Whole genomic analysis reveals atypical non-homologous off-target large structural variants induced by CRISPR-Cas9-mediated genome editing

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 and John Yu ()
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Hsiu-Hui Tsai: Chang Gung Memorial Hospital at Linkou
Hsiao-Jung Kao: Academia Sinica
Ming-Wei Kuo: Chang Gung Memorial Hospital at Linkou
Chin-Hsien Lin: National Taiwan University Hospital and School of Medicine
Chun-Min Chang: Chang Gung Memorial Hospital at Linkou
Yi-Yin Chen: Chang Gung Memorial Hospital at Linkou
Hsiao-Huei Chen: Academia Sinica
Pui-Yan Kwok: Academia Sinica
Alice L. Yu: Chang Gung Memorial Hospital at Linkou
John Yu: Chang Gung Memorial Hospital at Linkou

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract CRISPR-Cas9 genome editing has promising therapeutic potential for genetic diseases and cancers, but safety could be a concern. Here we use whole genomic analysis by 10x linked-read sequencing and optical genome mapping to interrogate the genome integrity after editing and in comparison to four parental cell lines. In addition to the previously reported large structural variants at on-target sites, we identify heretofore unexpected large chromosomal deletions (91.2 and 136 Kb) at atypical non-homologous off-target sites without sequence similarity to the sgRNA in two edited lines. The observed large structural variants induced by CRISPR-Cas9 editing in dividing cells may result in pathogenic consequences and thus limit the usefulness of the CRISPR-Cas9 editing system for disease modeling and gene therapy. In this work, our whole genomic analysis may provide a valuable strategy to ensure genome integrity after genomic editing to minimize the risk of unintended effects in research and clinical applications.

Date: 2023
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DOI: 10.1038/s41467-023-40901-x

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