Closely spaced multiple mutations as potential signatures of transient hypermutability in human genes

Authors

  • Jian-Min Chen,

    Corresponding author
    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Etablissement Français du Sang (EFS) – Bretagne, Brest, France
    3. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
    4. Institut Fédératif de Recherche (IFR) 148, Brest, France
    • INSERM, U613 and EFS – Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France
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  • Claude Férec,

    1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France
    2. Etablissement Français du Sang (EFS) – Bretagne, Brest, France
    3. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
    4. Institut Fédératif de Recherche (IFR) 148, Brest, France
    5. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
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  • David N. Cooper

    1. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Communicated by Jacques Beckmann

Abstract

Data from diverse organisms suggests that transient hypermutability is a general mutational mechanism with the potential to generate multiple synchronous mutations, a phenomenon probably best exemplified by closely spaced multiple mutations (CSMMs). Here we have attempted to extend the concept of transient hypermutability from somatic cells to the germline, using human inherited disease-causing multiple mutations as a model system. Employing stringent criteria for data inclusion, we have retrospectively identified numerous potential examples of pathogenic CSMMs that exhibit marked similarities to the CSMMs reported in other systems. These examples include (1) eight multiple mutations, each comprising three or more components within a sequence tract of <100 bp; (2) three possible instances of “mutation showers”; and (3) numerous highly informative “homocoordinate” mutations. Using the proportion of CpG substitution as a crude indicator of the relative likelihood of transient hypermutability, we present evidence to suggest that CSMMs comprising at least one pair of mutations separated by ≤100 bp may constitute signatures of transient hypermutability in human genes. Although this analysis extends the generality of the concept of transient hypermutability and provides new insights into what may be considered a novel mechanism of mutagenesis underlying human inherited disease, it has raised serious concerns regarding current practices in mutation screening.Hum Mutat 30:1–14, 2009. © 2009 Wiley-Liss, Inc.

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