Human Molecular Genetics Advance Access originally published online on July 7, 2009
Human Molecular Genetics 2009 18(19):3605-3614; doi:10.1093/hmg/ddp308
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Elucidation of the complex structure and origin of the human trypsinogen locus triplication
1 Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, France, 2 Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France, 3 Etablissement Français du Sang (EFS) – Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France, 4 Institut Fédératif de Recherche (IFR) 148, Brest, France, 5 Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany, 6 Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK and 7 Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU), Hôpital Morvan, Brest, France
* To whom correspondence should be addressed at: INSERM, U613 and EFS – Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France. Tel: +33 298018102; Fax: +33 298430555; Email: jian-min.chen{at}univ-brest.fr
Received June 13, 2009; Accepted July 1, 2009
One of the causes of chronic pancreatitis is the duplication and triplication of a 
605 kb segment containing the trypsinogen locus. Employing array-comparative genomic hybridization, we fully characterized the triplication copy number mutation (CNM) and found it to be part of a complex rearrangement that also contains a triplicated 137 kb segment and 21 bp sequence tract. This triplication allele therefore constitutes a gain of two tandemly arranged composite duplication blocks, each comprising a copy of the 605 kb segment, a copy of the inverted 137 kb segment and a copy of the inverted 21 bp sequence tract. As such, it represents the first characterization of a human complex triplication CNM at the DNA sequence level. All triplications and duplications identified were found to arise from a common founder chromosome. A two-step process is proposed for the generation of this highly unusual triplication CNM. Thus, the first composite duplication block is envisaged to have been generated by break-induced serial replication slippage during mitosis. This duplication would have provided the sequence homology required to promote non-allelic homologous recombination (NAHR) during meiosis which would then, in a second step, have generated the complex triplication allele. Our data provide support for the view that many human germline copy number variants arise through replication-based mechanisms during the premeiotic mitotic divisions of germ cells. The low copy repeats thereby generated could then serve to promote NAHR during meiosis, giving rise to amplified DNA sequences which would themselves predispose to further recombinational events during both mitosis and meiosis.