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Systematic Exploration of Optimized Base Editing gRNA Design and Pleiotropic Effects with BExplorer
Gongchen Zhang1, Chenyu Zhu1, Xiaohan Chen1
1Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Bioinformatics Department, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
BExplorer optimizes base editing guide RNA design computationally, identifying numerous editable pathogenic SNPs and exploring their potential pleiotropic effects on diseases. This tool aids in the careful clinical application of base editing technology.
Area of Science:
- Genomics
- Bioinformatics
- Molecular Biology
Background:
- Current base editing guide RNA design relies heavily on empirical methods, lacking efficient in silico tools.
- The pleiotropic effects of base editing in disease treatment are largely unexplored, hindering clinical translation.
Purpose of the Study:
- To develop BExplorer, a computational pipeline for optimizing guide RNA design for 26 base editor types.
- To evaluate the pleiotropic effects of base editing on disease-associated loci.
Main Methods:
- Developed BExplorer, an integrated computational pipeline for in silico guide RNA design.
- Applied BExplorer to BE3 and ABE7.10 base editors to identify editable pathogenic SNPs.
- Systematically analyzed the pleiotropic effects of edited pathogenic SNPs on human diseases.
Main Results:
- BExplorer identified 524 and 900 optimized guide RNAs for BE3 and ABE7.10, respectively.
- Discovered 707 edited pathogenic SNP loci impacting 131 diseases, revealing significant pleiotropic effects.
- Highlighted the need for careful consideration of pleiotropic effects in base editing applications.
Conclusions:
- BExplorer provides a computational framework for optimizing base editing guide RNA design.
- The study underscores the importance of assessing pleiotropic effects for safe and effective clinical use of base editing.
- This work lays the groundwork for advancing base editing applications in disease treatment.
