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Title: Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations
Authors: Grajcarek, Janin
Monlong, Jean
Nishinaka-Arai, Yoko
Nakamura, Michiko
Nagai, Miki
Matsuo, Shiori
Lougheed, David
Sakurai, Hidetoshi
Saito, Megumu K.
Bourque, Guillaume
Woltjen, Knut
Author's alias: 櫻井, 英俊
齋藤, 潤
Issue Date: 24-Oct-2019
Publisher: Springer Nature
Journal title: Nature Communications
Volume: 10
Thesis number: 4856
Abstract: The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.
Description: Transforming DNA repair errors into assets. Kyoto University press release. 08 Nov. 2019.
Rights: © The Author(s) 2019. Open Access. This 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. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
URI: http://hdl.handle.net/2433/244706
DOI(Published Version): 10.1038/s41467-019-12829-8
PubMed ID: 31649251
Related Link: https://www.kyoto-u.ac.jp/en/research/research_results/2019/191024_1.html
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