| Abstract
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A prediction of the mitochondrial genetic paradigm is that some forms of chronic degenerative disease will be due to mitochondrial DNA (mtDNA) mutations (Wallace, 1992a). To investigate this possibility, my research had two related goals. The first was to characterize the natural genetic variation of the human mtDNA. These data would be essential to the second goal, which was to identify mtDNA mutations associated with disease. Investigation of natural mtDNA genetic variation also helped define the origins of both Asians and Amerindians. The majority of the mtDNA genetic variation in Asian populations is shared, indicating that they share a common ancestry (Ballinger et al., 1992a). Additionally, genetic remnants of the Papua New Guinea founders were observed in Malaysia, and a frequency cline for the COII/tRNALys intergenic deletion was observed along coastal Asia (Ballinger et al., 1992a). Comparison of Asian and Native American mtDNA haplotype data revealed that all Amerindians can be traced back to four Asian mtDNA lineages (Schurr et al., 1990; Torroni et al., 1992). Genetic analyses showed that several mtDNA mutations could be responsible for chronic degenerative disease. First, mtDNA point mutations were found to be responsible for both Myoclonic Epilepsy and Ragged Red Fiber disease (MERRF) and Leigh's disease. MERRF is a chronic neurodegenerative disease caused by a heteroplasmic A to G transition at np 8344 in tRNALys (Shoffner et al., 1990). Leigh's disease is an early onset neurodegenerative disorder caused by a heteroplasmic T to G transversion mutation at np 8993 in the ATPase 6 subunit of the mtDNA (Shoffner et al., 1992). The severity of both diseases correlated with the percent heteroplasmic mutant and age. Second, major mtDNA length mutations were found to cause both Pearson's syndrome (Rotig et al., 1988, 1990; Ballinger et al., 1993) and Diabetes mellitus (Ballinger et al., 1992b). MtDNA deletions were associated with Pearson's syndrome, a disease characterized by pancytopenia. Diabetes mellitus was found to be associated with major mtDNA length mutations in a family with adult onset diabetes. Consequently, these data show that mtDNA mutations can be responsible for at least four different types of chronic degenerative disease, supporting the hypothesis predicted by the mitochondrial genetic paradigm.
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