biostudies-literatureVerkuijl SANUnited States Department of Defense | Defense Advanced Research Projects AgencyNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesRCUK | Biotechnology and Biological Sciences Research CouncilU.S. Department of Health & Human Services | National Institutes of HealthBiotechnology and Biological Sciences Research Council7145https://www.ebi.ac.uk/biostudies/studies/S-EPMC9681865biostudies-literatureUnknown13(1)CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (w^GDe). Here, through an analysis using this linkage we show that in males inheritance bias of w^GDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same w^GDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.Nature communicationsA CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias.PMC9681865BBS/E/I/00007039BBS/E/I/00007038BBS/E/I/00007033R01 AI151004R01AI151004HR00111-16-2-0005BB/L00948X/1RO1AI148300BB/M011224/1HR0011-17-2-0047BB/V008110/1N66001-17-2-4054BB/H01814X/1R01 AI148300Gonzalez EBonsall MBAng JXDAnderson MAEAlphey LAkbari OSVerkuijl SANKandul NPLi MfalseA CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias.CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (w^GDe). Here, through an analysis using this linkage we show that in males inheritance bias of w^GDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same w^GDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.2022-01-01T00:00:00Z2022 Nov2026-06-03T11:16:59.299Z2025-04-06T08:34:03.448ZS-EPMC96818653641461810.1038/s41467-022-34739-y