A probabilistic method to identify compensatory substitutions for pathogenic mutations

B. C. Easton*, A. V. Isaev, G. A. Huttley, P. Maxwell

*Corresponding author for this work

    Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

    1 Citation (Scopus)

    Abstract

    Complex systems of interactions govern the structure and function of biomolecules. Mutations that substantially disrupt these interactions are deleterious and should not persist under selection. Yet, several instances have been reported where a variant confirmed as pathogenic in one species is fixed in the orthologs of other species. Here we introduce a novel method for detecting compensatory substitutions for these so-called compensated pathogenic deviations (CPDs), incorporating knowledge of pathogenic variants into a probabilistic method for detecting correlated evolution. The success of this approach is demonstrated for 26 of 31 CPDs observed in mitochondrial transfer RNAs and for one in beta hemoglobin. The detection of multiple compensatory sites is demonstrated for two of these CPDs. The methodology is applicable to comparative sequence data for biomolecules expressed in any alphabet, real or abstract. It provides a widely applicable approach to the prediction of compensatory substitutions for CPDs, avoiding any reliance on rigid non-probabilistic criteria or structural data. The detection of compensatory substitutions that facilitate the substitution of otherwise pathogenic variants offers valuable insight into the molecular constraints imposed on adaptive evolution.

    Original languageEnglish
    Title of host publicationProceedings of the 5th Asia-Pacific Bioinformatics Conference, APBC 2007
    PublisherImperial College Press
    Pages195-204
    Number of pages10
    ISBN (Print)9781860947834
    DOIs
    Publication statusPublished - 2007
    Event5th Asia-Pacific Bioinformatics Conference, APBC 2007 - Hong Kong, Hong Kong
    Duration: 15 Jan 200717 Jan 2007

    Publication series

    NameSeries on Advances in Bioinformatics and Computational Biology
    Volume5
    ISSN (Print)1751-6404

    Conference

    Conference5th Asia-Pacific Bioinformatics Conference, APBC 2007
    Country/TerritoryHong Kong
    CityHong Kong
    Period15/01/0717/01/07

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