Next Generation gene discovery in neurogenetics

神经遗传学中的下一代基因发现

基本信息

批准号：
8252166
负责人：
WENDY H RASKIND
金额：
$ 60.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8252166
关键词：
3&apos Splice Site Abbreviations Affect Alzheimer&apos s Disease Ataxia Benign Bioinformatics Biology Candidate Disease Gene Cerebellar Ataxia Charcot-Marie-Tooth Disease Chorea Clinic Clinical Code Collection Copy Number Polymorphism DNA Databases Deposition Detection Disease Dyskinetic syndrome Evaluation Exons Facial Myokymias Familial Dementias Family Family history of Family member Frontotemporal Dementia Genes Genome Genomics Genotype Goals Hereditary Disease Hereditary Neuralgic Amyotrophy Hereditary Spastic Paraplegia Human Human Genome Huntington Disease Hybridization Array Hybrids Late Onset Alzheimer Disease Link Methods Molecular Genetics Morbidity - disease rate Motor Movement Movement Disorders Mutation Myopathy Nerve Degeneration Neuropathy Nucleotides Open Reading Frames Pancytopenia Parkinson Disease Parkinsonian Disorders Paroxysmal Dystonia Participant Pathway interactions Peripheral Nervous System Diseases Persons Phase Phenotype Predisposition Primary Lateral Sclerosis Progranulin Proteins Publishing RNA Splicing Recording of previous events Relative (related person)Research Research Infrastructure Research Personnel Resolution Resources Role Sampling Sensory Sensory Ataxias Single Nucleotide Polymorphism Site Spinocerebellar Ataxias Tauopathies Techniques Technology Therapeutic Intervention Universities Validation Variant Washington abstracting aging population base case control comparative genomic hybridization comparative genomics database of Genotypes and Phenotypes disorder control exome experience gene discovery genetic linkage analysis genetic variant genome-wide innovation insertion/deletion mutation nervous system disorder neurogenetics next generation non-alzheimer dementia novel novel strategies positional cloning presenilin-1 presenilin-2 surveillance study tau Proteins

项目摘要

Abstract The goal of this proposal is to identify genes responsible for mendelian neurogenetic disorders in a collection of families that were ascertained, phenotyped and sampled over 30 years at the University of Washington Neurogenetics Clinics and Alzheimer's Disease Research Center. This extensive collection is a valuable resource for the discovery of new genes responsible for neurodegeneration. Our group has had a major role in discovery of genes for neurologic disorders. The disorders for which the causal genes remain to be found present a new challenge, as many of the families are too small to enable positional cloning. Previously there were no methods for gene identification even in families with an extensive history of disease when DNA from only a few affected persons is available. In this proposal we will exploit newly available methods for whole genome detection of rare sequence and copy number variants as a powerful and innovative approach to identify genes involved in neurogenetic disorders. These new techniques include array-based high-resolution comparative genomic hybridization to detect intragenic deletions and duplications, and massively parallel sequencing to detect sequence changes in the protein-coding portion of the genome (the "exome"). Our group of investigators already has substantial experience in applying these novel techniques toward gene identification We are poised to take maximal advantage of the confluence of infrastructure, our group's expertise in molecular genetics, existing well characterized samples, and advances in array and sequencing techniques that now make it feasible to apply this approach on the whole genome scale. Study of only two affected relatives can reduce the number of candidate genes from 20,000 to several dozen that will then be ranked by function and evaluated in other family members, unrelated cases and controls. For example, we recently published a study in which we used this approach to reduce the number of candidate genes for sensory and motor neuropathy with ataxia (SMNA) from the 300 contained in the large linkage region to one. Although the specific diseases to be investigated herein are not common, the genes and pathways involved may underlie phenotypic differences in and susceptibility to common disorders with which they share clinical features and that are responsible for considerable morbidity. These conditions include Alzheimer's disease, Parkinson's disease, cerebellar ataxia, muscle disease, and peripheral neuropathy, diseases that frequently afflict our aging population. Our innovative approach will likely become the new standard for gene discovery that will enable further advances in the understanding the biology of neurogenetic disorders and identifying targets for therapeutic interventions. )

抽象的该提案的目的是确定负责Mendelian神经源性疾病的基因在大学中确定，表型和取样的家庭收集了30多年华盛顿神经遗传学诊所和阿尔茨海默氏病研究中心。这个广泛的收藏是发现负责神经退行性的新基因的宝贵资源。我们的小组有一个在发现神经系统疾病基因的基因中的主要作用。因果基因仍然存在的疾病找到一个新的挑战，因为许多家庭太小而无法实现位置克隆。以前，即使在具有广泛疾病史的家族中，也没有用于基因鉴定的方法当只有少数受影响的人的DNA可用。在此提案中，我们将利用新近可用的全基因组检测稀有序列和拷贝数变体的方法是一种强大而创新的鉴定涉及神经遗传疾病的基因的方法。这些新技术包括基于阵列的高分辨率比较基因组杂交以检测基因内缺失和重复，并大规模平行测序以检测基因组蛋白质编码部分的序列变化（ “外显子”）。我们的研究人员已经在应用这些新技术方面拥有丰富的经验朝向基因鉴定我们准备利用基础设施汇合的最大优势，这是我们小组的专业知识分子遗传学，现有特征性良好的样品以及阵列和测序技术的进步现在，这使得在整个基因组量表上应用这种方法是可行的。仅研究两个亲戚可以将候选基因的数量从20,000减少到几十个，然后将其排名在其他家庭成员，无关的病例和对照中进行功能并评估。例如，我们最近发表了一项研究，我们使用这种方法来减少感官和从大型连锁区域中包含的300个共济失调（SMNA）的运动神经病变到一个。虽然本文要研究的特定疾病并不常见，涉及的基因和途径可能是基础表型的表型差异和对共享临床特征和共同疾病的敏感性和易感性负责大量发病的人。这些疾病包括阿尔茨海默氏病，帕金森氏病疾病，小脑共济失调，肌肉疾病和周围神经病，经常折磨我们的疾病人口老龄化。我们的创新方法可能会成为基因发现的新标准在理解神经遗传疾病的生物学方面取得进一步的进步，并确定目标治疗干预措施。）