Journal Article

Chromothripsis as a mechanism driving complex <i>de novo</i> structural rearrangements in the germline<sup>†</sup>

Wigard P. Kloosterman, Victor Guryev, Mark van Roosmalen, Karen J. Duran, Ewart de Bruijn, Saskia C.M. Bakker, Tom Letteboer, Bernadette van Nesselrooij, Ron Hochstenbach, Martin Poot and Edwin Cuppen

in Human Molecular Genetics

Volume 20, issue 10, pages 1916-1924
Published in print May 2011 | ISSN: 0964-6906
Published online February 2011 | e-ISSN: 1460-2083 | DOI:
Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline†

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A variety of mutational mechanisms shape the dynamic architecture of human genomes and occasionally result in congenital defects and disease. Here, we used genome-wide long mate-pair sequencing to systematically screen for inherited and de novo structural variation in a trio including a child with severe congenital abnormalities. We identified 4321 inherited structural variants and 17 de novo rearrangements. We characterized the de novo structural changes to the base-pair level revealing a complex series of balanced inter- and intra-chromosomal rearrangements consisting of 12 breakpoints involving chromosomes 1, 4 and 10. Detailed inspection of breakpoint regions indicated that a series of simultaneous double-stranded DNA breaks caused local shattering of chromosomes. Fusion of the resulting chromosomal fragments involved non-homologous end joining, since junction points displayed limited or no homology and small insertions and deletions. The pattern of random joining of chromosomal fragments that we observe here strongly resembles the somatic rearrangement patterns—termed chromothripsis—that have recently been described in deranged cancer cells. We conclude that a similar mechanism may also drive the formation of de novo structural variation in the germline.

Journal Article.  5605 words.  Illustrated.

Subjects: Genetics and Genomics

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