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Limitations of gene editing assessments in human preimplantation embryos

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Title
Limitations of gene editing assessments in human preimplantation embryos
Author(s)
Liang, Dan; Mikhalchenko, Aleksei; Ma, Hong; Marti Gutierrez, Nuria; Chen, Tailai; Lee, Yeonmi; Sang-Wook Park; Tippner-Hedges, Rebecca; Koski, Amy; Darby, Hayley; Li, Ying; Van Dyken, Crystal; Zhao, Han; Wu, Keliang; Zhang, Jingye; Hou, Zhenzhen; So, Seongjun; Han, Jongsuk; Park, Jumi; Kim, Chong-Jai; Zong, Kai; Gong, Jianhui; Yuan, Yilin; Gu, Ying; Shen, Yue; Olson, Susan B.; Yang, Hui; Battaglia, David; O'Leary, Thomas; Krieg, Sacha A.; Lee, David M.; Wu, Diana H.; Duell, P Barton; Kaul, Sanjiv; Jin Soo Kim; Heitner, Stephen B.; Kang, Eunju; Chen, Zi-Jiang; Amato, Paula; Mitalipov, Shoukhrat
Publication Date
2023-03
Journal
Nature Communications, v.14, no.1
Publisher
Nature Research
Abstract
Range of DNA repair in response to double-strand breaks induced in human preimplantation embryos remains uncertain due to the complexity of analyzing single- or few-cell samples. Sequencing of such minute DNA input requires a whole genome amplification that can introduce artifacts, including coverage nonuniformity, amplification biases, and allelic dropouts at the target site. We show here that, on average, 26.6% of preexisting heterozygous loci in control single blastomere samples appear as homozygous after whole genome amplification indicative of allelic dropouts. To overcome these limitations, we validate on-target modifications seen in gene edited human embryos in embryonic stem cells. We show that, in addition to frequent indel mutations, biallelic double-strand breaks can also produce large deletions at the target site. Moreover, some embryonic stem cells show copy-neutral loss of heterozygosity at the cleavage site which is likely caused by interallelic gene conversion. However, the frequency of loss of heterozygosity in embryonic stem cells is lower than in blastomeres, suggesting that allelic dropouts is a common whole genome amplification outcome limiting genotyping accuracy in human preimplantation embryos. © 2023, The Author(s).
URI
https://pr.ibs.re.kr/handle/8788114/13312
DOI
10.1038/s41467-023-36820-6
ISSN
2041-1723
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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