4.7 Article

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

Journal

COMMUNICATIONS BIOLOGY
Volume 3, Issue 1, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-019-0745-3

Keywords

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Funding

  1. Intramural Research Programs (IRPs) of National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  2. National Heart, Lung, and Blood Institute (NHLBI)
  3. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005907] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK061000, ZICDK071001] Funding Source: NIH RePORTER

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Hye Kyung Lee, Harold E. Smith et al. examined the fidelity of cytosine base editor 4 (BE4) and adenine base editors (ABEs) in mouse embryos using whole-genome sequencing of a family-based trio cohort. They show that BE4-edited mice carry more single-nucleotide variants and deletions than ABE-edited mice. 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.

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