in membrane protein biochemistry.Biochimica et biophysica acta. Biomembranes · 2018Review
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3 authors.
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Abstract
Recent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein's core, which explains covariation methods' ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the "coevolution paradox": The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations.
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