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

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 (ABE7.10^F148A) 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, ABE7.10^F148A shows no detectable off-target DNA

SUBMITTER: Yan N 

PROVIDER: S-EPMC10063651 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature