De novo deletions and duplications at recombination hotspots in mouse germlines Journal Article


Authors: Lukaszewicz, A.; Lange, J.; Keeney, S.; Jasin, M.
Article Title: De novo deletions and duplications at recombination hotspots in mouse germlines
Abstract: Numerous DNA double-strand breaks (DSBs) arise during meiosis to initiate homologous recombination. These DSBs are usually repaired faithfully, but here, we uncover a distinct type of mutational event in which deletions form via joining of ends from two closely spaced DSBs (double cuts) within a single hotspot or at adjacent hotspots on the same or different chromatids. Deletions occur in normal meiosis but are much more frequent when DSB formation is dysregulated in the absence of the ATM kinase. Events between chromosome homologs point to multi-chromatid damage and aborted gap repair. Some deletions contain DNA from other hotspots, indicating that double cutting at distant sites creates substrates for insertional mutagenesis. End joining at double cuts can also yield tandem duplications or extrachromosomal circles. Our findings highlight the importance of DSB regulation and reveal a previously hidden potential for meiotic mutagenesis that is likely to affect human health and genome evolution. © 2021 Elsevier Inc.
Keywords: atm; deletions; germline mutations; nhej; copy number variants; double cuts; extrachromosomal circles; meiotic dsbs; spo11double-strand breaks; tandem duplications
Journal Title: Cell
Volume: 184
Issue: 24
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2021-11-24
Start Page: 5970
End Page: 5984.e18
Language: English
DOI: 10.1016/j.cell.2021.10.025
PROVIDER: scopus
PMCID: PMC8616837
PUBMED: 34793701
DOI/URL:
Notes: Article -- Export Date: 1 December 2021 -- Source: Scopus
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MSK Authors
  1. Scott N Keeney
    138 Keeney
  2. Julian Lange
    18 Lange
  3. Maria Jasin
    251 Jasin