TY - JOUR T1 - Inherently confinable split-drive systems in <em>Drosophila</em> JF - bioRxiv DO - 10.1101/2020.09.03.282079 SP - 2020.09.03.282079 AU - Gerard Terradas AU - Anna B. Buchman AU - Jared B. Bennett AU - Isaiah Shriner AU - John M. Marshall AU - Omar S. Akbari AU - Ethan Bier Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/03/2020.09.03.282079.abstract N2 - CRISPR-based gene drive systems, which copy themselves based on gene conversion mediated by the homology directed repair (HDR) pathway, have potential to revolutionize vector control. However, mutant alleles generated by the competing non-homologous end-joining (NHEJ) pathway that are rendered resistant to Cas9 cleavage can interrupt the spread of genedrive elements. We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences to restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles, combined with recessive Mendelian processes. Here, we test split gene-drive (sGD) systems in Drosophila melanogaster that were 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 multi-generational cage trials, sGD follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage or lethal/sterile mosaic phenotypes, leading to inherently confineable drive outcomes.Competing Interest StatementEB has equity interests in Synbal, Inc. and Agragene, Inc., companies that may potentially benefit from the research results and also serve on the company's Scientific Advisory Board and Board of Directors. OSA also has equity interests in Agragene, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. GT, ABB, JBB, IS, JMM declare no competing interests. ER -