Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
Open accessPublished version of a preprint
Abstract
Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR-Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR-Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.
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Double-stranded break repair can cause larger chromosomal rearrangements such as chromothripsis.
“Additionally, DSBs repair can cause larger chromosomal rearrangements such as chromothripsis.11”
From Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools (2024) · cites this paper as [11]
Repair of DSBs introduced by Cas9 has been shown to be error prone and may result in complex rearrangements, including chromothripsis, at the site of repair.
“The repair of DSBs introduced by Cas9 has been shown to be error prone and may result in complex rearrangements, including chromothripsis, at the site of repair25–27.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [27]
A few point mutations are less detrimental to the cell compared to large-scale chromosomal rearrangements described in conventional Cas9 proteins.
“While these off-target effects are a downside of this strategy, we argue that a few point mutations are less detrimental to the cell compared to the large-scale chromosomal rearrangements that have been described in the use of conventional Cas9 proteins to achieve desired mutations27.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [27]
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- Authors
- Leibowitz, M. L., Papathanasiou, S., Doerfler, P. A., Blaine, L. J., Sun, L., Yao, Y., Zhang, C.-Z., Weiss, M. J., & Pellman, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- St. Jude Children's Research Hospital (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Weiss, Mitchell J.
- Pellman, David
- ORCID
- Venue
- Nature Genetics
- Published
- 2021-04-12
- Volume
- 53
- Issue
- 6
- Pages
- 895-905
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC8192433
- OpenAlex
- W3155280715
- Cited by
- 583
- References
- 20
- Citations by year
- 2026: 89 · 2025: 97 · 2024: 106 · 2023: 133 · 2022: 95 · 2021: 57 · 2020: 6
- FWCI
- 30.69
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01 CA213404, K22CA216319)
- National Science Foundation (DGE1144152)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (F32 DK118822)
- Assisi Foundation of Memphis
- St. Jude Children’s Research Hospital
- American Lebanese Syrian Associated Charities
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- chromothripsis, CRISPR/Cas9, DNA double-strand breaks, chromosomal rearrangements, micronuclei, chromosome bridges, single-cell whole-genome sequencing
- MeSH terms
- Gene Editing, Chromothripsis, CRISPR-Associated Protein 9, Anemia, Sickle Cell, Cell Division, Chromosomes, Human, Humans, Genome, Human, Tumor Suppressor Protein p53, Antigens, CD34, Micronucleus, Germline, DNA Cleavage, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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