Sex ratio distortion in Aedes aegypti

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Project Summary Aedes aegypti is a major vector of dengue, chikungunya, and Zika viruses. The global incidence of dengue has increased dramatically in recent decades. The first dengue vaccine, Dengvaxia®, is recommended for a very limited population. Current prevention depends mainly on effective vector control, which is hindered by increasing insecticide-resistance. Novel genetic strategies for vector control are actively explored, including both population suppression and population replacement. Recent field releases of either transgenic and Wolbachia-infected sterile male mosquitoes show promising results for suppressing Aedes populations in areas of modest size. Given the biological, geographical, economic and cultural complexity facing global mosquito-borne infectious disease control programs, diverse measures that can be integrated to address various challenges are urgently needed. Female to male sex ratio distortion is an attractive concept for developing new control measures, as females are responsible for disease transmission and population growth. Aedes and Culex mosquitoes contain homomorphic sex- determining chromosomes and maleness is conferred by a dominant male-determining factor (M factor) within an M locus that is on one of a pair of chromosome 1. Male-biased sex-ratio distortion occurs in natural populations in Ae. aegypti, which is associated with m-chromosome breakage during meiosis at a few sites. The Distorter locus is linked to the M-locus on the M-chromosome, conferring a meiotic drive as it increases the probability of its own inheritance. We recently discovered the M factor, an RNA-binding protein named Nix and identified the M and m locus in Ae. aegypti. By analysing male and female Illumina reads across a few strains, we found a number of m-specific repeats that can be targeted for breakage by CRISPR/cas9 during male meiosis, potentially leading to a male-biased sex ratio distortion. We will pursue the following specific aims: 1) Systematically characterize components to develop m-shredders. Research performed here will also improve our understanding of the male germline and the homomorphic sex chromosomes and facilitate any future genetic manipulations involving the male germline. 2) Develop m-shredder lines with various degrees of M-linkage to optimize effective population suppression. 3) Model various applications of m-shredders in population suppression and transgene recall. In summary, innovative technologies will be used to gain fundamental insights into male germline expression and the differentiation of the homomorphic sex chromosomes of Ae. aegypti. m-shredders with various levels of efficiency and transmissibility will be developed and modelled for population suppression and transgene recall, expanding the tool box for integrated vector management. 1