Exonizaton of Alu Insertion Polymorphisms

Alu 插入多态性的外显子化

基本信息

批准号：
9444067
负责人：
KATHLEEN H BURNS
金额：
$ 32.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9444067
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 Mediating Mental Depression Messenger RNA Modeling Molecular Phenotype Plant Roots Play Population Positioning Attribute Protein Isoforms RNA Sequences RNA Splicing RNA-Directed DNA Polymerase Relative Risks Reporter Risk Role Structure Technology Testing The Cancer Genome Atlas Tissues Transcript Universities Untranslated RNA Variant base computerized tools disorder risk endonuclease experimental study follow-up genetic variant genome editing genome wide association study 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.

常见的遗传变异导致广泛的人类表型和风险发展多种疾病。区分致病性变异和非功能性变异理解前者的分子机制是一个重要的挑战。 Alu 散布重复序列是人类基因组中常见的结构变异类型。铝插入本质上能够影响 mRNA 序列并导致疾病——即使重复序列位于基因座内明显非编码的内含子序列中。我们的假设是，一些遗传性 Alu 插入多态性起着致病作用人类疾病风险的变体。我们建议通过确定这些 Alu 来缩小候选人名单与疾病风险相关并影响相关 mRNA 转录物结构的插入。我们将开发计算方法来识别 RNA-seq 数据中的 Alu 外显子化事件，以及我们将通过实验评估 Alu 插入多态性对 mRNA 剪接的影响报告基因检测和基因组编辑策略。