Genome-wide profiling of adenine base editor specificity by EndoV-seq

Puping Liang, Xiaowei Xie, Shengyao Zhi, Hongwei Sun, Xiya Zhang, Yu Chen, Yuxi Chen, Yuanyan Xiong, Wenbin Ma, Dan Liu, Junjiu Huang () and Zhou Songyang ()
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Puping Liang: Sun Yat-sen University
Xiaowei Xie: Sun Yat-sen University
Shengyao Zhi: Sun Yat-sen University
Hongwei Sun: Sun Yat-sen University
Xiya Zhang: Sun Yat-sen University
Yu Chen: Sun Yat-sen University
Yuxi Chen: Sun Yat-sen University
Yuanyan Xiong: Sun Yat-sen University
Wenbin Ma: Sun Yat-sen University
Dan Liu: Baylor College of Medicine
Junjiu Huang: Sun Yat-sen University
Zhou Songyang: Sun Yat-sen University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract The adenine base editor (ABE), capable of catalyzing A•T to G•C conversions, is an important gene editing toolbox. Here, we systematically evaluate genome-wide off-target deamination by ABEs using the EndoV-seq platform we developed. EndoV-seq utilizes Endonuclease V to nick the inosine-containing DNA strand of genomic DNA deaminated by ABE in vitro. The treated DNA is then whole-genome sequenced to identify off-target sites. Of the eight gRNAs we tested with ABE, 2–19 (with an average of 8.0) off-target sites are found, significantly fewer than those found for canonical Cas9 nuclease (7–320, 160.7 on average). In vivo off-target deamination is further validated through target site deep sequencing. Moreover, we demonstrated that six different ABE-gRNA complexes could be examined in a single EndoV-seq assay. Our study presents the first detection method to evaluate genome-wide off-target effects of ABE, and reveals possible similarities and differences between ABE and canonical Cas9 nuclease.

Date: 2019
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DOI: 10.1038/s41467-018-07988-z

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