Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos.,Communications Biology

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Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos.
Communications Biology ( IF 5.2 ) Pub Date : 2020-01-09 , DOI: 10.1038/s42003-019-0745-3
Hye Kyung Lee ₁ , Harold E Smith ₂ , Chengyu Liu ₃ , Michaela Willi ₁ , Lothar Hennighausen ₁

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Deaminase base editing has emerged as a tool to install or correct point mutations in the genomes of living cells in a wide range of organisms. However, the genome-wide off-target effects introduced by base editors in the mammalian genome have been examined in only one study. Here, we have investigated the fidelity of cytosine base editor 4 (BE4) and adenine base editors (ABE) in mouse embryos using unbiased whole-genome sequencing of a family-based trio cohort. The same sgRNA was used for BE4 and ABE. We demonstrate that BE4-edited mice carry an excess of single-nucleotide variants and deletions compared to ABE-edited mice and controls. Therefore, an optimization of cytosine base editors is required to improve its fidelity. While the remarkable fidelity of ABE has implications for a wide range of applications, the occurrence of rare aberrant C-to-T conversions at specific target sites needs to be addressed.

中文翻译：

胞嘧啶碱基编辑器 4 但腺嘌呤碱基编辑器不会在小鼠胚胎中产生脱靶突变。

脱氨酶碱基编辑已成为在多种生物体的活细胞基因组中安装或纠正点突变的工具。然而，只有一项研究检查了哺乳动物基因组中碱基编辑器引入的全基因组脱靶效应。在这里，我们使用基于家族的三人组的无偏全基因组测序研究了小鼠胚胎中胞嘧啶碱基编辑器 4 (BE4) 和腺嘌呤碱基编辑器 (ABE) 的保真度。 BE4 和 ABE 使用相同的 sgRNA。我们证明，与 ABE 编辑的小鼠和对照相比，BE4 编辑的小鼠携带过量的单核苷酸变异和缺失。因此，需要对胞嘧啶碱基编辑器进行优化以提高其保真度。虽然 ABE 卓越的保真度对广泛的应用具有影响，但需要解决特定目标位点上罕见的异常 C 到 T 转换的问题。

更新日期：2020-01-09

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