@article{baa3195a3a214e96ad72412e8a591393,
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.",
author = "Colby Chiang and Jacobsen, {Jessie C.} and Carl Ernst and Carrie Hanscom and Adrian Heilbut and Ian Blumenthal and Mills, {Ryan E.} and Andrew Kirby and Lindgren, {Amelia M.} and Rudiger, {Skye R.} and McLaughlan, {Clive J.} and Bawden, {C. Simon} and Reid, {Suzanne J.} and Faull, {Richard L.M.} and Snell, {Russell G.} and Hall, {Ira M.} and Yiping Shen and Ohsumi, {Toshiro K.} and Borowsky, {Mark L.} and Daly, {Mark J.} and Charles Lee and Morton, {Cynthia C.} and MacDonald, {Marcy E.} and Gusella, {James F.} and Talkowski, {Michael E.}",
note = "Funding Information: We thank all study participants, their families and the referring clinicians for their invaluable contributions. We thank T. Gillis, M.A. Anderson, W. Varney, J. Ruliera, T. Henderson, C. Zhang, L. Griffin, The Genomics Core of the Massachusetts General Hospital Center for Human Genetic Research, the Genome Sequencing Platform at the Broad Institute and the Partners Center for Personalized Genomic Medicine for technical assistance. We thank M. Sun for performing the multiplex ligation-dependent probe amplification (MLPA) experiments. We also thank the Partners Research Computing at Massachusetts General Hospital. This work was funded by grants from the US National Institutes of Health (GM061354, HD065286, MH087123, NS32765 and NS16367), the Simons Foundation Autism Research Initiative, Autism Speaks and the CHDI Foundation. J.C.J. was the recipient of the Philip Wrightson Fellowship of the Neurological Foundation of New Zealand, C.E. received a Bisby Fellowship from the Canadian Institute for Health Research (CIHR).",
year = "2012",
month = apr,
doi = "10.1038/ng.2202",
language = "English",
volume = "44",
pages = "390--397",
journal = "Nature Genetics",
issn = "1061-4036",
number = "4",
}