Insects vary in their susceptibility to viral infection, and this variation affects disease transmission by vectors and the survival of beneficial insects. Identifying the genes that cause this variation will provide insights into both the molecular interactions between insects and their parasites, and the processes that maintain this variation in populations. We propose to do this in Drosophila, where genome-wide association studies are now possible thanks to the publication of large numbers of genome sequences. Furthermore, new techniques allow the sequence of Drosophila genes to be precisely altered, which will allow the exact molecular changes affecting resistance to be confirmed experimentally. Using these powerful techniques, we will first identify genes that affect resistance to a diverse panel of different viruses, which will allow us to understand the molecular and cellular basis of how resistance to different groups of viruses evolves in nature. Next, we will repeat this analysis using different isolates of the same virus, to identify the molecular basis of the ‘specific’ resistance commonly observed in invertebrates, where different host genotypes are resistant to different parasite genotypes. Once we have identified the polymorphisms that affect resistance, we can then use these results to examine the evolutionary processes that maintain this variation in populations: are alleles that increase resistance costly, how has natural selection acted on the polymorphisms, and is there more variation if the virus has naturally coevolved with Drosophila than if the virus was isolated from another insect. Finally, by hybridising D. melanogaster to D. simulans, we will extend these experiments to identify genes that cause species to differ in resistance, which will reveal the molecular basis of how resistance evolves over millions of years and how viruses adapt to their hosts.
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