Streptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics. Due to their multicellular lifestyle as well as their prolific production of secondary metabolites, Str...Show moreStreptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics. Due to their multicellular lifestyle as well as their prolific production of secondary metabolites, Streptomyces are of unique fundamental and applied importance. However, Streptomyces have unstable genomes, an attribute that can cause genomic rearrangements and dramatically alter their phenotype. Previous studies have failed to explain this phenomenon. In this dissertation, we investigate the evolutionary functions and mechanisms of genomic instability in Streptomyces coelicolor. We first find that a subpopulation of cells generated through large genomic rearrangements becomes specialized to produce antibiotics. This results in a division of labor which benefits the entire colony, while the yield and diversity of antibiotics are maximized, despite significant fitness costs to this altruistic subpopulation. Next, we show that these altruistic mutants continue to lose fitness due to the irreversible accumulation of large deletions and deleterious mutations, coupled to an increased mutation rate. Finally, we explore the molecular consequences of large genomic rearrangements for development and antibiotic production using detailed proteomics and metabolomics analyses, which highlight key pathways that are impacted by these genomic events. Overall, this dissertation provides new insights of genomic instability in Streptomyces. Show less
Cutaneous lymphomas are hematological malignancies that present in the skin without evidence of extracutaneous disease at the time of diagnosis. This thesis explores the pathogenetic basis of... Show moreCutaneous lymphomas are hematological malignancies that present in the skin without evidence of extracutaneous disease at the time of diagnosis. This thesis explores the pathogenetic basis of common and rare cutaneous lymphoma entities (i.e. tumor-stage mycosis fungoides, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma, blastic plasmacytoid dendritic cell neoplasm) by studying them using next-generation sequencing approaches. These studies had a special focus on structural genomic alterations (i.e. genomic rearrangements, copy number alterations), since a detailed examination of this type of genetic defects in cutaneous lymphomas using high-resolution techniques had been largely neglected in prior molecular studies. The body of work presented in this thesis expanded the understanding of the pathogenetic basis of four different cutaneous lymphoma entities. Firstly, it showed that structural genomic alterations play important roles in the pathobiology of cutaneous lymphomas. Secondly, it identified recurrently affected genes and cellular processes/pathways in each of the analyzed malignancies. Finally, it provided molecular insights that may be instrumental for the development of novel therapies in the future. Show less
