Next Generation Mendelian Genetics

下一代孟德尔遗传学

• 批准号: 7943999
• 负责人: MICHAEL Joseph BAMSHAD
• 金额: $ 195.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943999
• 关键词: Address; Adult; Affect; Biology; Candidate Disease Gene; Childhood; Chromosome Mapping; Code; Collection; Coupled; Coupling; DNA Resequencing; DNA Sequence; Data; Development; Diagnosis; Disease; Disease Management; Exhibits; Family; Gene Mutation; Genes; Genetic; Genetic Research; Genotype; Goals; Hereditary Disease; Human; Human Genetics; Human Genome; Individual; Inheritance Patterns; Medical; Medical Genetics; Medicine; Methods; Molecular; Mutation; National Human Genome Research Institute; Online Mendelian Inheritance In Man; Open Reading Frames; Proteins; Public Health; Rare Diseases; Sampling; Structure; Variant; abstracting; base; cohort; comparative; database of Genotypes and Phenotypes; exome; follow-up; genetic linkage analysis; genetic pedigree; genome-wide; human disease; improved; next generation; novel strategies; novel therapeutics; tool; Address; Adult; Affect; Biology; Candidate Disease Gene; Childhood; Chromosome Mapping; Code; Collection; Coupled; Coupling; DNA Resequencing; DNA Sequence; Data; Development; Diagnosis; Disease; Disease Management; Exhibits; Family; Gene Mutation; Genes; Genetic; Genetic Research; Genotype; Goals; Hereditary Disease; Human; Human Genetics; Human Genome; Individual; Inheritance Patterns; Medical; Medical Genetics; Medicine; Methods; Molecular; Mutation; National Human Genome Research Institute; Online Mendelian Inheritance In Man; Open Reading Frames; Proteins; Public Health; Rare Diseases; Sampling; Structure; Variant; abstracting; base; cohort; comparative; database of Genotypes and Phenotypes; exome; follow-up; genetic linkage analysis; genetic pedigree; genome-wide; human disease; improved; next generation; novel strategies; novel therapeutics; tool

DESCRIPTION (provided by applicant): This application addresses NHGRI RFA-OD-09-004 for Medical Sequencing Discovery Projects. The ultimate goal of this proposal is to scale a new approach to identify the candidate genes and mutations that underlie rare Mendelian diseases in humans by exome resequencing. For decades, linkage analysis has been the mainstay of human genetics. However, for rare Mendelian diseases where family collection is difficult or pedigrees are small, this approach is less useful. Although the molecular bases of more than 2,600 Mendelian diseases have been determined by linkage mapping or a candidate gene approach, a nearly equal number remain to be solved (OMIM). We have assembled a collection of rare pediatric and adult Mendelian diseases that are representative of this unsolved set. In every instance, the identification of the causal gene remains intractable to either linkage mapping or exhaustive candidate gene analysis. Exome resequencing offers a new way forward for dissecting the underlying causes of rare Mendelian diseases. In our preliminary studies, we show that selective capture of protein coding sequences across the human genome coupled with massively parallel resequencing to define coding variation can accurately identify the gene underlying a monogenic disorder. In this example, comparative analysis of exome variation data from as few as two unrelated individuals affected with the disease reduced the list of candidate genes to less than ten. The candidate list was further reduced to a single gene with exome data from as few as four unrelated cases. Once identified, each candidate gene will be screened for disease-causing variants by conventional methods in a larger set of cases. Discovery of the genetic basis of a large collection of rare disorders that have, to date, been unyielding to traditional analysis will substantially expand our understanding of the biology of the human genome, facilitate accurate diagnosis and improved management of these diseases, and provide the information needed for the development of novel therapeutics. If successful, this approach is likely to replace linkage analysis as the dominant paradigm for studying diseases exhibiting Mendelian inheritance patterns and will provide a new path forward for medical genetics. PUBLIC HEALTH RELEVANCE: As we enter an era of personalized medicine, DNA sequencing will be increasingly important to public health, contributing to our understanding of the genetic basis of human disease. The targeted capture and massively parallel sequencing of all protein coding regions in the human genome (the exome) has the potential to markedly accelerate human genetics research as an efficient method for identifying highly penetrant variants at a genome-wide scale. This project will apply and evaluate exome resequencing as a new tool to rapidly identify the causes of dozens of rare genetic diseases in humans.

描述（由申请人提供）：此申请地址为医学测序发现项目的NHGRI RFA-OD-09-004。该提案的最终目的是扩展一种新方法，以确定候选基因和突变，这些基因和突变是通过外部重新定位的罕见孟德尔疾病的基础。几十年来，连锁分析一直是人类遗传学的中流。但是，对于罕见的孟德尔疾病，家庭收集很困难或小家谱很小，这种方法不太有用。尽管已通过连锁映射或候选基因方法确定了超过2,600种孟德尔疾病的分子碱基，但仍有几乎相等的数量要解决（OMIM）。我们组装了一组罕见的儿科和成人孟德尔疾病，这些疾病代表了这种未解决的套件。在每种情况下，因果基因的鉴定仍然与连锁映射或详尽的候选基因分析相关。外显子重新陈述为剖析了罕见的孟德尔疾病的根本原因提供了一种新的方向。在我们的初步研究中，我们表明，对人类基因组的蛋白质编码序列的选择性捕获以及大规模平行的重新取证以定义编码变化可以准确地识别单基因疾病的基因。在此示例中，对来自受疾病影响的两个无关个体的外显子变异数据的比较分析使候选基因列表降低到小于十。将候选人列表进一步缩小为单个基因，该基因具有来自几乎四个无关病例的外来数据。一旦确定，在较大的病例中，将通过常规方法筛选每个候选基因引起疾病的变体。发现大量罕见疾病的遗传基础，这些疾病迄今为止一直不愿进行传统分析，这将大大扩展我们对人类基因组生物学的理解，促进准确的诊断和改善对这些疾病的治疗，并提供新型疗法发展所需的信息。如果成功的话，这种方法可能会取代连锁分析，作为研究表现出Mendelian遗传模式的疾病的主要范式，并将为医学遗传学提供新的途径。 公共卫生相关性：当我们进入个性化医学时代时，DNA测序对公共卫生将越来越重要，这有助于我们对人类疾病的遗传基础的理解。人类基因组中所有蛋白质编码区域（外显子组）中所有蛋白质编码区的有针对性捕获和大规模平行的测序有可能显着加速人类遗传学研究，作为一种有效的方法，可以在全基因组范围内识别高渗透变体。该项目将应用和评估外显子的重新方程，作为一种新工具，以快速识别人类中数十种罕见遗传疾病的原因。