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Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing

Author

Listed:
  • Stamatis Papathanasiou

    (Department of Cell Biology, Blavatnik Institute, Harvard Medical School
    Department of Pediatric Oncology, Dana-Farber Cancer Institute)

  • Styliani Markoulaki

    (Whitehead Institute)

  • Logan J. Blaine

    (Department of Cell Biology, Blavatnik Institute, Harvard Medical School
    Department of Pediatric Oncology, Dana-Farber Cancer Institute)

  • Mitchell L. Leibowitz

    (Department of Cell Biology, Blavatnik Institute, Harvard Medical School
    Department of Pediatric Oncology, Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

  • Cheng-Zhong Zhang

    (Department of Biomedical Informatics, Harvard Medical School
    Department of Data Sciences, Dana-Farber Cancer Institute)

  • Rudolf Jaenisch

    (Whitehead Institute
    Massachusetts Institute of Technology, Department of Biology)

  • David Pellman

    (Department of Cell Biology, Blavatnik Institute, Harvard Medical School
    Department of Pediatric Oncology, Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

Abstract

Karyotype alterations have emerged as on-target complications from CRISPR-Cas9 genome editing. However, the events that lead to these karyotypic changes in embryos after Cas9-treatment remain unknown. Here, using imaging and single-cell genome sequencing of 8-cell stage embryos, we track both spontaneous and Cas9-induced karyotype aberrations through the first three divisions of embryonic development. We observe the generation of abnormal structures of the nucleus that arise as a consequence of errors in mitosis, including micronuclei and chromosome bridges, and determine their contribution to common karyotype aberrations including whole chromosome loss that has been recently reported after editing in embryos. Together, these data demonstrate that Cas9-mediated germline genome editing can lead to unwanted on-target side effects, including major chromosome structural alterations that can be propagated over several divisions of embryonic development.

Suggested Citation

  • Stamatis Papathanasiou & Styliani Markoulaki & Logan J. Blaine & Mitchell L. Leibowitz & Cheng-Zhong Zhang & Rudolf Jaenisch & David Pellman, 2021. "Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26097-y
    DOI: 10.1038/s41467-021-26097-y
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    5. Zhiqian Li & Lang You & Anita Hermann & Ethan Bier, 2024. "Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Dmitrii Degtev & Jack Bravo & Aikaterini Emmanouilidi & Aleksandar Zdravković & Oi Kuan Choong & Julia Liz Touza & Niklas Selfjord & Isabel Weisheit & Margherita Francescatto & Pinar Akcakaya & Michel, 2024. "Engineered PsCas9 enables therapeutic genome editing in mouse liver with lipid nanoparticles," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Hsiu-Hui Tsai & Hsiao-Jung Kao & Ming-Wei Kuo & Chin-Hsien Lin & Chun-Min Chang & Yi-Yin Chen & Hsiao-Huei Chen & Pui-Yan Kwok & Alice L. Yu & John Yu, 2023. "Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    8. Ju-Chan Park & Yun-Jeong Kim & Gue-Ho Hwang & Chan Young Kang & Sangsu Bae & Hyuk-Jin Cha, 2024. "Enhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    9. Jianli Tao & Qi Wang & Carlos Mendez-Dorantes & Kathleen H. Burns & Roberto Chiarle, 2022. "Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. G. Cullot & J. Boutin & S. Fayet & F. Prat & J. Rosier & D. Cappellen & I. Lamrissi & P. Pennamen & J. Bouron & S. Amintas & C. Thibault & I. Moranvillier & E. Laharanne & J. P. Merlio & V. Guyonnet-D, 2023. "Cell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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