Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing

Erica McGrath, Hyunsu Shin, Linyi Zhang, Je-Nie Phue, Wells W. Wu, Rong-Fong Shen, Yoon-Young Jang, Javier Revollo () and Zhaohui Ye ()
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Erica McGrath: Food and Drug Administration
Hyunsu Shin: Food and Drug Administration
Linyi Zhang: Food and Drug Administration
Je-Nie Phue: Food and Drug Administration
Wells W. Wu: Food and Drug Administration
Rong-Fong Shen: Food and Drug Administration
Yoon-Young Jang: Johns Hopkins School of Medicine
Javier Revollo: Food and Drug Administration
Zhaohui Ye: Food and Drug Administration

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13342-8

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