Neurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks... Show moreNeurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks of neurodegeneration are still not fully understood. In this thesis, we make use of bioinformatics approaches to analyze a high-resolution spatial gene expression atlas of the healthy human brain generated by the Allen Institute of Brain Science. Spatial transcriptomics allows examining the molecular and functional organization of the human brain and can be combined with neuroimaging data to identify brain regions and anatomical structures that are vulnerable to cell loss in neurodegenerative diseases. By combining both data modalities, we examined healthy molecular functions in brain regions associated with disease vulnerability based on neuroimaging features, namely gray matter loss within brain networks in individuals with Parkinson’s disease, Huntington’s disease, and individuals at risk of schizophrenia. With this thesis, we have shown that by applying data-driven computational methods we can explore the whole genome and find gene expression patterns informative of regional brain vulnerability in neurodegenerative diseases. Our methods can similarly be applied to unravel the molecular mechanisms in other neurodegenerative diseases, and potentially even reveal shared mechanisms between neurological disorders. Show less
The order Nidovirales, including families Coronaviridae and Arteriviridae, is a monophyletic group of highly divergent (+)ssRNA viruses that infect vertebrate and invertebrate hosts; they share... Show moreThe order Nidovirales, including families Coronaviridae and Arteriviridae, is a monophyletic group of highly divergent (+)ssRNA viruses that infect vertebrate and invertebrate hosts; they share conserved genome organization and replication mechanisms. The genome sequence is the only information available about many newly discovered nidoviruses whose number is fast increasing driven by technology advancements. This development makes comparative genomics, an approach that already has been used extensively in nidovirology, increasingly important. In this thesis, diverse methods of comparative genomics were used to address scientific questions about composition and evolution of the nidovirus genome and proteome, and their connection to the biology of nidoviruses. Three studies were conducted in collaboration with experimental researchers, and ranged from the analysis of the highly divergent polyprotein N-terminus in arteriviruses, to identification of the fifth universally conserved domain of nidoviruses, and to characterization of a nidovirus with the largest known RNA genome. The latter study prompted the development of a bioinformatics tool facilitating functional annotation of large multidomain polyproteins. The thesis illustrates how a notion of nidovirus-specific conservation has been steadily refined as a result of recent discoveries. Show less
