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Nat Commun. 2018 Nov 15;9(1):4804. doi: 10.1038/s41467-018-07322-7.

Targeting fidelity of adenine and cytosine base editors in mouse embryos.

Author information

1
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA. hyekyung.lee@nih.gov.
2
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA.
3
Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
4
Howard Hughes Medical Institute, Harvard University, Cambridge, MA, 02138, USA.
5
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, 02138, USA.
6
Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, MD, 20892, USA.
7
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD, 20892, USA. lotharh@niddk.nih.gov.

Abstract

Base editing directly converts a target base pair into a different base pair in the genome of living cells without introducing double-stranded DNA breaks. While cytosine base editors (CBE) and adenine base editors (ABE) are used to install and correct point mutations in a wide range of organisms, the extent and distribution of off-target edits in mammalian embryos have not been studied in detail. We analyze on-target and proximal off-target editing at 13 loci by a variety of CBEs and ABE in more than 430 alleles generated from mouse zygotic injections using newly generated and published sequencing data. ABE predominantly generates anticipated A•T-to-G•C edits. Among CBEs, SaBE3 and BE4, result in the highest frequencies of anticipated C•G-to-T•A products relative to editing byproducts. Together, these findings highlight the remarkable fidelity of ABE in mouse embryos and identify preferred CBE variants when fidelity in vivo is critical.

PMID:
30442934
PMCID:
PMC6238002
DOI:
10.1038/s41467-018-07322-7
[Indexed for MEDLINE]
Free PMC Article

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