Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

doi:10.1126/science.aaw7166

. 2019 Apr 19;364(6437):292-295.

doi: 10.1126/science.aaw7166. Epub 2019 Feb 28.

Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

Shuai Jin^#^{1

2}, Yuan Zong^#^{1

2}, Qiang Gao^#³, Zixu Zhu^{1

2}, Yanpeng Wang¹, Peng Qin⁴, Chengzhi Liang^{2

3}, Daowen Wang^{1

2}, Jin-Long Qiu⁵, Feng Zhang⁶, Caixia Gao^{7

2}

Affiliations

¹ State Key Laboratory of Plant Cell and Chromosome Engineering, Center for Genome Editing, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
² University of Chinese Academy of Sciences, Beijing 100864, China.
³ State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
⁴ Rice Research Institute, Sichuan Agricultural University, Chengdu 611130, China.
⁵ State Key Laboratory of Plant Genomics, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Department of Plant and Microbial Biology, Center for Plant Precision Genomics, The Microbial and Plant Genomics Institute, University of Minnesota, Minneapolis, MN 55108, USA.
⁷ State Key Laboratory of Plant Cell and Chromosome Engineering, Center for Genome Editing, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China. cxgao@genetics.ac.cn.

^# Contributed equally.

PMID: 30819931
DOI: 10.1126/science.aaw7166

Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

Shuai Jin et al. Science. 2019.

. 2019 Apr 19;364(6437):292-295.

doi: 10.1126/science.aaw7166. Epub 2019 Feb 28.

Authors

Shuai Jin^#^{1

2}, Yuan Zong^#^{1

2}, Qiang Gao^#³, Zixu Zhu^{1

2}, Yanpeng Wang¹, Peng Qin⁴, Chengzhi Liang^{2

3}, Daowen Wang^{1

2}, Jin-Long Qiu⁵, Feng Zhang⁶, Caixia Gao^{7

2}

Affiliations

¹ State Key Laboratory of Plant Cell and Chromosome Engineering, Center for Genome Editing, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
² University of Chinese Academy of Sciences, Beijing 100864, China.
³ State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China.
⁴ Rice Research Institute, Sichuan Agricultural University, Chengdu 611130, China.
⁵ State Key Laboratory of Plant Genomics, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁶ Department of Plant and Microbial Biology, Center for Plant Precision Genomics, The Microbial and Plant Genomics Institute, University of Minnesota, Minneapolis, MN 55108, USA.
⁷ State Key Laboratory of Plant Cell and Chromosome Engineering, Center for Genome Editing, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100101, China. cxgao@genetics.ac.cn.

^# Contributed equally.

PMID: 30819931
DOI: 10.1126/science.aaw7166

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Abstract

Cytosine and adenine base editors (CBEs and ABEs) are promising new tools for achieving the precise genetic changes required for disease treatment and trait improvement. However, genome-wide and unbiased analyses of their off-target effects in vivo are still lacking. Our whole-genome sequencing analysis of rice plants treated with the third-generation base editor (BE3), high-fidelity BE3 (HF1-BE3), or ABE revealed that BE3 and HF1-BE3, but not ABE, induce substantial genome-wide off-target mutations, which are mostly the C→T type of single-nucleotide variants (SNVs) and appear to be enriched in genic regions. Notably, treatment of rice with BE3 or HF1-BE3 in the absence of single-guide RNA also results in the rise of genome-wide SNVs. Thus, the base-editing unit of BE3 or HF1-BE3 needs to be optimized in order to attain high fidelity.

Comment in

Cytosine base editors go off-target.
Wrighton KH. Wrighton KH. Nat Rev Genet. 2019 May;20(5):254-255. doi: 10.1038/s41576-019-0110-x. Nat Rev Genet. 2019. PMID: 30872767 No abstract available.
In vivo ways to unveil off-targets.
Zhang G, Zhou Z, Wei W. Zhang G, et al. Cell Res. 2019 May;29(5):339-340. doi: 10.1038/s41422-019-0159-2. Epub 2019 Mar 19. Cell Res. 2019. PMID: 30890764 Free PMC article. No abstract available.
Off-target effects and the solution.
Tang J, Chen L, Liu YG. Tang J, et al. Nat Plants. 2019 Apr;5(4):341-342. doi: 10.1038/s41477-019-0406-z. Nat Plants. 2019. PMID: 30962524 No abstract available.
Base Editors and Off-Targeting: The Deaminase Matters.
Willmann MR. Willmann MR. CRISPR J. 2019 Apr;2:71-73. doi: 10.1089/crispr.2019.29054.mrw. CRISPR J. 2019. PMID: 30998097 No abstract available.
When genome editing goes off-target.
Kempton HR, Qi LS. Kempton HR, et al. Science. 2019 Apr 19;364(6437):234-236. doi: 10.1126/science.aax1827. Epub 2019 Apr 18. Science. 2019. PMID: 31000651 No abstract available.

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Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

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Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

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