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Title: The role of germline and somatic nuclear and mitochondrial DNA variation in neurodegenerative disorders
Author: Keogh, Michael
ISNI:       0000 0004 7232 1049
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Neurodegenerative disorders are a group of age-related conditions resulting in neuronal cell death and protein accumulation. It is estimated that around 5-10% of these cases are genetically mediated. Most commonly this is by pathogenic single nuclear variants (SNVs), though combinations of rare variants (termed oligogenic variation), copy-number variation (CNVs), somatic mutations in nuclear DNA, and somatically acquired mitochondrial DNA variants have all been hypothesised to increase disease risk or cause disease. Firstly, using a combination of exome sequencing and array genotyping on 1511 post-mortem brain samples within the MRC Brain Bank, we detected 61 monogenic cases of disease, 349 brains carrying disease risk factors, and identified that variants in GRN and PRPH may increase the risk of developing dementia with lewy bodies (DLB) and Alzheimer’s disease (AD) respectively. Secondly, we detected a previously unknown systematic bias in the interpretation of oligogenic interactions with implications for our understanding of disease mechanisms and coexistent clinical diagnostic utility. Thirdly, we detected a novel copy-number gain in LAMA5 associated with Creutzfeldt-Jakob disease (CJD), and fourthly, we determine that at least 1% of the population carry high level somatic protein-coding mutations affecting at least 10% of cells within the brain. Subsequently, additional focussed deep-sequencing studies revealed that several regions of the brain are likely to contain clones of low-level somatic mutations that are pathogenic when present in the germline, and that age-related clonal mutations that arise in blood are present at high levels within the aging brain and are associated with Lewy Body pathology. Finally, using transgenic mice that over express human α-synuclein and which either accrue or transmit mtDNA mutations, we determine that the presence of mtDNA mutations exacerbate some phenotypic traits of Lewy body disorders, and may reduce the volume of critical neuroanatomical brain regions whilst paradoxically reducing α-synuclein accumulation. Taken together, these data enable the first genetically stratified brain tissue resource in the UK, describe new disease genetic risk factors (both SNVs and CNVs) for neurodegenerative disorders, and also help define the somatic genetic architecture of the human brain. In addition, we describe the in vivo interaction between mutations in the mitochondrial genome and a progressive neurodegenerative disorder in mice.
Supervisor: Chinnery, Patrick Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Neurodegeneration ; genetics ; neurogenetics ; alzheimer's ; parkinson's ; frontotemporal dementia ; amyotrophic lateral sclerosis