Mechanisms of sex determination in Anopheles and their implementation to control mosquito vectors

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The molecular developmental processes that determine gender in animals are astonishingly variable. Because genes governing these processes often undergo rapid changes, information on the components of the sex determination pathway gathered in one species may provide little or no clue to facilitate identification of the sex determination genes in other, more distantly related, species. In insects, the pathway has been characterised in detail in the fruit fly Drosophila melanogaster; however, despite efforts, it remains unexplored or poorly understood in other insect groups, including mosquitoes. Recently, we have identified a gene (named Yob), which in the malaria mosquito, Anopheles gambiae, is located on the male-specific Y chromosome and controls the development of an individual into a male. Surprisingly, Yob kills female embryos, if expressed (activated) during early steps of female development. The mechanisms through which Yob regulates male development and kills females remain unknown. To fill these knowledge gaps, we propose exploration of an extensive, high-throughput sequence data of genes active during the development of A. gambiae. The data, already generated by our group and collected separately for males and females at a number of time points, starting from early embryos to adults, will be filtered to identify sex-specifically expressed genes that may be involved in the mentioned above processes. In a parallel approach, we will perform a molecular study of genetically modified mosquito strains, with Yob either inactivated in males, or activated in females, to detect genes with perturbed expression, indicative of their direct or indirect interaction with Yob. Such transgenic strains were recently generated by our group and are available for this study. The role of the identified genes in sexual development of Anopheles will be tested by a number of experimental approaches. We will also identify DNA regulatory regions in the A. gambiae genome necessary to activate gene expression in early embryos, and evaluate their function in transgenic mosquitoes. Our proposed research will significantly contribute to the understanding of insect sex determination pathways, and is expected to have a great impact on novel strategies of mosquito control. The sex determination genes, when manipulated in transgenic technology, could be used to eliminate females and produce male-only generations by causing female lethality or, potentially, sex reversal of genetic females into males. In a broader context, the outputs of this study will facilitate identification of sex determination genes in other insect pest species, including mosquito vectors of arboviruses, and will stimulate new avenues of research on genetic control of these insect groups.