title: Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.forename: Mark
authors.initials: M
authors.lastname: van Roosmalen
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Duran
authors.forename: Ewart
authors.initials: E
authors.lastname: de Bruijn
authors.forename: Saskia C M
authors.initials: SC
authors.lastname: Bakker
authors.forename: Tom
authors.initials: T
authors.lastname: Letteboer
authors.forename: Bernadette
authors.initials: B
authors.lastname: van Nesselrooij
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D001483:Base Sequence; D002648:Child; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D019295:Computational Biology; D005260:Female; D023061:Gene Order; D015321:Gene Rearrangement / Q000235:genetics*; D005854:Germ Cells; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA