Complex gene rearrangements caused by serial replication slippage

Authors

  • Jian-Min Chen,

    Corresponding author
    1. INSERM (Institut National de la Santé et de la Recherche Médicale) U613 – Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang – Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire, Brest, France
    • INSERM U613, Etablissement Français du Sang – Bretagne, 46 rue Félix Le Dantec, 29220 Brest, France
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  • Nadia Chuzhanova,

    1. Biostatistics and Bioinformatics Unit, Cardiff University, Heath Park, Cardiff, United Kingdom
    2. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, United Kingdom
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  • Peter D. Stenson,

    1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, United Kingdom
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  • Claude Férec,

    1. INSERM (Institut National de la Santé et de la Recherche Médicale) U613 – Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang – Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire, Brest, France
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  • David N. Cooper

    1. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, United Kingdom
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  • Communicated by Michel Goossens

Abstract

The now-classical model of replication slippage can in principle account for both simple deletions and tandem duplications associated with short direct repeats. Invariably, a single replication slippage event is invoked, irrespective of whether simple deletions or tandem duplications are involved. However, we recently identified three complex duplicational insertions that could also be accounted for by a model of serial replication slippage. We postulate that a sizeable proportion of hitherto inexplicable complex gene rearrangements may be explained by such a model. To test this idea, and to assess the generality of our initial findings, a number of complex gene rearrangements were selected from the Human Gene Mutation Database (HGMD). Some 95% (20/21) of these mutations were found to be explicable by twin or multiple rounds of replication slippage, the sole exception being a double deletion in the F9 gene that is associated with DNA sequences that appear capable of adopting non-B conformations. Of the 20 complex gene rearrangements, 19 (seven simple double deletions, one triple deletion, two double mutational events comprising a simple deletion and a simple insertion, six simple indels that may constitute a novel and non-canonical class of gene conversion, and three complex indels) were compatible with the model of serial replication slippage in cis; the remaining indel in the MECP2 gene, however, appears to have arisen via interchromosomal replication slippage in trans. Our postulate that serial replication slippage may account for a variety of complex gene rearrangements has therefore received broad support from the study of the above diverse series of mutations. Hum Mutat 26(2), 1–10, 2005. © 2005 Wiley-Liss, Inc.

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