Regulation of X chromosome dosage compensation by the protein SOA in Anopheles mosquitos

• Applicant: Dr. Claudia Isabelle Keller Valsecchi, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513744403

Malaria is a life-threatening disease caused by the parasite plasmodium, which is transmitted through bites from Anopheles gambiae mosquitos. Because of increasing resistance against insecticides, gene drives (“selfish” genetic elements capable of spreading in a population and aimed at diminishing mosquito populations) - have recently gained attention. Since only female mosquitos are blood-feeding and thereby able to transmit malaria, research into sex differences, sexually dimorphic gene expression and sex-specific epigenetic mechanisms of Anopheles is highly relevant, yet still in an early stage. However, this would be a pre-requisite to develop better gene drives, reveal new potential targets and more generally, to understand the transmission of malaria. Males are genetically different from females in carrying only a single X and a Y, while females contain two X chromosomes. This chromosomal imbalance is corrected by a cellular process termed dosage compensation (DC), which mediates equal expression of genes on the X chromosome between the sexes. DC mechanisms are conferred by changes at the chromatin level, e.g. the X-chromosome specific deposition of histone acetylation. Mutations in DC-factors typically result in sex-specific lethality. A. gambiae males display chromosome-wide DC by upregulation of their single-copy X-linked genes. Surprisingly, we recently found that this process is achieved by an entirely different molecular mechanism than in the closely related model organism Drosophila melanogaster. In our preliminary work, we have now identified a candidate gene termed soa, which is likely responsible for mediating DC in Anopheles. Its characterization and mode-of-action is the main aim of this project. Using next generation sequencing (ChIPseq), microscopy and biochemistry, we will characterize the ability of the SOA protein to be recognizing the X chromosomal DNA. We will analyze the in vivo functions of SOA and connection to X chromosome regulation by performing RNAseq studies in soa knock-out mosquitos. These expression profiles will be complemented by ATACseq, which will inform on changes in chromatin accessibility upon loss of SOA. Lastly, we will identify the SOA interaction partners using immunoprecipitation coupled with mass-spectrometry, which will inform on the downstream actions and molecular mechanisms once SOA gets recruited to the X. Together, these studies will yield novel insights into A. gambiae sexual dimorphism and the characterization of an entirely new DC mechanism. This will be the first case of a molecular mechanism of DC in a non-model organisms and will be likely uncovering new strategies to fight malaria by controlling its vector.

• DFG Programme: Research Grants