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CopyCatchers are versatile active genetic elements that detect and quantify inter-homolog somatic gene conversion

Author

Listed:
  • Zhiqian Li

    (University of California San Diego)

  • Nimi Marcel

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

  • Sushil Devkota

    (University of California San Diego)

  • Ankush Auradkar

    (University of California San Diego)

  • Stephen M. Hedrick

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

  • Valentino M. Gantz

    (University of California San Diego)

  • Ethan Bier

    (University of California San Diego
    Tata Institute for Genetics and Society-UCSD)

Abstract

CRISPR-based active genetic elements, or gene-drives, copied via homology-directed repair (HDR) in the germline, are transmitted to progeny at super-Mendelian frequencies. Active genetic elements also can generate widespread somatic mutations, but the genetic basis for such phenotypes remains uncertain. It is generally assumed that such somatic mutations are generated by non-homologous end-joining (NHEJ), the predominant double stranded break repair pathway active in somatic cells. Here, we develop CopyCatcher systems in Drosophila to detect and quantify somatic gene conversion (SGC) events. CopyCatchers inserted into two independent genetic loci reveal unexpectedly high rates of SGC in the Drosophila eye and thoracic epidermis. Focused RNAi-based genetic screens identify several unanticipated loci altering SGC efficiency, one of which (c-MYC), when downregulated, promotes SGC mediated by both plasmid and homologous chromosome-templates in human HEK293T cells. Collectively, these studies suggest that CopyCatchers can serve as effective discovery platforms to inform potential gene therapy strategies.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22927-1
    DOI: 10.1038/s41467-021-22927-1
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    Cited by:

    1. Gerard Terradas & Jared B. Bennett & Zhiqian Li & John M. Marshall & Ethan Bier, 2023. "Genetic conversion of a split-drive into a full-drive element," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Sebald A. N. Verkuijl & Estela Gonzalez & Ming Li & Joshua X. D. Ang & Nikolay P. Kandul & Michelle A. E. Anderson & Omar S. Akbari & Michael B. Bonsall & Luke Alphey, 2022. "A CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. 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.
    4. Jie Du & Weizhe Chen & Xihua Jia & Xuejiao Xu & Emily Yang & Ruizhi Zhou & Yuqi Zhang & Matt Metzloff & Philipp W. Messer & Jackson Champer, 2024. "Germline Cas9 promoters with improved performance for homing gene drive," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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