COMPARATIVE DNA SEQUENCE VARIATION IN ALZHEIMER GENES

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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.