Cytosine base editors induce off-target mutations and adverse phenotypic effects in transgenic mice

Nana Yan, Hu Feng, Yongsen Sun, Ying Xin, Haihang Zhang, Hongjiang Lu, Jitan Zheng, Chenfei He, Zhenrui Zuo, Tanglong Yuan, Nana Li, Long Xie, Wu Wei (), Yidi Sun () and Erwei Zuo ()
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Nana Yan: Chinese Academy of Agricultural Sciences
Hu Feng: Chinese Academy of Agricultural Sciences
Yongsen Sun: Chinese Academy of Agricultural Sciences
Ying Xin: Chinese Academy of Agricultural Sciences
Haihang Zhang: Chinese Academy of Agricultural Sciences
Hongjiang Lu: Chinese Academy of Agricultural Sciences
Jitan Zheng: Chinese Academy of Agricultural Sciences
Chenfei He: Chinese Academy of Agricultural Sciences
Zhenrui Zuo: Chinese Academy of Agricultural Sciences
Tanglong Yuan: Chinese Academy of Agricultural Sciences
Nana Li: Chinese Academy of Agricultural Sciences
Long Xie: Chinese Academy of Agricultural Sciences
Wu Wei: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yidi Sun: Chinese Academy of Sciences
Erwei Zuo: Chinese Academy of Agricultural Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Base editors have been reported to induce off-target mutations in cultured cells, mouse embryos and rice, but their long-term effects in vivo remain unknown. Here, we develop a Systematic evaluation Approach For gene Editing tools by Transgenic mIce (SAFETI), and evaluate the off-target effects of BE3, high fidelity version of CBE (YE1-BE3-FNLS) and ABE (ABE7.10F148A) in ~400 transgenic mice over 15 months. Whole-genome sequence analysis reveals BE3 expression generated de novo mutations in the offspring of transgenic mice. RNA-seq analysis reveals both BE3 and YE1-BE3-FNLS induce transcriptome-wide SNVs, and the numbers of RNA SNVs are positively correlated with CBE expression levels across various tissues. By contrast, ABE7.10F148A shows no detectable off-target DNA or RNA SNVs. Notably, we observe abnormal phenotypes including obesity and developmental delay in mice with permanent genomic BE3 overexpression during long-time monitoring, elucidating a potentially overlooked aspect of side effects of BE3 in vivo.

Date: 2023
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DOI: 10.1038/s41467-023-37508-7

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