A general theoretical framework to design base editors with reduced bystander effects

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dc.citation.articleNumber6529en_US
dc.citation.journalTitleNature Communicationsen_US
dc.citation.volumeNumber12en_US
dc.contributor.authorWang, Qianen_US
dc.contributor.authorYang, Jieen_US
dc.contributor.authorZhong, Zhichengen_US
dc.contributor.authorVanegas, Jeffrey A.en_US
dc.contributor.authorGao, Xueen_US
dc.contributor.authorKolomeisky, Anatoly B.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2022-04-28T14:29:13Zen_US
dc.date.available2022-04-28T14:29:13Zen_US
dc.date.issued2021en_US
dc.description.abstractBase editors (BEs) hold great potential for medical applications of gene therapy. However, high precision base editing requires BEs that can discriminate between the target base and multiple bystander bases within a narrow active window (4 – 10 nucleotides). Here, to assist in the design of these optimized editors, we propose a discrete-state stochastic approach to build an analytical model that explicitly evaluates the probabilities of editing the target base and bystanders. Combined with all-atom molecular dynamic simulations, our model reproduces the experimental data of A3A-BE3 and its variants for targeting the “TC” motif and bystander editing. Analyzing this approach, we propose several general principles that can guide the design of BEs with a reduced bystander effect. These principles are then applied to design a series of point mutations at T218 position of A3G-BEs to further reduce its bystander editing. We verify experimentally that the new mutations provide different levels of stringency on reducing the bystander editing at different genomic loci, which is consistent with our theoretical model. Thus, our study provides a computational-aided platform to assist in the scientifically-based design of BEs with reduced bystander effects.en_US
dc.identifier.citationWang, Qian, Yang, Jie, Zhong, Zhicheng, et al.. "A general theoretical framework to design base editors with reduced bystander effects." <i>Nature Communications,</i> 12, (2021) Springer Nature: https://doi.org/10.1038/s41467-021-26789-5.en_US
dc.identifier.digitals41467-021-26789-5en_US
dc.identifier.doihttps://doi.org/10.1038/s41467-021-26789-5en_US
dc.identifier.urihttps://hdl.handle.net/1911/112195en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleA general theoretical framework to design base editors with reduced bystander effectsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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