Delineating the functional impact of recurrent repeat expansions in ALS using integrative multiomic analysis

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that affects nerve cells in the brain and spinal cord, resulting in muscle weakness, difficulty speaking and swallowing, and eventually, respiratory failure. There is no known cure and the average life expectancy of an ALS patient is 3-5 years from the time of diagnosis. Therefore, it is important to identify the genetic alterations that are involved in the molecular pathogenesis of ALS in order to develop targets for therapeutics. Genome-wide occurrence of DNA repeat expansions has been identified as a common genetic cause or marker of several neurodegenerative diseases, including ALS. Here we propose to survey the whole genome sequencing data from a population of ALS patients and healthy individuals for recurrent repeat expansions, correlate these findings with gene expressions, and finally study mechanisms of regulation of identified genes by integration of gene expression, chromatin accessibility, and 3D genome organization data. We hypothesize that many of the overlooked repeat expansions are located in the non-coding regions of the genome and are involved in regulation of genes that might contribute to the death of motor neurons. To this end, we will first identify the recurrent repeat expansions that act as tissue- specific expression quantitative trait loci using GTEx data. We will then integrate multi-omics data from ALS patients with 3D genome data from the 4DN project to identify gene regulatory circuitry. We envision that the proposed work will allow scientists to generate experimentally testable hypotheses by creating a link between non-coding repeat expansions and genes in a tissue-specific manner and help identify new therapeutic targets.