A confinable home-and-rescue gene drive for population modification

TLDR

Homing‑based CRISPR/Cas9 gene drives aim to spread desirable genes, but their spread can be impeded by the accumulation of resistant alleles. The study engineers a confinable HomeR drive targeting an essential gene in *Drosophila* to overcome resistance. The authors construct the HomeR drive and use mathematical modeling to compare its performance to other gene drive architectures across varying fitness costs, transmission rates, and release regimens. Experiments show that recessive lethal resistant alleles are disadvantaged, HomeR increases in frequency in cage experiments but is limited by Cas9 insertion fitness costs, and it could be adapted to other species for safe, confinable population modification.

Abstract

Homing-based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification home-and-rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy. Finally, we conduct mathematical modeling comparing HomeR to contemporary gene drive architectures for population modification over wide ranges of fitness costs, transmission rates, and release regimens. HomeR could potentially be adapted to other species, as a means for safe, confinable, modification of wild populations.