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Prediction of base editor off-targets by deep learning

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  • Chengdong Zhang

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University
    Shanghai Jiao Tong University School of Medicine
    Hubei University of Medicine)

  • Yuan Yang

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University
    Shanghai Jiao Tong University School of Medicine)

  • Tao Qi

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Yuening Zhang

    (School of Life Sciences and Biotechnology) Shanghai Jiao Tong University)

  • Linghui Hou

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Jingjing Wei

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Jingcheng Yang

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Leming Shi

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Sang-Ging Ong

    (University of Illinois College of Medicine
    University of Illinois College of Medicine)

  • Hongyan Wang

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Hui Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Bo Yu

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University)

  • Yongming Wang

    (Fudan University Pudong Medical Center; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University
    The First Affiliated Hospital of Zhengzhou University
    Shanghai Engineering Research Center of Industrial Microorganisms)

Abstract

Due to the tolerance of mismatches between gRNA and targeting sequence, base editors frequently induce unwanted Cas9-dependent off-target mutations. Here, to develop models to predict such off-targets, we design gRNA-off- target pairs for adenine base editors (ABEs) and cytosine base editors (CBEs) and stably integrate them into the human cells. After five days of editing, we obtain valid efficiency datasets of 54,663 and 55,727 off-targets for ABEs and CBEs, respectively. We use the datasets to train deep learning models, resulting in ABEdeepoff and CBEdeepoff, which can predict off-target sites. We use these tools to predict off-targets for a panel of endogenous loci and achieve Spearman correlation values varying from 0.710 to 0.859. Finally, we develop an integrated tool that is freely accessible via an online web server http://www.deephf.com/#/bedeep/bedeepoff . These tools could facilitate minimizing the off-target effects of base editing.

Suggested Citation

  • Chengdong Zhang & Yuan Yang & Tao Qi & Yuening Zhang & Linghui Hou & Jingjing Wei & Jingcheng Yang & Leming Shi & Sang-Ging Ong & Hongyan Wang & Hui Wang & Bo Yu & Yongming Wang, 2023. "Prediction of base editor off-targets by deep learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41004-3
    DOI: 10.1038/s41467-023-41004-3
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    References listed on IDEAS

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    1. Daqi Wang & Chengdong Zhang & Bei Wang & Bin Li & Qiang Wang & Dong Liu & Hongyan Wang & Yan Zhou & Leming Shi & Feng Lan & Yongming Wang, 2019. "Optimized CRISPR guide RNA design for two high-fidelity Cas9 variants by deep learning," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    3. Nicole M. Gaudelli & Alexis C. Komor & Holly A. Rees & Michael S. Packer & Ahmed H. Badran & David I. Bryson & David R. Liu, 2017. "Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage," Nature, Nature, vol. 551(7681), pages 464-471, November.
    4. Josh Tycko & Luis A. Barrera & Nicholas C. Huston & Ari E. Friedland & Xuebing Wu & Jonathan S. Gootenberg & Omar O. Abudayyeh & Vic E. Myer & Christopher J. Wilson & Patrick D. Hsu, 2018. "Publisher Correction: Pairwise library screen systematically interrogates Staphylococcus aureus Cas9 specificity in human cells," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
    5. Yihan Zhang & Wei Qin & Xiaochan Lu & Jason Xu & Haigen Huang & Haipeng Bai & Song Li & Shuo Lin, 2017. "Programmable base editing of zebrafish genome using a modified CRISPR-Cas9 system," Nature Communications, Nature, vol. 8(1), pages 1-5, December.
    6. Changyang Zhou & Yidi Sun & Rui Yan & Yajing Liu & Erwei Zuo & Chan Gu & Linxiao Han & Yu Wei & Xinde Hu & Rong Zeng & Yixue Li & Haibo Zhou & Fan Guo & Hui Yang, 2019. "Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis," Nature, Nature, vol. 571(7764), pages 275-278, July.
    7. Josh Tycko & Luis A. Barrera & Nicholas C. Huston & Ari E. Friedland & Xuebing Wu & Jonathan S. Gootenberg & Omar O. Abudayyeh & Vic E. Myer & Christopher J. Wilson & Patrick D. Hsu, 2018. "Pairwise library screen systematically interrogates Staphylococcus aureus Cas9 specificity in human cells," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
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    Cited by:

    1. Emily Zhang & Monica E. Neugebauer & Nicholas A. Krasnow & David R. Liu, 2024. "Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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