Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing
Abstract
DNA base editors have enabled genome editing without generating DNA double strand breaks. The applications of this technology have been reported in a variety of animal and plant systems, however, their editing specificity in human stem cells has not been studied by unbiased genome-wide analysis. Here we investigate the fidelity of cytidine deaminase-mediated base editing in human induced pluripotent stem cells (iPSCs) by whole genome sequencing after sustained or transient base editor expression. While base-edited iPSC clones without significant off-target modifications are identified, this study also reveals the potential of APOBEC-based base editors in inducing unintended point mutations outside of likely in silico-predicted CRISPR-Cas9 off-targets. The majority of the off-target mutations are C:G->T:A transitions or C:G->G:C transversions enriched for the APOBEC mutagenesis signature. These results demonstrate that cytosine base editor-mediated editing may result in unintended genetic modifications with distinct patterns from that of the conventional CRISPR-Cas nucleases.
- Authors:
-
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Div. of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Facility for Biotechnology Resources, Center for Biologics Evaluation and Research
- Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Oncology
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Division of Genetic and Molecular Toxicology, National Center for Toxicology Research
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE; FDA; National Institutes of Health (NIH)
- OSTI Identifier:
- 1624218
- Grant/Contract Number:
- SC0014664; R01EB023812; R03HD091264
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics
Citation Formats
McGrath, Erica, Shin, Hyunsu, Zhang, Linyi, Phue, Je-Nie, Wu, Wells W., Shen, Rong-Fong, Jang, Yoon-Young, Revollo, Javier, and Ye, Zhaohui. Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-13342-8.
McGrath, Erica, Shin, Hyunsu, Zhang, Linyi, Phue, Je-Nie, Wu, Wells W., Shen, Rong-Fong, Jang, Yoon-Young, Revollo, Javier, & Ye, Zhaohui. Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing. United States. https://doi.org/10.1038/s41467-019-13342-8
McGrath, Erica, Shin, Hyunsu, Zhang, Linyi, Phue, Je-Nie, Wu, Wells W., Shen, Rong-Fong, Jang, Yoon-Young, Revollo, Javier, and Ye, Zhaohui. Mon .
"Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing". United States. https://doi.org/10.1038/s41467-019-13342-8. https://www.osti.gov/servlets/purl/1624218.
@article{osti_1624218,
title = {Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing},
author = {McGrath, Erica and Shin, Hyunsu and Zhang, Linyi and Phue, Je-Nie and Wu, Wells W. and Shen, Rong-Fong and Jang, Yoon-Young and Revollo, Javier and Ye, Zhaohui},
abstractNote = {DNA base editors have enabled genome editing without generating DNA double strand breaks. The applications of this technology have been reported in a variety of animal and plant systems, however, their editing specificity in human stem cells has not been studied by unbiased genome-wide analysis. Here we investigate the fidelity of cytidine deaminase-mediated base editing in human induced pluripotent stem cells (iPSCs) by whole genome sequencing after sustained or transient base editor expression. While base-edited iPSC clones without significant off-target modifications are identified, this study also reveals the potential of APOBEC-based base editors in inducing unintended point mutations outside of likely in silico-predicted CRISPR-Cas9 off-targets. The majority of the off-target mutations are C:G->T:A transitions or C:G->G:C transversions enriched for the APOBEC mutagenesis signature. These results demonstrate that cytosine base editor-mediated editing may result in unintended genetic modifications with distinct patterns from that of the conventional CRISPR-Cas nucleases.},
doi = {10.1038/s41467-019-13342-8},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {Mon Nov 25 00:00:00 EST 2019},
month = {Mon Nov 25 00:00:00 EST 2019}
}
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