Gene conversion causing human inherited disease: Evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair

Authors

  • Nadia Chuzhanova,

    Corresponding author
    1. School of Computing, Engineering and Physical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
    • School of Computing, Engineering and Physical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
    Search for more papers by this author
  • Jian-Min Chen,

    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. Université de Bretagne Occidentale (UBO), Faculté de Médecine et des Sciences de la Santé, Brest, France
    4. Institut Fédératif de Recherche (IFR) 148, Brest, France
    Search for more papers by this author
  • Albino Bacolla,

    1. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston TX, USA
    Current affiliation:
    1. University of Texas MD Anderson Cancer Center, Department of Carcinogenesis, Smithville, TX 78957, USA
    Search for more papers by this author
  • George P. Patrinos,

    1. Erasmus University Medical Center, Faculty of Medicine and Health Sciences, MGC—Department of Cell Biology and Genetics, 3000 CA, Rotterdam, The Netherlands
    Current affiliation:
    1. University of Patras, School of Health Sciences, Department of Pharmacy, University Campus, Rion, GR-26504, Patras, Greece
    Search for more papers by this author
  • 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. Université de Bretagne Occidentale (UBO), Faculté de Médecine et des Sciences de la Santé, Brest, France
    4. Institut Fédératif de Recherche (IFR) 148, Brest, France
    5. Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, France
    Search for more papers by this author
  • Robert D. Wells,

    1. Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston TX, USA
    Search for more papers by this author
  • David N. Cooper

    1. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
    Search for more papers by this author

  • Communicated by Haig H. Kazazian, Jr.

Abstract

A variety of DNA sequence motifs including inverted repeats, minisatellites, and the χ recombination hotspot, have been reported in association with gene conversion in human genes causing inherited disease. However, no methodical statistically based analysis has been performed to formalize these observations. We have performed an in silico analysis of the DNA sequence tracts involved in 27 nonoverlapping gene conversion events in 19 different genes reported in the context of inherited disease. We found that gene conversion events tend to occur within (C+G)- and CpG-rich regions and that sequences with the potential to form non-B-DNA structures, and which may be involved in the generation of double-strand breaks that could, in turn, serve to promote gene conversion, occur disproportionately within maximal converted tracts and/or short flanking regions. Maximal converted tracts were also found to be enriched (P<0.01) in a truncated version of the χ-element (a TGGTGG motif), immunoglobulin heavy chain class switch repeats, translin target sites and several novel motifs including (or overlapping) the classical meiotic recombination hotspot, CCTCCCCT. Finally, gene conversions tend to occur in genomic regions that have the potential to fold into stable hairpin conformations. These findings support the concept that recombination-inducing motifs, in association with alternative DNA conformations, can promote recombination in the human genome. Hum Mutat 30:1–10, 2009. © 2009 Wiley-Liss, Inc.

Ancillary