Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis

胞嘧啶 DNA 核糖核酸 点突变 突变 生物 基因组DNA 突变 基因 遗传学 分子生物学 碱基对 计算生物学 RNA编辑
作者
Changyang Zhou,Yidi Sun,Rui Yan,Yajing Liu,Erwei Zuo,Chan Gu,Linxiao Han,Wei Yu,Xinde Hu,Rong Zeng,Yixue Li,Haibo Zhou,Fan Guo,Hui Yang
出处
期刊:Nature [Springer Nature]
卷期号:571 (7764): 275-278 被引量:359
标识
DOI:10.1038/s41586-019-1314-0
摘要

Recently developed DNA base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1-3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4-8, it is now clear that the deaminases that are integral to commonly used DNA base editors often bind to RNA9-13. For example, the cytosine deaminase APOBEC1-which is used in cytosine base editors (CBEs)-targets both DNA and RNA12, and the adenine deaminase TadA-which is used in adenine base editors (ABEs)-induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA base editors is of great concern14-16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine base editor BE3 and the adenine base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases.
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