We propose to use the large, pedigreed baboon colony at Southwest Foundation for Biomedical Research (SFBR) in San Antonio, TX, to develop the baboon (Papio hamadryas anubis, Papio hamadryas cynocephalus, and their hybrids) as a nonhuman primate model for the genetics of primary generalized epilepsy in humans. Epilepsy is easily studied in the baboon because these animals are highly susceptible to photic stimulation to provoke neuronal discharges and seizures that are sensitive markers of their epileptic syndrome. The baboon is also an ideal animal for development as a genetic model, because baboon and human share many genetic, anatomical, biochemical, and physiological features. The evolutionary proximity of baboon and human, and the high degree of conservation of gene order between these species, imply that genetic factors identified in the baboon genome will be directly relevant to the genetic situation in the human. Candidate genes identified in the baboon are therefore likely to be relevant for identifying genes in humans. Although the red baboon (Papio hamadryas papio) was first explored more than thirty years ago as a nonhuman primate model of primary generalized epilepsy in humans, and remains one of the best characterized electroclinical animal models for juvenile myoclonic epilepsy, the red baboon cannot be developed further as a genetic model. Development of a genetic model requires large samples, and an accurate knowledge of the relatedness between individuals, in order to separate genetic and environmental sources of variation. Neither of these requirements can be met using the red baboon, however. We will therefore use the large, pedigreed baboon colony at SFBR. Nearly 1500 baboons are members of a single pedigree. About 1000 of these baboons have already been genotyped at 370 or more polymorphic human DNA microsatellite marker loci, and a baboon linkage map is available for genetic linkage analysis. Using these resources we will identify genes that significantly affect variation in the clinical and electroencephalographic features of epilepsy in baboons and are therefore likely to be relevant in human epilepsy. Identification of genes involved in the epilepsy syndrome will implicate specific physiological and biochemical pathways that can be targeted for intervention, and potentially contribute to improvements in existing treatments for epilepsy and the development of novel therapies. ? ?
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