Natural Genetic Variation Underlying UVR Sensitivity in Drosophila melanogaster
thesisposted on 10.07.2018, 13:43 by Kamaldeep Chana
Solar ultraviolet radiation has been a major environmental factor throughout the evolution of life. Nature has evolved a plethora of defence mechanisms against this biologically harmful agent, and the genes underlying these mechanisms (e.g. DNA repair) have been the direct target of natural selection. The main aim of this study was to assess the level of genetic diversity in Drosophila, and phenotypic variation in Ultraviolet Radiation (UVR) sensitivity amongst a naturally-derived panel of fly strains (DGRP), and to evaluate the extent of genetic variation underlying this trait. The DGRP strains were screened for UVR-sensitivity using simulated solar radiation, and substantial phenotypic variation was identified. A genome-wide association analysis detected 114 SNPs across all three major chromosomes, at a FDR of 0.0001. Some of these SNPs lie within known UV response genes (Xpac, hay), and some novel UVR-associated genes were identified (TwdIB, raw). Subsequently, a significant association, SNP 3R:12383617 in gene CG42342 was validated using complementation tests. In addition, enriched network analysis detected both novel UVR-associated pathways (e.g. GPCRs), and pathways wholly implicated in UV response. In parallel, a candidate gene focussed approach was taken to identify natural phenotypic variation in an allelic series of p53 strains (27 congenic strains) derived from European populations. These strains exhibited both phenotypic and genotypic variation. Association analysis revealed single intronic SNP (3R:18875989), which was associated with UVR-induced oxidative stress. Another set of experiments addressed the role of BTK, a kinase triggered by UVR, in ageing. Two BTK inhibitors (X and Y) were tested as potential novel anti-ageing drugs. The drugs were administrated at different doses in the food, and both extended lifespan, in a p53-dependent manner. The treated flies also showed a weight gain and improved motor function. Patents are currently pending for these two drugs in anti-ageing therapy.