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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-04

AUTHORS

Peter Ly, Simon F. Brunner, Ofer Shoshani, Dong Hyun Kim, Weijie Lan, Tatyana Pyntikova, Adrienne M. Flanagan, Sam Behjati, David C. Page, Peter J. Campbell, Don W. Cleveland

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. More... »

PAGES

705-715

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-019-0360-8

    DOI

    http://dx.doi.org/10.1038/s41588-019-0360-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112507947

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30833795


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