Exonizaton of Alu Insertion Polymorphisms

Alu 插入多态性的外显子化

基本信息

批准号：
10227617
负责人：
KATHLEEN H BURNS
金额：
$ 29.39万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227617
关键词：
Alleles Biological Assay Burn injury CRISPR/Cas technology Catalogs Complement Computational Biology Consult DNA Insertion Elements DNA Sequence DNA Transposable Elements Data Data Set Disease Elements Encyclopedia of DNA Elements European Event Exons Genes Genetic Genetic Medicine Genetic Polymorphism Genetic Transcription Genome Genomic DNA Genomics Genotype Haplotypes Health Healthcare Human Human Cell Line Human Genome Inherited Institutes Interspersed Repetitive Sequences Laboratories Libraries Light Link Linkage Disequilibrium Long Interspersed Elements Maps Mental Depression Messenger RNA Modeling Molecular Nonsense-Mediated Decay Phenotype Plant Roots Play Population Positioning Attribute Protein Isoforms RNA Sequences RNA Splicing RNA-Directed DNA Polymerase Relative Risks Reporter Risk Role Structure Testing The Cancer Genome Atlas Tissues Transcript Universities Untranslated RNA Variant base causal variant computerized tools disorder risk endonuclease experimental study follow-up genetic variant genome editing genome wide association study genomic locus human disease medical schools mouse genome novel personalized approach reference genome trait transcriptome sequencing

项目摘要

Common genetic variants contribute to a wide spectrum of human phenotypes and risks of developing many types of diseases. Differentiating causative from non-functional variants and understanding molecular mechanisms of the former together represent important challenges. Alu interspersed repeats are a common type of structural variant in the human genome. Alu insertions are intrinsically capable of impacting mRNA sequence and resulting in disease - even when the repeat is positioned in apparently non-coding, intronic sequence within the gene locus. Our hypothesis is that some inherited Alu insertion polymorphisms are functioning as causative variants for human disease risk. We propose to narrow the list of candidates by identifying those Alu insertions that associate with disease risk and that impact the structure of a relevant mRNA transcript. We will develop computational approaches to identify Alu exonization events in RNA-seq data, and we will experimentally evaluate Alu insertion polymorphisms for effects on mRNA splicing using reporter assays and genome editing strategies.

常见的遗传变异有助于广泛的人类表型和风险发展多种类型的疾病。将因果关系与非功能变体区分开了解前者的分子机制代表着重要的挑战。 Alu散布的重复序列是人类基因组中结构变体的一种常见类型。 Alu插入在本质上能够影响mRNA序列并导致疾病 - 即使重复位于基因基因座中明显的非编码，内含子序列中。我们的假设是，某些遗传的ALU插入多态性正在起作用人类疾病风险的变体。我们建议通过识别那些Alu来缩小候选人列表插入与疾病风险相关的插入，并影响相关mRNA转录的结构。我们将开发计算方法，以识别RNA-seq数据中的Alu驱除事件，以及我们将通过实验评估ALU插入多态性，以便使用MRNA剪接的影响记者分析和基因组编辑策略。