Prioritization of splicing-altering genetic variants in Alzheimer's disease

阿尔茨海默病中剪接改变遗传变异的优先顺序

• 批准号: 9370754
• 负责人: Xinshu Grace Xiao
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370754
• 关键词: Address; Affect; Alleles; Alternative Splicing; Alzheimer' s Disease; Bayesian Analysis; Bayesian Modeling; Binding; Bioinformatics; Biological; Biological Process; Catalogs; Cell Line; Code; Collection; Complement; Computer Simulation; Computer software; DNA Sequence Alteration; Data; Data Set; Disease; Elements; Event; Future; Gene Expression; Genes; Genetic Annotation; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genotype; Goals; Hereditary Disease; Human; Human Genetics; Individual; Intervention; Introns; Knowledge; Link; Literature; Mediating; Messenger RNA; Methodology; Methods; Modeling; Nucleotides; Pathologic; Pathway interactions; Patients; Pattern; Point Mutation; Process; Protein Isoforms; Proteins; RNA Splicing; RNA-Binding Proteins; Regulation; Regulatory Element; Reporter; Reporting; Research; Resolution; Resources; Signal Transduction; Site; Tertiary Protein Structure; Untranslated RNA; Validation; Variant; Work; cohort; design; disorder control; genetic analysis; genetic regulatory protein; genetic variant; mRNA Expression; mRNA Precursor; novel; online resource; open source; programs; promoter; rare variant; success; therapeutic gene; transcriptome; transcriptome sequencing; web interface

Project Summary The goal of this project is to develop computational pipelines that allow in silico prediction of functional genetic variants that disrupt pre-mRNA splicing and related pathways in Alzheimer's disease (AD). Recently, tremendous success has been achieved in constructing a catalog of genetic variants in AD genomes of various patient cohorts. The next great challenge is to identify causal variants and elucidate their potential function relevant to disease processes. To this end, research efforts have been directed to studying variants located in protein-coding, promoter, and splice site regions due to their apparent impacts on gene expression. However, many of the newly identified disease-associated variants reside in other non-coding regions, such as introns, that may confer regulatory function to the related gene. The mechanisms of these variants have been hard to decipher. It is expected that many of them may function at the post-transcriptional level, thus affecting mRNA expression. In human, a myriad of processes mediate RNA expression at the post-transcriptional stage, one of which being splicing. Splicing is an essential step of mammalian gene expression and alternative splicing affects most human genes. Recent literature reported that RNA splicing is a primary link between GVs and disease. In general, it was estimated that 15-60% of point mutations that result in human genetic diseases disrupt splicing, highlighting the importance of this regulatory step. In AD, aberrant splicing has been detected in many functionally critical genes, some of which are modulated by GVs. Despite the importance, how to accurately identify functional genetic variants in splicing regulation remains a key question in the field. To address this question, the large collection of RNA-Seq and genotyping data sets collected from AD and control subjects represent an invaluable resource. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and experimental validations. This work will allow a previously unattained level of understanding of genetic variants in splicing regulation and provide new means to tackle the imperative task of functional annotations of genetic variants in AD.

项目摘要 该项目的目的是开发允许用于硅硅预测的计算管道 在阿尔茨海默氏症中破坏前mRNA剪接和相关途径的功能遗传变异 疾病（AD）。最近，在构建一个目录中取得了巨大成功 各种患者队列的AD基因组中的遗传变异。下一个巨大的挑战是 确定因果变异，并阐明其潜在功能与疾病过程有关。到 这一目的，研究工作已针对研究蛋白质编码中的变体， 启动子和剪接位点区域由于其对基因表达的明显影响。然而， 许多新确定的与疾病相关的变体都存在于其他非编码区域， 例如内含子，可能赋予相关基因的调节功能。机制 这些变体很难破译。预计其中许多可能在 转录后水平，因此影响mRNA表达。在人类中，无数过程 在转录后介导RNA表达，其中之一是剪接。剪接 是哺乳动物基因表达和替代剪接的重要步骤会影响大多数人类 基因。最近的文献报道，RNA剪接是GVS与疾病之间的主要联系。 通常，估计有15-60％的点突变导致人类遗传 疾病破坏了剪接，强调了该监管步骤的重要性。在广告中，异常 在许多功能上关键的基因中都检测到剪接，其中一些是由 GVS。尽管很重要，但如何准确识别剪接中的功能遗传变异 法规仍然是该领域的关键问题。为了解决这个问题，大量 从AD和控制受试者收集的RNA-SEQ和基因分型数据集代表 宝贵的资源。我们将开发和应用新颖的方法来充分利用这些方法 数据集，以进一步的生物信息学预测和实验验证进行补充。这 工作将允许以前未经鉴定的对剪接遗传变异的理解水平 监管并提供新的手段来应对功能性注释的命令 AD中的遗传变异。