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

Alena L. Bishop, Víctor López Del Amo, Emily M. Okamoto, Zsolt Bodai, Alexis C. Komor and Valentino M. Gantz ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29868-3

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