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Double-tap gene drive uses iterative genome targeting to help overcome resistance alleles

Author

Listed:
  • Alena L. Bishop

    (University of California San Diego)

  • Víctor López Del Amo

    (University of California San Diego)

  • Emily M. Okamoto

    (University of California San Diego)

  • Zsolt Bodai

    (University of California San Diego)

  • Alexis C. Komor

    (University of California San Diego)

  • Valentino M. Gantz

    (University of California San Diego)

Abstract

Homing CRISPR gene drives could aid in curbing the spread of vector-borne diseases and controlling crop pest and invasive species populations due to an inheritance rate that surpasses Mendelian laws. However, this technology suffers from resistance alleles formed when the drive-induced DNA break is repaired by error-prone pathways, which creates mutations that disrupt the gRNA recognition sequence and prevent further gene-drive propagation. Here, we attempt to counteract this by encoding additional gRNAs that target the most commonly generated resistance alleles into the gene drive, allowing a second opportunity at gene-drive conversion. Our presented “double-tap” strategy improved drive efficiency by recycling resistance alleles. The double-tap drive also efficiently spreads in caged populations, outperforming the control drive. Overall, this double-tap strategy can be readily implemented in any CRISPR-based gene drive to improve performance, and similar approaches could benefit other systems suffering from low HDR frequencies, such as mammalian cells or mouse germline transformations.

Suggested Citation

  • Alena L. Bishop & Víctor López Del Amo & Emily M. Okamoto & Zsolt Bodai & Alexis C. Komor & Valentino M. Gantz, 2022. "Double-tap gene drive uses iterative genome targeting to help overcome resistance alleles," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29868-3
    DOI: 10.1038/s41467-022-29868-3
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    References listed on IDEAS

    as
    1. Víctor López Del Amo & Alena L. Bishop & Héctor M. Sánchez C. & Jared B. Bennett & Xuechun Feng & John M. Marshall & Ethan Bier & Valentino M. Gantz, 2020. "A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Andrew Hammond & Paola Pollegioni & Tania Persampieri & Ace North & Roxana Minuz & Alessandro Trusso & Alessandro Bucci & Kyros Kyrou & Ioanna Morianou & Alekos Simoni & Tony Nolan & Ruth Müller & And, 2021. "Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    3. Hannah A. Grunwald & Valentino M. Gantz & Gunnar Poplawski & Xiang-Ru S. Xu & Ethan Bier & Kimberly L. Cooper, 2019. "Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline," Nature, Nature, vol. 566(7742), pages 105-109, February.
    4. Megan Scudellari, 2019. "Self-destructing mosquitoes and sterilized rodents: the promise of gene drives," Nature, Nature, vol. 571(7764), pages 160-162, July.
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    Cited by:

    1. Lukas Möller & Eric J. Aird & Markus S. Schröder & Lena Kobel & Lucas Kissling & Lilly van de Venn & Jacob E. Corn, 2022. "Recursive Editing improves homology-directed repair through retargeting of undesired outcomes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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