title: Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination.
abstract: Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, 2600, Denmark.|Department of Cellular and Molecular Medicine (ICMM), Faculty of Health Science, University of Copenhagen, Copenhagen, N. 2200, Denmark.
authors.forename: Lusine
authors.initials: L
authors.lastname: Nazaryan-Petersen
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, 2600, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, N. 2200, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, O. 2100, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Jønson
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, N. 2200, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, 84112.
authors.forename: Dustin C
authors.initials: DC
authors.lastname: Hancks
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, 2600, Denmark.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D056905:Chromosome Breakpoints; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D000072837:Chromothripsis; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D018598:Minisatellite Repeats; D016254:Mutagenesis, Insertional; D018626:Retroelements; D017384:Sequence Deletion
chemical_list: D018626:Retroelements
keywords: Alu; L1; LINE-1; NAHR; SINE-VNTR-Alu; SVA; chromothripsis; nonallelic homologous recombination