Genome Wide Association Studies of Phagocytosis and the Cellular Immune Response in Drosophila melanogaster.

Phagocytosis of bacteria by specialized blood cells, known as hemocytes, is a vital component of Drosophila cellular immunity. To identify novel genes that mediate the cellular response to bacteria, we conducted three separate genetic screens using the Drosophila Genetic Reference Panel (DGRP). Adult DGRP lines were tested for the ability of their hemocytes to phagocytose the Gram-positive bacteria Staphylococcus aureus or the Gram-negative bacteria Escherichia coli. The DGRP lines were also screened for the ability of their hemocytes to clear S. aureus infection through the process of phagosome maturation. Genome-wide association analyses were performed to identify potentially relevant single nucleotide polymorphisms (SNPs) associated with the cellular immune phenotypes. The S. aureus phagosome maturation screen identified SNPs near or in 528 candidate genes, many of which have no known role in immunity. Three genes, dpr10, fred, and CG42673, were identified whose loss-of-function in blood cells significantly impaired the innate immune response to S. aureus. The DGRP S. aureus screens identified variants in the gene, Ataxin 2 Binding Protein-1 (A2bp1) as important for the cellular immune response to S. aureus. A2bp1 belongs to the highly conserved Fox-1 family of RNA-binding proteins. Genetic studies revealed that A2bp1 transcript levels must be tightly controlled for hemocytes to successfully phagocytose S. aureus. The transcriptome of infected and uninfected hemocytes from wild type and A2bp1 mutant flies was analyzed and it was found that A2bp1 negatively regulates the expression of the Immunoglobulin-superfamily member Down syndrome adhesion molecule 4 (Dscam4). Silencing of A2bp1 and Dscam4 in hemocytes rescues the fly’s immune response to S. aureus indicating that Dscam4 negatively regulates S. aureus phagocytosis. Overall, we present an examination of the cellular immune response to bacteria with the aim of identifying and characterizing roles for novel mediators of innate immunity in Drosophila. By screening panel of lines in which all genetic variants are known, we successfully identified a large set of candidate genes that could provide a basis for future studies of Drosophila cellular immunity. Finally, we describe a novel, immune-specific role for the highly conserved Fox-1 family member, A2bp1.

THERE GOES THE ELECTORAL NEIGHBORHOOD: LOCAL NETWORKS, ATTRIBUTION OF RESPONSIBILITY, AND THE (UN) FAIRNESS OF ELECTIONS

During the last two decades there have been but a handful of recorded cases of electoral fraud in Latin America. However, survey research consistently shows that often citizens do not trust the integrity of the electoral process. This dissertation addresses the puzzle by explaining the mismatch between how elections are conducted and how the process is perceived. My theoretical contribution provides a double-folded argument. First, voters’ trust in their community members (“the local experience”) impacts their level of confidence in the electoral process. Since voters often find their peers working at polling stations, negative opinions about them translate into negative opinions about the election. Second, perceptions of unfairness of the system (“the global effect”) negatively impact the way people perceive the transparency of the electoral process. When the political system fails to account for social injustice, citizens lose faith in the mechanism designed to elect representatives -and ultimately a set of policies. The fact that certain groups are systematically disregarded by the system triggers the notion that the electoral process is flawed. This is motivated by either egotropic or sociotropic considerations. To test these hypotheses, I employ a survey conducted in Costa Rica, El Salvador, Honduras, and Guatemala during May/June 2014, which includes a population-based experiment. I show that Voters who trust their peers consistently have higher confidence in the electoral process. Whereas respondents who were primed about social unfairness (treatment) expressed less confidence in the quality of the election. Finally, I find that the local experience is predominant over the global effect. The treatment has a statistically significant effect only for respondents who trust their community. Attribution of responsibility for voters who are skeptics of their peers is clear and simple, leaving no room for a more diffuse mechanism, the unfairness of the political system. Finally, now I extend analysis to the Latin America region. Using data from LAPOP that comprises four waves of surveys in 22 countries, I confirm the influence of the “local experience” and the “global effect” as determinants of the level of confidence in the electoral process.