Journal Article

Elucidation of the complex structure and origin of the human trypsinogen locus triplication

Angélique Chauvin, Jian-Min Chen, Sylvia Quemener, Emmanuelle Masson, Hildegard Kehrer-Sawatzki, Barbara Ohmle, David N. Cooper, Cédric Le Maréchal and Claude Férec

in Human Molecular Genetics

Volume 18, issue 19, pages 3605-3614
Published in print October 2009 | ISSN: 0964-6906
Published online July 2009 | e-ISSN: 1460-2083 | DOI:
Elucidation of the complex structure and origin of the human trypsinogen locus triplication

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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.

Journal Article.  5907 words.  Illustrated.

Subjects: Genetics and Genomics

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