title: Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration.
abstract: We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically interpreted translocations and inversions. We confirm that the recently described phenomenon of 'chromothripsis' (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline, where it can resolve to a relatively balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign copy-number variants (CNVs). We compared these results to experimentally generated DNA breakage-repair by sequencing seven transgenic animals, revealing extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion was the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Colby
authors.initials: C
authors.lastname: Chiang
authors.forename: Jessie C
authors.initials: JC
authors.lastname: Jacobsen
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
authors.forename: Carrie
authors.initials: C
authors.lastname: Hanscom
authors.forename: Adrian
authors.initials: A
authors.lastname: Heilbut
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Mills
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.forename: Amelia M
authors.initials: AM
authors.lastname: Lindgren
authors.forename: Skye R
authors.initials: SR
authors.lastname: Rudiger
authors.forename: Clive J
authors.initials: CJ
authors.lastname: McLaughlan
authors.forename: C Simon
authors.initials: CS
authors.lastname: Bawden
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Reid
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.forename: Russell G
authors.initials: RG
authors.lastname: Snell
authors.forename: Ira M
authors.initials: IM
authors.lastname: Hall
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Toshiro K
authors.initials: TK
authors.lastname: Ohsumi
authors.forename: Mark L
authors.initials: ML
authors.lastname: Borowsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019457:Chromosome Breakage; D007446:Chromosome Inversion; D059766:DNA End-Joining Repair / Q000235:genetics*; D015321:Gene Rearrangement; D018095:Germ-Line Mutation; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic