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

Stamatis Papathanasiou, Styliani Markoulaki, Logan J. Blaine, Mitchell L. Leibowitz, Cheng-Zhong Zhang, Rudolf Jaenisch () and David Pellman ()
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Stamatis Papathanasiou: Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Styliani Markoulaki: Whitehead Institute
Logan J. Blaine: Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Mitchell L. Leibowitz: Department of Cell Biology, Blavatnik Institute, Harvard Medical School
Cheng-Zhong Zhang: Department of Biomedical Informatics, Harvard Medical School
Rudolf Jaenisch: Whitehead Institute
David Pellman: Department of Cell Biology, Blavatnik Institute, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26097-y

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