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Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements

Ly, P; Brunner, SF; Shoshani, O; Kim, DH; Lan, W; Pyntikova, T; Flanagan, AM; ... Cleveland, DW; + view all (2019) Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nature Genetics , 51 (4) pp. 705-715. 10.1038/s41588-019-0360-8. Green open access

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Abstract

Cancer genomes are frequently characterized by numerical and structural chromosomal abnormalities. Here we integrated a centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy termed CEN-SELECT, to systematically interrogate the structural landscape of mis-segregated chromosomes. We show that single-chromosome mis-segregation into a micronucleus can directly trigger a broad spectrum of genomic rearrangement types. Cytogenetic profiling revealed that mis-segregated chromosomes exhibit 120-fold-higher susceptibility to developing seven major categories of structural aberrations, including translocations, insertions, deletions, and complex reassembly through chromothripsis coupled to classical non-homologous end joining. Whole-genome sequencing of clonally propagated rearrangements identified random patterns of clustered breakpoints with copy-number alterations resulting in interspersed gene deletions and extrachromosomal DNA amplification events. We conclude that individual chromosome segregation errors during mitotic cell division are sufficient to drive extensive structural variations that recapitulate genomic features commonly associated with human disease.

Type: Article
Title: Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41588-019-0360-8
Publisher version: https://doi.org/10.1038/s41588-019-0360-8
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10085296
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