Surveying the Genetic Risk Landscape Of Amyotrophic Lateral Sclerosis in The Era of Next-Generation Sequencing

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Downie, Jonathan M.
Title Surveying the Genetic Risk Landscape Of Amyotrophic Lateral Sclerosis in The Era of Next-Generation Sequencing
Date 2017
Description Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an adult-onset fatal disease in which the upper and lower motor neurons of the body progressively degenerate. Efforts to understand the pathophysiology of ALS over the past two decades have shown that mutations in genes involved in a wide variety of cellular processes can cause ALS. Patients who develop ALS and have a family history of the disease are termed familial ALS (FALS) and represent 10% of ALS cases. However, similar genetic mutations occur in patients with no family history of ALS, which suggests genetic factors also play a role in sporadic ALS (SALS). Studies that utilize low-resolution single nucleotide variant (SNV) and microsatellite assays have identified over 30 ALS-associated genes. However, only 68% of FALS and 11% of SALS cases have an identifiable genetic cause. The identification of the genetic factors responsible for these unexplained ALS cases has been challenging because of the technological limitations of SNV and microsatellite assays. The increasing availability of next-generation sequencing (NGS) allows for the potential identification of such elusive disease-causing genetic variants. The aim of this dissertation is to better understand ALS genetic risk factors using NGS technology and computational methods. The first chapter will review ALS and the importance of genetic factors in its pathogenesis. The analyses presented in Chapter 2 try to determine whether NGS approaches can identify known and potentially novel ALS genetic risk loci in individual FALS patients. Next, efforts to better understand the importance of known ALS risk loci in SALS pathogenesis will be covered in Chapter 3. Chapter 4 will focus on attempts to find novel ALS risk genes in a cohort of SALS patients. Chapter 5 will focus on the results of functional studies aimed at validating TP73 as an ALS candidate risk gene. Lastly, Chapter 6 will be focused on determining whether SALS can be caused by deleterious genetic variation shared between distantly related patients. The
Type Text
Publisher University of Utah
Subject Neurosciences; Genetics; Medicine; Physiology
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Jonathan M. Downie
Format Medium application/pdf
ARK ark:/87278/s62c3cw8
Setname ir_etd
Date Created 2019-04-26
Date Modified 2021-05-06
ID 1423217
Reference URL