Comprehensive evaluation and prediction of editing outcomes for near-PAMless adenine and cytosine base editors

IF 5.2 1区 生物学 Q1 BIOLOGY Communications Biology Pub Date : 2024-10-25 DOI:10.1038/s42003-024-07078-5
Xiaoyu Zhou, Jingjing Gao, Liheng Luo, Changcai Huang, Jiayu Wu, Xiaoyue Wang
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Abstract

Base editors enable the direct conversion of target bases without inducing double-strand breaks, showing great potential for disease modeling and gene therapy. Yet, their applicability has been constrained by the necessity for specific protospacer adjacent motif (PAM). We generate four versions of near-PAMless base editors and systematically evaluate their editing patterns and efficiencies using an sgRNA-target library of 45,747 sequences. Near-PAMless base editors significantly expanded the targeting scope, with both PAM and target flanking sequences as determinants for editing outcomes. We develop BEguider, a deep learning model, to accurately predict editing results for near-PAMless base editors. We also provide experimentally measured editing outcomes of 20,541 ClinVar sites, demonstrating that variants previously inaccessible by NGG PAM base editors can now be precisely generated or corrected. We make our predictive tool and data available online to facilitate development and application of near-PAMless base editors in both research and clinical settings. Systematic evaluation of near-PAMless base editors enables a robust deep learning model for predicting editing outcomes, facilitating broader and more precise targeting of disease-associated variants for research and therapy.

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全面评估和预测近无 PAM 腺嘌呤和胞嘧啶碱基编辑器的编辑结果。
碱基编辑器能直接转换目标碱基,而不会引起双链断裂,在疾病建模和基因治疗方面具有巨大潜力。然而,它们的适用性一直受到特定原间隔相邻基序(PAM)的限制。我们利用一个包含 45,747 条序列的 sgRNA 目标文库生成了四种版本的近无 PAM 碱基编辑器,并系统地评估了它们的编辑模式和效率。近无 PAM 碱基编辑器显著扩大了靶向范围,PAM 和靶侧翼序列都是编辑结果的决定因素。我们开发了深度学习模型 BEguider,以准确预测近无 PAM 碱基编辑器的编辑结果。我们还提供了 20,541 个 ClinVar 位点的实验测量编辑结果,证明以前 NGG PAM 碱基编辑器无法访问的变体现在可以精确生成或校正。我们在线提供我们的预测工具和数据,以促进研究和临床环境中近无 PAM 碱基编辑器的开发和应用。
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来源期刊
Communications Biology
Communications Biology Medicine-Medicine (miscellaneous)
CiteScore
8.60
自引率
1.70%
发文量
1233
审稿时长
13 weeks
期刊介绍: Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.
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