Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements
Name
nihms-1519498.pdf
Description
Accepted version
Size
3.4 MB
Format
Adobe PDF
Checksum (MD5)
2b30b089479093063451aa344eeacd22
Author(s)
Pyntikova, Tatyana
Page, David C.
Date Issued
April 2019
Journal
Nature genetics
Publisher
Springer Science and Business Media LLC
Citation
Ly, Peter et al. “Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements.” Nature genetics 51 (2019): 705-715 © 2019 The Author(s)
Version
Author's final manuscript
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.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/S41588-019-0360-8
