Publication

Extracting phylogenetic dimensions of coevolution reveals hidden functional signals

Résumé

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.

À propos de ce résultat
Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.

Graph Chatbot

Chattez avec Graph Search

Posez n’importe quelle question sur les cours, conférences, exercices, recherches, actualités, etc. de l’EPFL ou essayez les exemples de questions ci-dessous.

AVERTISSEMENT : Le chatbot Graph n'est pas programmé pour fournir des réponses explicites ou catégoriques à vos questions. Il transforme plutôt vos questions en demandes API qui sont distribuées aux différents services informatiques officiellement administrés par l'EPFL. Son but est uniquement de collecter et de recommander des références pertinentes à des contenus que vous pouvez explorer pour vous aider à répondre à vos questions.