The DOI matches its Crossref record; 44 of the 46 references it cites were found in a registry or an index, and 1 are not checked yet.
Allele-Specific Chromosome Removal after Cas9 Cleavage in Human Embryos
Open accessPublished version of a preprint
Abstract
Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.
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“and that microhomology-mediated end-joining (MMEJ) is the dominant repair pathway in this context (37).”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [37]
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“This suggests that MMEJ-derived large deletions (14, 37) are more likely than microhomology-mediated gene conversion in this context, though protein expression has yet to be fully characterised.”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [37]
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Cites
Search-and-replace genome editing without double-strand breaks or donor DNA
Anzalone, A. V., Randolph, P. B., Davis, J. R., Sousa, A. A., Koblan, L. W., Levy, J. M., Chen, P. J., Wilson, C., Newby, G. A., Raguram, A., et al. (2019) · Nature · doi:10.1038/s41586-019-1711-4 · Cited by 4,767
To err (meiotically) is human: the genesis of human aneuploidy
Hassold, T. J., & Hunt, P. A. (2001) · Nature Reviews Genetics · doi:10.1038/35066065 · Cited by 2,456
Kosicki, M., Tomberg, K., & Bradley, A. (2018) · Nature Biotechnology · doi:10.1038/nbt.4192 · Cited by 1,883
CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes
Liang, P., Xu, Y., Zhang, X., Ding, C., Huang, R., Zhang, Z., Lv, J., Xie, X., Chen, Y., Li, Y., et al. (2015) · Protein & Cell · doi:10.1007/s13238-015-0153-5 · Cited by 1,135
Correction of a pathogenic gene mutation in human embryos
Ma, H., Marti-Gutierrez, N., Park, S.-W., Wu, J., Lee, Y., Suzuki, K., Koski, A., Ji, D., Hayama, T., Ahmed, R., et al. (2017) · Nature · doi:10.1038/nature23305 · Cited by 992
Repair of Strand Breaks by Homologous RecombinationPreprint
Jasin, M., & Rothstein, R. J. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012740 · Cited by 929
Self-citationChromosome instability is common in human cleavage-stage embryos
Vanneste, E., Voet, T., Le Caignec, C., Ampe, M., Konings, P., Melotte, C., Debrock, S., Amyere, M., Vikkula, M., Schuit, F., et al. (2009) · Nature Medicine · doi:10.1038/nm.1924 · Cited by 880
Hastings, P. J., Ira, G., & Lupski, J. R. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000327 · Cited by 818
Microhomology-Mediated End Joining: A Back-up Survival Mechanism or Dedicated Pathway?
Sfeir, A., & Symington, L. S. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.08.006 · Cited by 636
Lin, Y., Cradick, T. J., Brown, M. T., Deshmukh, H., Ranjan, P., Sarode, N., Wile, B. M., Vertino, P. M., Stewart, F. J., & Bao, G. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku402 · Cited by 634
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Items 301–305 of 305
Optimization of AsCas12f1-mediated long-term gene repression
Sun, Y., Li, L., Wang, X., Han, L., Zhao, Y., Tan, Y., Feng, Y., Qi, W., & Ma, H. (2026) · Molecular Therapy · doi:10.1016/j.ymthe.2026.09.001
Programmable enzymes for targeted gene insertion
Lampe, G. D., King, R. T., & Sternberg, S. H. (2026) · Nature Reviews Genetics · doi:10.1038/s41576-026-01002-9
Self-citationGenome edited sheep generated by zygote electroporation of prime editor ribonucleoproteins
Yu, Z., Li, J., Liu, M., Qi, Q., Duan, Z., Yang, Z., Guan, B., Chen, J., & Hou, J. (2026) · Frontiers in Genome Editing · doi:10.3389/fgeed.2026.1931608
Chovanec, P., He, S., & Yin, Y. A. (2026) · eLife · doi:10.7554/elife.112073.2
Mahmud, A., & Efremov, L. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1948686
Metadata
- Authors
- Zuccaro, M. V., Xu, J., Mitchell, C., Marin, D., Zimmerman, R., Rana, B., Weinstein, E., King, R. T., Palmerola, K. L., Smith, M. E., Tsang, S. H., Goland, R., Jasin, M., Lobo, R., Treff, N., & Egli, D.
- Affiliations
- Columbia University Irving Medical Center (US)
- Genomic Prediction (United States) (US)
- Columbia University (US)
- Rutgers, The State University of New Jersey (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Egli, Dieter
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 183
- Issue
- 6
- Pages
- 1650-1664.e15
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3095871885
- Cited by
- 303
- References
- 46
- Citations by year
- 2026: 27 · 2025: 30 · 2024: 51 · 2023: 64 · 2022: 63 · 2021: 57 · 2020: 11
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- Funders
- Irving Medical Center, Columbia University
- New York Stem Cell Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
- Keywords
- CRISPR/Cas9, human embryo, frameshift mutation, microhomology-mediated end joining, DNA double-strand break repair, zygote, paternal allele, chromosome loss, off-target cleavage, indels, embryo mosaicism, germline editing, inherited blindness
- MeSH terms
- Human Embryonic Stem Cells, Gene Editing, CRISPR-Associated Protein 9, Alleles, Animals, Base Sequence, Blastocyst, Cell Cycle, Cell Line, Chromosome Deletion, Chromosomes, Human, Embryo, Mammalian, Eye Proteins, Fertilization, Genotype, Heterozygote, Humans, Mitosis, Embryo Implantation, Gene Rearrangement, Genome, Human, Open Reading Frames, Polymorphism, Single Nucleotide, Mice, DNA Breaks, Double-Stranded, INDEL Mutation, Genetic Loci, DNA End-Joining Repair
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