Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos

Communications Biology - Tập 3 Số 1
Hye‐Kyung Lee1, Harold E. Smith2, Chengyu Liu3, Michaela Willi1, Lothar Hennighausen1
1Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
2Genomics Core, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, 20892, USA
3Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, Maryland, 20892, USA

Tóm tắt

AbstractDeaminase 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.

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Communications Biology

Tập 3 Số 1

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