The haplolethal gene wupA of Drosophila exhibits potential as a target for an X-poisoning gene drive

Lawler C., D. , Hernandes, N., Nunez, A. K. P., Bhide, S., Baxter, S. and Robin, C.,  bioRxiv,  2023.06.23.546292. 2023.

A synthetic gene drive that targets haplolethal genes on the X-chromosome can skew the sex ratio towards males. Like an X-shredder strategy it does not involve homing and that has advantages including the reduction in gene drive resistance allele formation. We examine this X-poisoning strategy by targeting four of the 11 known X-linked haplolethal/haplosterile genes of Drosophila melanogaster with CRISPR/cas9. We find that targeting the wupA gene during spermatogenesis skews the sex ratio so fewer than 14% of progeny are daughters. That is unless we cross the mutagenic males to X^XY female flies that bear attached-X chromosomes, which reverses the inheritance of the poisoned X chromosome so that sons inherit it from their mother; in which case only 2% of the progeny are sons. These sex ratio biases suggests that most of the CRISPR/cas9 mutants we induced in the wupA gene are haplolethal but some are recessive lethal. We have used simulations to model release strategies of a gene drive where an X-poisoning Y chromosome is introduced to invasive populations of the pest Drosophila suzukii. While the reproductive output of carriers of X-poisoning drives is less than that of X-shredding drives due to their post-zygotic mode of action, the threshold dynamics of an X-poisoning drive result in more predictable outcomes than X-shredders that tend to exhibit chasing more often. Like D. melanogaster and D. suzukii, the wupA orthologs in Anopheles mosquitos are found on X chromosomes making it a viable target in multiple species.

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