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

文献类型： 外文期刊

作者： 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;Erwei Zuo

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期刊名称： Nature communications

ISSN： 2041-1723

年卷期： 2023 年 14 卷 1 期

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收录情况： SCIE（2023版）

摘要： 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.

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