Yale Center for Mendelian Disorders

耶鲁大学孟德尔疾病中心

• 批准号: 8393218
• 负责人: MURAT GUNEL
• 金额: $ 264.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-05 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393218
• 关键词: Accounting; Address; Affect; Alleles; Biochemical Pathway; Biological; Cerebrum; Chromosome Mapping; Code; Collaborations; Collection; Communities; Consent; DNA; DNA Sequence; Data; Databases; Deposition; Development; Direct Costs; Disease; Dominant Genetic Conditions; Drops; Early Diagnosis; Embryo; Family; Family member; Foundations; Frequencies; Future; Gene Mutation; Genes; Genetic; Genome; Goals; Grant; Hand; Health; Health Benefit; Heterogeneity; Human; Human Genome; Hypertension; Inherited; Institutes; Knowledge; Life; Maps; Methods; Metric; Molecular; Molecular Genetics; Mutation; National Human Genome Research Institute; Nature; Online Mendelian Inheritance In Man; Paper; Pathway interactions; Patients; Phenotype; Physicians; Proteins; Publishing; Reporting; Research; Research Infrastructure; Research Personnel; Sampling; Science; Scientist; Solutions; Specificity; Technology; Time; United States National Institutes of Health; Variant; analytical tool; base; body system; cost; cost effective; exome; exome sequencing; fitness; gene discovery; human disease; improved; indexing; kindred; new technology; next generation; next generation sequencing; public health relevance; recessive genetic trait; reproductive; technology development; tool; trait; transmission process; web interface

DESCRIPTION (provided by applicant): The identification of mutations causing Mendelian diseases has revolutionized the understanding of diseases of every organ system. While over 3,000 such diseases have been solved at the molecular level, with 21,000 genes in the human genome and about 15% embryonic lethal loci, it is clear that many remain to be discovered. This includes both described and presently undescribed human traits that contribute to both health and disease. With the spectacular 6-log drop in the cost of DNA sequencing over the last 12 years, it has become apparent that selectively sequencing all of the genes in the genome, which comprise only ~1 % of the human genome represents a very cost-effective means for discovering the basis of new Mendelian diseases. We have pioneered the development of the exome sequencing method as well as the tools for analysis, and have shown that both are scalable, with current cost under $1,500 per exome and expected to be under $1,000 in the near future. We have demonstrated the utility of this approach with the identification of a range of disease genes that were previously intractable due to difficulties in gene mapping owing to high locus heterogeneity, de novo mutations, or small one-of-a-kind families. These considerations motivate new efforts to efficiently solve substantially all Mendelian traits using these technologies. To this end we have established the Yale Center for Mendelian Disorders which will ascertain and acquire samples from patients and families with known or suspected Mendelian diseases, sequence exomes to high coverage sufficient to call 95% of all variants with high specificity and use new analytic approaches we have devised to identify new Mendelian trait genes. We will make all sequences available to the research community as allowed and will establish a Web interface to enable physicians and investigators to submit research samples and retrieve annotated results. These studies will rapidly expand our understanding of the genes and pathways underlying human disease.

描述（由申请人提供）：导致孟德尔疾病的突变的鉴定已彻底改变了对每个器官系统疾病的理解。尽管超过3,000种此类疾病在分子水平上解决了，但人类基因组中有21,000个基因和约15％的胚胎致命基因座，但很明显，许多基因仍然有待发现。这包括对健康和疾病有助的描述和目前未描述的人类特征。在过去的12年中，DNA测序成本的壮观六型物中心下降，很明显，选择性测序基因组中的所有基因，该基因组中仅构成人类基因组的约1％代表了一种非常具有成本效益的手段，可以发现发现新的门德利疾病的基础。我们率先开发了外显子测序方法以及分析工具，并表明两者都是可扩展的，目前的成本低于每个外显子，预计在不久的将来将低于1,000美元。我们通过鉴定了由于基因映射的困难，由于基因座的异质性，从头突变或小型独一无二的家庭而造成的一系列疾病基因，因此证明了这种方法的实用性。这些考虑因素激发了新的努力，以使用这些技术有效地解决所有门德尔的特征。为此，我们建立了耶鲁大学孟德尔疾病中心，该中心将确定并从患有已知或怀疑的孟德尔疾病的患者和家庭中获取样品，序列外部序列外观具有高覆盖范围，足以使所有具有高特异性的变体中的95％，并使用我们已经确定新的Mendelian特质基因的新分析方法。我们将尽可能地向研究社区提供所有序列，并建立一个网络界面，以使医生和研究人员能够提交研究样本并检索带注释的结果。这些研究将迅速扩大我们对人类疾病基因和途径的理解。