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

项目总结 肌萎缩侧索硬化症(ALS)是一种进行性神经退行性疾病，影响 大脑和脊髓，导致肌肉无力，说话和吞咽困难，最终， 呼吸衰竭。目前还没有已知的治愈方法，ALS患者的平均预期寿命为3-5年 诊断的时间。因此，确定分子中所涉及的基因改变是很重要的。 肌萎缩侧索硬化症的发病机制，为治疗提供靶点。全基因组范围内DNA重复的发生 扩张已被确定为几种神经退行性疾病的常见遗传原因或标志， 包括肌萎缩侧索硬化症。在这里，我们建议调查ALS患者群体的全基因组测序数据 和健康个体反复重复扩张，将这些发现与基因表达相关联，并且 最后研究了基因表达、染色质整合对已识别基因的调控机制 可访问性和3D基因组组织数据。我们假设许多被忽视的重复扩张 它们位于基因组的非编码区，并参与调节可能有助于 运动神经元的死亡。为此，我们将首先确定作为组织的反复重复扩张- 利用GTEx数据进行特异性表达的数量性状基因座。然后我们将整合来自肌萎缩侧索硬化症的多组学数据 患者使用3D基因组数据从4DN项目中识别基因调控电路。我们设想， 拟议中的工作将允许科学家通过在以下两个因素之间建立联系来产生可实验验证的假说 非编码重复扩增和基因以组织特有的方式进行，并有助于识别新的治疗靶点。

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.