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. )

抽象的该提案的目标是鉴定与孟德尔神经遗传疾病相关的基因。收集了 30 年来在大学进行确定、表型分析和采样的家庭集合华盛顿神经遗传学诊所和阿尔茨海默病研究中心。这个广泛的收藏是发现导致神经变性的新基因的宝贵资源。我们组曾经有过一次在发现神经系统疾病基因方面发挥着重要作用。致病基因仍然存在的疾病发现提出了新的挑战，因为许多家族太小而无法进行定位克隆。以前，即使在有广泛疾病史的家族中也没有基因鉴定的方法当只有少数受影响者的 DNA 可用时。在本提案中，我们将利用新的可用稀有序列和拷贝数变异的全基因组检测方法是一种强大且创新的方法鉴定与神经遗传性疾病有关的基因的方法。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，以及大规模并行测序来检测基因组蛋白质编码部分（ “外显子组”）。我们的研究小组在应用这些新技术方面已经拥有丰富的经验走向基因鉴定我们准备最大程度地利用基础设施的融合以及我们团队在以下方面的专业知识分子遗传学、现有的特征明确的样本以及阵列和测序技术的进步现在使得在整个基因组规模上应用这种方法变得可行。仅对两个受影响的人进行研究亲属可以将候选基因的数量从20,000个减少到几十个，然后按功能并在其他家庭成员、不相关的病例和对照中进行评估。比如我们最近发表了一项研究，其中我们使用这种方法来减少感觉和运动神经病伴共济失调（SMNA）从包含300个大连锁区域到1个。虽然本文要研究的特定疾病并不常见，所涉及的基因和途径可能是其基础具有共同临床特征的常见疾病的表型差异和易感性导致相当大的发病率。这些疾病包括阿尔茨海默病、帕金森病疾病、小脑共济失调、肌肉疾病和周围神经病变，这些疾病经常困扰我们人口老龄化。我们的创新方法可能会成为基因发现的新标准促进对神经遗传性疾病生物学的理解和确定治疗目标的进一步进展治疗干预。）