IDENTIFICATION AND CHARACTERIZATION OF GENES INFLUENCING CHANGES IN IMMUNITY AND SLEEP USING DROSOPHILA

Abstract

The innate immune response and sleep are evolutionarily conserved traits observed across all animal species. However, immune and sleep functions begin to decline with age, posing a serious risk to human health; the age-related decline in immune functions is known as immunosenescence. The effect of age on these traits varies greatly among individuals, and has a significant genetic component, though, the genes contributing to this variation are unknown. This dissertation focuses on elucidating the genetic basis of these two traits, separately, with future directions aimed to assess the two together. First, I used the Drosophila melanogaster genetic reference panel (DGRP), a standard bacterial clearance assay, genome wide association (GWA) tests, and post-GWA analyses to assess and identify genes and networks associated with the age-specific ability to clear a bacterial infection. The effect of age on clearance ability varied significantly among genotypes, with clearance ability declining by ~70% with age. The GWA of clearance ability identified several genes associated with each age, many involved in various signaling pathways contributing to variation in immunity. I then validated 15 candidate genes for their role in the age-specific immune response using the GAL4/UAS system and RNA interference (RNAi). Small, but significant differences in clearance ability were observed in two genes, nebu and Rho1. Next, I measured sleep in the Drosophila simulans genetic reference panel (SGRP) and compared the data to sleep data in the DGRP. Results revealed that sleep is significantly variable and sexually dimorphic in Drosophila simulans, like that of Drosophila melanogaster. However, estimates of broad sense heritability (H2) were higher in Drosophila melanogaster compared to Drosophila simulans. A future goal is to perform a GWA of sleep in the SGRP and compare the results to those obtained in the DGRP to assess the degree of conservation in the genetic architecture of sleep. Collectively, the information gained through this dissertation aids in our understanding of immunosenescence and sleep. Future research should focus on elucidating the complex interactions between immunity and sleep. The insights gained from these and future results could lead to treatments that improve or maintain immune and sleep health.