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Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier

Author

Listed:
  • Zhiqian Li

    (University of California, San Diego
    University of California, San Diego)

  • Lang You

    (University of California, San Diego
    University of California, San Diego)

  • Anita Hermann

    (University of California, San Diego
    University of California, San Diego)

  • Ethan Bier

    (University of California, San Diego
    University of California, San Diego)

Abstract

DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Factors influencing the choice of particular repair pathways, however remain poorly characterized. Here we develop an Integrated Classification Pipeline (ICP) to decompose and categorize CRISPR/Cas9 generated mutations on genomic target sites in complex multicellular insects. The ICP outputs graphic rank ordered classifications of mutant alleles to visualize discriminating DSB repair fingerprints generated from different target sites and alternative inheritance patterns of CRISPR components. We uncover highly reproducible lineage-specific mutation fingerprints in individual organisms and a developmental progression wherein Microhomology-Mediated End-Joining (MMEJ) or Insertion events predominate during early rapid mitotic cell cycles, switching to distinct subsets of Non-Homologous End-Joining (NHEJ) alleles, and then to Homology-Directed Repair (HDR)-based gene conversion. These repair signatures enable marker-free tracking of specific mutations in dynamic populations, including NHEJ and HDR events within the same samples, for in-depth analysis of diverse gene editing events.

Suggested Citation

  • Zhiqian Li & Lang You & Anita Hermann & Ethan Bier, 2024. "Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46479-2
    DOI: 10.1038/s41467-024-46479-2
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    1. Michelle M. Chan & Zachary D. Smith & Stefanie Grosswendt & Helene Kretzmer & Thomas M. Norman & Britt Adamson & Marco Jost & Jeffrey J. Quinn & Dian Yang & Matthew G. Jones & Alex Khodaverdian & Nir , 2019. "Molecular recording of mammalian embryogenesis," Nature, Nature, vol. 570(7759), pages 77-82, June.
    2. Suresh Ramakrishna & Seung Woo Cho & Sojung Kim & Myungjae Song & Ramu Gopalappa & Jin-Soo Kim & Hyongbum Kim, 2014. "Surrogate reporter-based enrichment of cells containing RNA-guided Cas9 nuclease-induced mutations," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    3. Stamatis Papathanasiou & Styliani Markoulaki & Logan J. Blaine & Mitchell L. Leibowitz & Cheng-Zhong Zhang & Rudolf Jaenisch & David Pellman, 2021. "Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    4. Rajeswari Jayavaradhan & Devin M. Pillis & Michael Goodman & Fan Zhang & Yue Zhang & Paul R. Andreassen & Punam Malik, 2019. "CRISPR-Cas9 fusion to dominant-negative 53BP1 enhances HDR and inhibits NHEJ specifically at Cas9 target sites," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    5. Max W. Shen & Mandana Arbab & Jonathan Y. Hsu & Daniel Worstell & Sannie J. Culbertson & Olga Krabbe & Christopher A. Cassa & David R. Liu & David K. Gifford & Richard I. Sherwood, 2018. "Predictable and precise template-free CRISPR editing of pathogenic variants," Nature, Nature, vol. 563(7733), pages 646-651, November.
    6. Pedro A. Mateos-Gomez & Fade Gong & Nidhi Nair & Kyle M. Miller & Eros Lazzerini-Denchi & Agnel Sfeir, 2015. "Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination," Nature, Nature, vol. 518(7538), pages 254-257, February.
    7. Weiwei Sun & Ce Gao & Ciputra Adijaya Hartana & Matthew R. Osborn & Kevin B. Einkauf & Xiaodong Lian & Benjamin Bone & Nathalie Bonheur & Tae-Wook Chun & Eric S. Rosenberg & Bruce D. Walker & Xu G. Yu, 2023. "Phenotypic signatures of immune selection in HIV-1 reservoir cells," Nature, Nature, vol. 614(7947), pages 309-317, February.
    8. Wouter Koole & Robin van Schendel & Andrea E. Karambelas & Jane T. van Heteren & Kristy L. Okihara & Marcel Tijsterman, 2014. "A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    9. Ragini Bhargava & Manbir Sandhu & Sanychen Muk & Gabriella Lee & Nagarajan Vaidehi & Jeremy M. Stark, 2018. "C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    10. Annabel Guichard & Tisha Haque & Marketta Bobik & Xiang-Ru S. Xu & Carissa Klanseck & Raja Babu Singh Kushwah & Mateus Berni & Bhagyashree Kaduskar & Valentino M. Gantz & Ethan Bier, 2019. "Efficient allelic-drive in Drosophila," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    11. Zhiqian Li & Nimi Marcel & Sushil Devkota & Ankush Auradkar & Stephen M. Hedrick & Valentino M. Gantz & Ethan Bier, 2021. "CopyCatchers are versatile active genetic elements that detect and quantify inter-homolog somatic gene conversion," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    12. Aisha Yesbolatova & Yuichiro Saito & Naomi Kitamoto & Hatsune Makino-Itou & Rieko Ajima & Risako Nakano & Hirofumi Nakaoka & Kosuke Fukui & Kanae Gamo & Yusuke Tominari & Haruki Takeuchi & Yumiko Saga, 2020. "The auxin-inducible degron 2 technology provides sharp degradation control in yeast, mammalian cells, and mice," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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