COMPARATIVE DNA SEQUENCE VARIATION IN ALZHEIMER GENES

这项提议的目标是鉴定和表征黑猩猩在四个基因编码区域的DNA序列变异，这些基因包含与阿尔茨海默病（AD）发病机制有关的突变。我们将从四个已知的黑猩猩亚种中选择一个遗传多样性的样本，并通过筛选与AD相关的4个候选基因（载脂蛋白E、淀粉样蛋白前体蛋白和早老素1和2）的新DNA序列来表征DNA序列变化。黑猩猩在遗传和生理上与人类非常相似，但它们表现出大量的种内遗传和表型分化。这种与人类的系统发育接近性和种内遗传变异的结合可以识别AD相关基因的DNA序列变异，推进AD基因/疾病关联的研究，并有助于确定具有成本效益的突变筛选方法。此外，通过对黑猩猩的脑组织进行基因表征，这些脑组织已经被行为表征并提供给神经科学家，这个项目可以增加我们正在进行的类人猿脑库计划的价值。神经病理学研究与阿尔茨海默病相关突变的相关性可以详细调查阿尔茨海默病和其他神经退行性疾病的遗传基础，并促进药物基因组学方法在人类试验之前在神经遗传学定义的黑猩猩中测试新型药物。拟议的商业应用：该项目具有商业价值，因为它可以促进我们对黑猩猩ad相关基因与神经病理学之间关系的理解。黑猩猩神经遗传位点的特征在新药的药物遗传学研究中是有用的。这些知识可以帮助减轻人类的痛苦，减少与AD和相关神经退行性疾病相关的公共卫生负担，这些疾病对老龄化社会的威胁越来越大。

The goal of this proposal is to identify and characterize DNA sequence variation in chimpanzees at coding regions of four genes that contain mutations implicated in the pathogenesis of Alzheimer Disease (AD). We will select a genetically diverse sample from the four recognized chimpanzee subspecies and characterize DNA sequence variation by screening for novel DNA sequences in 4 candidate genes implicated in AD: Apolipoprotein E, Amyloid Precursor Protein, and Presenilins 1 and 2. Chimpanzees are very similar to humans genetically and physiologically, yet they exhibit substantial intraspecific genetic and phenotypic differentiation. This combination of phylogenetic proximity to humans and intraspecific genetic variation can allow identification of DNA sequence variation in AD-related genes, advance investigation of gene/disease associations in AD, and help identify cost-effective methods of mutation screening. Furthermore, by genetically characterizing brain tissues from chimpanzees that have been behaviorally characterized and made available to neuroscientists, this project can increase the value of our on-going Great Ape Brain Bank initiative. The correlation of neuropathological studies with AD-related mutations can allow detailed investigation of the genetic basis of AD and other neurodegenerative diseases and facilitate a pharmacogenomics approach to testing novel pharmaceuticals in neurogenetically defined chimpanzees prior to human trials. PROPOSED COMMERCIAL APPLICATIONS: This project has commercial value in that it can advance our understanding of the relationship between AD-related genes and neuropathology in chimpanzees. The characterization of neurogenetic loci in chimpanzees can be useful in pharmacogenetic studies of new drugs. This knowledge can help alleviate human suffering and reduce the public health burden associated with AD and related neurodegenerative disorders, which are growing threats to an aging society.