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    Identification of Novel Genetic Variations for Amyotrophic Lateral Sclerosis (ALS)

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    Authors
    Xu, Guang
    Faculty Advisor
    Robert Brown; Jeffrey Bailey
    Academic Program
    Bioinformatics and Computational Biology
    UMass Chan Affiliations
    Program in Bioinformatics and Integrative Biology
    Neurology
    Document Type
    Master's Thesis
    Publication Date
    2018-02-27
    Keywords
    Amyotrophic Lateral Sclerosis
    Genetics
    Bioinformatics
    Next-generation Sequencing
    Bioinformatics
    Computational Biology
    Genomics
    Nervous System Diseases
    Neurology
    Neuroscience and Neurobiology
    
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    Abstract
    A list of genes have been identified to carry mutations causing familial ALS such as SOD1, TARDBP, C9orf72. But for sporadic ALS, which is 90% of all ALS cases, the underlying genetic variants are still largely unknown. There are multiple genome-wide association study (GWAS) for sporadic ALS, but usually a large number nominated SNP can hardly be replicated in larger cohort analysis. Also majority of GWAS SNP lie within noncoding region of genome, imposing a huge challenge to study their biological role in ALS pathology. With the rapid development of next-generation sequencing technology, we are able to sequence exome and whole-genome of a large number of ALS patients to search for novel genetic variants and their potential biological function. Here by analyzing exam data, we discovered two novel or extremely rare missense mutations of DPP6 from a Mestizo Mexican ALS family. We showed the two mutations could exert loss-of-function effect by affecting electrophysiological properties of Potassium channels as well as the membrane localization of DPP6. To our knowledge this is the first report of DPP6 nonsynonymous mutations in familial ALS patients. In addition, by analyzing whole-genome data, we discovered strong linkage disequilibrium between SNP rs12608932, a repeatedly significant ALS GWAS signal, and one polymorphic TGGA tetra-nucleotide tandem repeat, which is further flanked by large TGGA repetitive sequences. We also demonstrated rs12608932 risk allele is associated with reduced UNC13A expression level in human cerebellum and UNC13A knockout could lead to shorter survival in SOD1-G93A ALS mice. Thus the TGGA repeat might be the real underlying genetic variation that confer risk to sporadic ALS.
    DOI
    10.13028/M2VQ38
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32343
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2VQ38
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