Discovering Splicing Defects in Human Genes

发现人类基因中的剪接缺陷

基本信息

批准号：
9769075
负责人：
William G Fairbrother
金额：
$ 60.1万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-23 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769075
关键词：
Affect Age of Onset Alleles Asses Cell Line Code Data Data Set Databases Defect Disease Early treatment Electronic Health Record Elements Enrollment Exhibits Frequencies Genes Genetic Genetic Diseases Genetic Polymorphism Genome Genotype Grain Health Personnel Health Service Area Healthcare Systems Hereditary Nonpolyposis Colorectal Neoplasms High Density Lipoproteins Human In Vitro Incidental Findings Individual Institution Lipids Maps Medical Mutation Nature Pathogenicity Patients Penetrance Pennsylvania Pharmacologic Substance Phenotype Pilot Projects Policies Publishing Quantitative Trait Loci RNA Splicing Recommendation Reporter Research Resolution Sampling Severities Signal Transduction Site Specificity Spliceosome Assembly Pathway Symptoms Syndrome System Technology Testing Tissues Training Untranslated RNA Variant body system cancer type cohort cost disease-causing mutation exhaustion exome exome sequencing falls genome sequencing high throughput screening in vivo innovation mRNA Precursor mutant phenotypic data rare variant screening tool trait

项目摘要

It is currently feasible for small research groups to sequence individual genomes and for larger groups to sequence tens of thousands of individuals. Unfortunately, our ability to identify variants that impact phenotype has not kept pace with our sequencing capacity. This is particularly true of non-coding variants. This proposal presents a pilot screen of 4,972 disease alleles that revealed 10% of exonic mutations affect splicing. The pilot study also revealed that splicing mutations are not uniformly distributed across disease genes. Preliminary results identify 64 diseases significantly more likely to be caused by a splicing mutation. This proposal will utilize a reporter system to test the effect of substitutions and in/dels on splicing and to annotate splicing element in medically relevant genes. The data set created by this approach will be used to train an online splicing mutation prediction tool. This project will also screen all variants that fall within 75nucleotides of a splice site in the set of 130 “actionable genes”. The study will utilize a variety of cell lines reflecting distinct tissues of origin and determine which stage of spliceosome assembly is disrupted to provide better characterization of these variants. Finally, Geisinger HealthCare System GHS in partnership with Regeneron (RGN) Pharmaceuticals has created a unique dataset of paired genotypic and phenotypic data. The GHS MyCode project has enrolled over 160,000 patients and completed whole exome sequencing (WES) on over 60,000 of those patient samples. This set will be used to identify (and verify) carriers of variants predict to alter splicing. A deep re-phenotyping of patients to asses the contribution of splicing defects to EHR QTLs, age of onset, severity, penetrance and differential engagement across multiple organ systems).

目前，对于小型研究小组来说，对单个基因组进行测序和较大的研究是可行的不幸的是，我们的成千上万个人的群体。影响表型的变体与我们的测序能力保持同步该提案的非编码变体特别是4,972个疾病的试验启示10％外显子突变的等位基因会影响剪接。剪接突变不均匀分布在疾病基因上识别64种疾病更多地是由剪接突变引起的。是否会利用记者系统来测试替换的效果以及/dels对剪接和在医学上相关基因中的剪接元件。将用于在线剪接预测工具。在130个“可起作基因”中落下75核苷酸的变体研究将利用各种反映不同原始组织的细胞系，并确定哪个细胞系剪接组装的阶段被破坏，以更好地表征这些变体。最后，Geisinger Healthcare System GHS与Regeneron（RGN）合作 Pharmaceuticals创建了一个成对的基因型和表型数据的独特数据集 GHS MyCode项目已招募了160,000多名患者，并完成了整个Exome 超过60,000个患者样品的测序（WES）将用于识别（并验证）变体的载体预测会改变剪接。驴子对EHR QTL的贡献，发病年龄，严重性，外观和跨多器官系统的英语差异）。