Inherently confinable split-drive systems in Drosophila

Gerard Terradas, Anna B. Buchman, Jared B. Bennett, Isaiah Shriner, John M. Marshall, Omar S. Akbari and Ethan Bier ()
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Gerard Terradas: University of California, San Diego
Anna B. Buchman: University of California, San Diego
Jared B. Bennett: University of California
Isaiah Shriner: University of California, San Diego
John M. Marshall: University of California
Omar S. Akbari: University of California, San Diego
Ethan Bier: University of California, San Diego

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract CRISPR-based gene-drive systems, which copy themselves via gene conversion mediated by the homology-directed repair (HDR) pathway, have the potential to revolutionize vector control. However, mutant alleles generated by the competing non-homologous end-joining (NHEJ) pathway, resistant to Cas9 cleavage, can interrupt the spread of gene-drive elements. We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences that restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles combined with recessive Mendelian culling processes. Here, we test split gene-drive (sGD) systems in Drosophila melanogaster that are inserted into essential genes required for viability (rab5, rab11, prosalpha2) or fertility (spo11). In single generation crosses, sGDs copy with variable efficiencies and display sex-biased transmission. In multigenerational cage trials, sGDs follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage and/or lethal/sterile mosaic Cas9-dependent phenotypes, leading to inherently confinable drive outcomes.

Date: 2021
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DOI: 10.1038/s41467-021-21771-7

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