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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\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    that are inserted into essential genes required for viability (\n                    <jats:italic>rab5<\/jats:italic>\n                    ,\n                    <jats:italic>rab11<\/jats:italic>\n                    ,\n                    <jats:italic>prosalpha2<\/jats:italic>\n                    ) or fertility (\n                    <jats:italic>spo11<\/jats:italic>\n                    ). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-21771-7","type":"journal-article","created":{"date-parts":[[2021,3,5]],"date-time":"2021-03-05T06:03:22Z","timestamp":1614924202000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Inherently confinable split-drive systems in Drosophila"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4285-4007","authenticated-orcid":false,"given":"Gerard","family":"Terradas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B.","family":"Buchman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4718-257X","authenticated-orcid":false,"given":"Jared B.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaiah","family":"Shriner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0603-7341","authenticated-orcid":false,"given":"John M.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-9884","authenticated-orcid":false,"given":"Omar S.","family":"Akbari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-3005","authenticated-orcid":false,"given":"Ethan","family":"Bier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"key":"21771_CR1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.tibtech.2017.10.001","volume":"36","author":"GR McFarlane","year":"2018","unstructured":"McFarlane, G. 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O.S.A. also has equity interests in Agragene. 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. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1480"}}