Mechanism and application of male determination in aedine mosquitoes

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 DESCRIPTION (provided by applicant): Aedes aegypti is a major vector for dengue, yellow fever, and chikungunya viruses. The global incidence of dengue has increased dramatically in recent decades and nearly half of the world population is now at risk. No specific treatment for dengue exists and current prevention depends solely on effective vector control, which is hindered by increasing insecticide- resistance. Novel control strategies, informed by improved understanding of mosquito biology, are urgently needed. The long-term objective of this research is to decipher the mechanism of sex-determination in Ae. aegypti and translate such fundamental knowledge into safe and efficient methods to control mosquito-borne infectious diseases. Only female mosquitoes feed on blood and transmit pathogens. Thus maleness is the ultimate disease-refractory trait. Genetic evidence suggests that sex determination in aedine mosquitoes is governed by a dominant male-determining factor (M factor) that resides in the M-locus of a homomorphic sex- determining chromosome. Despite its importance as the master switch of sex-determination in many insects including mosquitoes, no M factor had been determined. Overcoming several technical bottlenecks, we have recently identified an M factor in Ae. aegypti we called Nix. Nix exhibits early embryonic expression and is the only gene that is persistently linked to the M- locus. We performed two complementary transient assays: Nix knockout with CRISPR/Cas9 resulted in largely feminized genetic males and the production of female isoforms of two key regulators of sexual differentiation; ectopic expression of Nix resulted in genetic females with nearly complete male genitalia. Thus, Nix is both required and sufficient to initiate male development. In this study, we will pursue the following specific aims: 1) Determine whether a Nix transgene is sufficient to convert females into fertile males and exploit Nix transgenics as a means for sex separation and population reduction of Ae. aegypti, 2) Elucidate the molecular mechanism underlying Nix function, and 3) Examine the species distribution, evolution, and functional conservation of Nix.