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Investigations of phenotypic robustness and effector peptide function in Drosophila Toll signaling


This dissertation contains two parts, linked by their study of the Toll pathway, a widely conserved signaling pathway required for both embryonic development and innate immunity in Drosophila. The experiments presented in Chapter I employ the Toll pathway as a tool to investigate normally occurring fluctuations in gene expression and their impact on phenotype. This study focused on a set of alleles of the tube gene, which encodes a Toll pathway adaptor protein. I found that females carrying any of these tube alleles produced embryos across an unusually wide spectrum of phenotypes associated with defective dorsoventral patterning, even in the absence of variations in genetic background or environment. Using sequencing, asymmetric PCR, and site-directed recombination techniques, I discovered that transposable element insertions near, but not within, the tube gene were responsible for the hypervariable phenotypes of the five tube alleles. These transposable elements acted combinatorially to reduce maternal tube expression below the threshold required for wild-type patterning. By measuring transcript levels in individual embryos, I found that there was a normal level of inter-embryo tube expression variability. The phenotypic hypervariability of these alleles revealed normal transcriptional fluctuations around a reduced mean expression level. In Chapter II, I delve into the question of how Toll pathway signaling mediates pathogen resistance in Drosophila adults. I characterized a novel gene family, the Bomanins (Boms), which encodes small effector peptides that are massively upregulated upon Toll activation by infection. Using targeted genome engineering, I generated a deletion of a gene cluster containing ten of the twelve Bom genes in the D. melanogaster genome. Flies lacking these ten Bom genes succumbed to infection at the same rate and with the same specificity as flies incapable of Toll signaling, despite the fact that Toll signaling is unaffected by the Bom cluster deletion. By comparing the bacterial load of Bom cluster deletion mutants and wild- type flies, I found that Boms mediate infection resistance, not tolerance. I additionally examined the survival of flies lacking a smaller subset of Bom genes or single Bom genes to find that at least some, although not all, Boms have overlapping functions

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