Inherently confinable split-drive systems in Drosophila

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