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Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos

Bieke Bekaert (UGent) , Annekatrien Boel (UGent) , Lisa De Witte (UGent) , Winter Vandenberghe (UGent) , Mina Popovic, Panagiotis Stamatiadis, Gwenny Cosemans (UGent) , Lise Tordeurs (UGent) , Athina-Maria De Loore, Susana Marina Chuva de Sousa Lopes (UGent) , et al.
(2023) MOLECULAR THERAPY. 31(8). p.2326-2341
Author
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Abstract
Human germline gene correction by targeted nucleases holds great promise for reducing mutation transmission. However, recent studies have reported concerning observations in CRISPR-Cas9-targeted human embryos, including mosaicism and loss of heterozygosity (LOH). The latter has been associated with either gene conversion or (partial) chromosome loss events. In this study, we aimed to correct a heterozygous basepair substitution in PLCZ1, related to infertility. In 36% of the targeted embryos that originated from mutant sperm, only wild-type alleles were observed. By performing genomewide double-digest restriction site-associated DNA sequencing, integrity of the targeted chromosome (i.e., no deletions larger than 3 Mb or chromosome loss) was confirmed in all seven targeted GENType-analyzed embryos (mutant editing and absence of mutation), while short-range LOH events (shorter than 10 Mb) were clearly observed by single-nucleotide polymorphism assessment in two of these embryos. These results fuel the currently ongoing discussion on double-strand break repair in early human embryos, making a case for the occurrence of gene conversion events or partial template-based homology-directed repair.
Keywords
Drug Discovery, Pharmacology, Genetics, Molecular Biology, Molecular Medicine

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MLA
Bekaert, Bieke, et al. “Retained Chromosomal Integrity Following CRISPR-Cas9-Based Mutational Correction in Human Embryos.” MOLECULAR THERAPY, vol. 31, no. 8, Elsevier BV, 2023, pp. 2326–41, doi:10.1016/j.ymthe.2023.06.013.
APA
Bekaert, B., Boel, A., De Witte, L., Vandenberghe, W., Popovic, M., Stamatiadis, P., … Heindryckx, B. (2023). Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos. MOLECULAR THERAPY, 31(8), 2326–2341. https://doi.org/10.1016/j.ymthe.2023.06.013
Chicago author-date
Bekaert, Bieke, Annekatrien Boel, Lisa De Witte, Winter Vandenberghe, Mina Popovic, Panagiotis Stamatiadis, Gwenny Cosemans, et al. 2023. “Retained Chromosomal Integrity Following CRISPR-Cas9-Based Mutational Correction in Human Embryos.” MOLECULAR THERAPY 31 (8): 2326–41. https://doi.org/10.1016/j.ymthe.2023.06.013.
Chicago author-date (all authors)
Bekaert, Bieke, Annekatrien Boel, Lisa De Witte, Winter Vandenberghe, Mina Popovic, Panagiotis Stamatiadis, Gwenny Cosemans, Lise Tordeurs, Athina-Maria De Loore, Susana Marina Chuva de Sousa Lopes, Petra De Sutter, Dominic Stoop, Paul Coucke, Björn Menten, and Björn Heindryckx. 2023. “Retained Chromosomal Integrity Following CRISPR-Cas9-Based Mutational Correction in Human Embryos.” MOLECULAR THERAPY 31 (8): 2326–2341. doi:10.1016/j.ymthe.2023.06.013.
Vancouver
1.
Bekaert B, Boel A, De Witte L, Vandenberghe W, Popovic M, Stamatiadis P, et al. Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos. MOLECULAR THERAPY. 2023;31(8):2326–41.
IEEE
[1]
B. Bekaert et al., “Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos,” MOLECULAR THERAPY, vol. 31, no. 8, pp. 2326–2341, 2023.
@article{01H6NJMYQFNXBCD95GF4AK8S79,
  abstract     = {{Human germline gene correction by targeted nucleases holds great promise for reducing mutation transmission. However, recent studies have reported concerning observations in CRISPR-Cas9-targeted human embryos, including mosaicism and loss of heterozygosity (LOH). The latter has been associated with either gene conversion or (partial) chromosome loss events. In this study, we aimed to correct a heterozygous basepair substitution in PLCZ1, related to infertility. In 36% of the targeted embryos that originated from mutant sperm, only wild-type alleles were observed. By performing genomewide double-digest restriction site-associated DNA sequencing, integrity of the targeted chromosome (i.e., no deletions larger than 3 Mb or chromosome loss) was confirmed in all seven targeted GENType-analyzed embryos (mutant editing and absence of mutation), while short-range LOH events (shorter than 10 Mb) were clearly observed by single-nucleotide polymorphism assessment in two of these embryos. These results fuel the currently ongoing discussion on double-strand break repair in early human embryos, making a case for the occurrence of gene conversion events or partial template-based homology-directed repair.}},
  author       = {{Bekaert, Bieke and Boel, Annekatrien and De Witte, Lisa and Vandenberghe, Winter and Popovic, Mina and Stamatiadis, Panagiotis and Cosemans, Gwenny and Tordeurs, Lise and De Loore, Athina-Maria and Chuva de Sousa Lopes, Susana Marina and De Sutter, Petra and Stoop, Dominic and Coucke, Paul and Menten, Björn and Heindryckx, Björn}},
  issn         = {{1525-0016}},
  journal      = {{MOLECULAR THERAPY}},
  keywords     = {{Drug Discovery,Pharmacology,Genetics,Molecular Biology,Molecular Medicine}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2326--2341}},
  publisher    = {{Elsevier BV}},
  title        = {{Retained chromosomal integrity following CRISPR-Cas9-based mutational correction in human embryos}},
  url          = {{http://doi.org/10.1016/j.ymthe.2023.06.013}},
  volume       = {{31}},
  year         = {{2023}},
}
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