Next Generation gene discovery in neurogenetics

摘要 这项提议的目标是识别导致孟德尔神经遗传性疾病的基因 在牛津大学进行了30多年的确定、表型分析和抽样的家庭集合 华盛顿神经遗传学诊所和阿尔茨海默病研究中心。这一广泛的收藏是一个 发现导致神经退行性变的新基因的宝贵资源。我们的团队已经有了一个 在发现神经性疾病的基因方面发挥了重要作用。致病基因仍然存在的疾病 被发现是一项新的挑战，因为许多家庭太小，无法进行位置克隆。 以前，即使在有广泛病史的家庭中，也没有基因鉴定的方法。 当只有几个受影响的人的DNA可用时。在这个提案中，我们将利用新的可用资源 全基因组稀有序列和拷贝数变异检测方法作为一种强有力的创新方法 识别神经遗传性疾病相关基因的方法。这些新技术包括基于数组的 高分辨率比较基因组杂交以检测基因内缺失和复制，以及 大规模并行测序以检测基因组蛋白质编码部分( “exome”)。我们的调查组在应用这些新技术方面已经有了丰富的经验 走向基因鉴定 我们准备最大限度地利用基础设施的融合，我们集团在 分子遗传学，现有的特征良好的样本，以及阵列和测序技术的进展 这使得现在在整个基因组范围内应用这种方法是可行的。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，然后按以下方式进行排序 并在其他家庭成员、无关病例和对照中进行评估。例如，我们最近 发表了一项研究，在这项研究中，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300个包含在大的连锁区到1个。尽管 这里要研究的特定疾病并不常见，涉及的基因和途径可能是 常见疾病的表型差异和易感性，这些疾病具有共同的临床特征和 这些疾病导致了相当大的发病率。这些疾病包括阿尔茨海默氏症、帕金森氏症 疾病、小脑性共济失调、肌肉疾病和周围神经病变，这些疾病经常困扰我们的 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， 在了解神经遗传性疾病的生物学和确定靶点方面取得进一步进展 治疗性干预。 )

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. )