Sex separation through targeting of conserved female-specific lethal genes in disease vector mosquitoes

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Project Summary Female mosquitoes differ from males in morphological, physiological, and behavioral traits that promote the spread of disease-causing pathogens. Although the majority of genes that regulate sexually dimorphic development in mosquitoes have not yet been identified, these genes may represent novel targets for mosquito control. Characterization of female-specific developmental genes could also elucidate genetic strategies for production and sorting of male mosquitoes, an obstacle that hinders global implementation of several emerging population-based mosquito control strategies that are dependent on mass releases of males. Clusters of loci that cause sex-specific lethal effects are believed to reside within the sex-determining M/m locus region of the dengue vector mosquito Aedes aegypti, but the identities of these genes were not previously known. A recent high-throughput RNAi-mediated screen uncovered female-specific larval lethal genes in the A. aegypti sex-determining locus region, including several genes with known orthologs in other species of disease vector mosquitoes. Yeast interfering RNA larvicides that target these genes kill female A. aegypti larvae during development, but do not impact male mosquitoes. The proposed research program will test the hypothesis, which is supported by preliminary data, that orthologs of these genes also function as female-specific larval lethal loci in Aedes albopictus (vector of multiple arboviruses), Anopheles gambiae (malaria vector), and Culex quinquefasciatus (West Nile and lymphatic filariasis vector). Specific aims of the proposed investigation include i) RNAi-mediated screening of prospective female-specific lethal genes in these disease vector mosquitoes, ii) construction and down-selection of female-specific yeast larvicides to target the genes in each species, and iii) development of protocols for yeast larvicide-based mass rearing of fit, mating- competitive male mosquitoes of all three species. It is anticipated that these studies will generate novel female-specific larvicidal control strategies, provide insight into the evolution of mosquito sex chromosomes and sex-specification mechanisms, and elucidate methodology for mass rearing of males that will facilitate emerging population-based control strategies in multiple species of human disease vector mosquitoes.