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Autophagy was first isolated as a marker of starvation but has since then been identified and implicated in a variety of process both pathological or not. Lysosome density within a cell has long been used as a marker of activity of this pathway, as it represents the final location of degradation. Under normal conditions, lab strains of Drosophila melanogaster exhibit a low lysosome density considered to be universally observed. When challenged with starvation, this activity is expected to increase 2fold. We do not know if these characteristics are representative of natural populations, or the regulatory factors used to control the lysosome density within tissues. By phenotyping 178 lines of the Drosophila Genetic Reference Panel for their lysosome density under resting and starved states, we were able to identify a previously uncharacterized variance in lysosome density phenotypes. Resting variation included multiple lines displaying an unusually dense lysosome phenotype previously not observed in lab strains. Furthermore, a Genome Wide Association Study performed on this data revealed that the gene sets associated with variance in resting and starved lysosome density were non-overlapping. Finally, RNA interference studies identified 4 previously non-implicated regulators of lysosome density; Myosin61F and corazonin as negative regulators and kin17 and elk as positive regulators. This analysis presents a more complete picture of natural variance of lysosome density, and thus autophagy activation, as well as identifies novel regulators that may be responsible for controlling this observed variation. CHAPTER 1. GENERAL INTRODUCTION Cells are delicate living machines, requiring a slew of different pathways to function properly. One of those pathways can be generally referred to as the autophagy pathway, although it comprises multiple types of actions. From the Greek "auto"-self and "phagy" –eating, autophagy allows cells to recycle damaged organelles and unused or malfunctioning proteins into their component parts, thus providing energy back to the cell (Codogno et al. 2011). This pathway is stimulated in cells as a housekeeping mechanism throughout their lives and can also be up-regulated in situations of stress to boost internal access to nutrients. The inception of autophagy characterization was in rat liver tissue when Dr. Christian De Duve identified vesicles termed "dense bodies", containing a very high concentration of various proteases and hydrolases (De Duve et al. 1955). This structure later termed "lysosome" is one of the central players in the autophagic process. This organelle is responsible for the breakdown of all material brought to it and is critical for proper function of the cell. The next landmark discovery happening in mouse kidney cells, where a secondary vacuole was identified as containing protein aggregates as well as various organelles including mitochondria (Arstila & Trump 1968). The presence of this specialized double membrane-bound vacuole, later termed "autophagosome", could be induced in the cell using stress assays, at which point it was established that nutrient stress was a very strong predictor for the presence of this structure. It was observed that while glucagon could induce its presence, insulin would repress its formation in the cell, thus cementing the function of these structures as being tightly linked with the nutritional state in the cell (Deter et al. 1967). The autophagosome would then be shown to fuse with the lysosome, losing one of its membrane layers in the process and allowing its cytosolic

The Power of GWAS: Leveraging Genome Wide Association Studies to identify novel regulators of autophagy in Drosophila melanogaster