Through a collaboration between the University of Pretoria, South Africa, and Emory University, U.S. the investigators propose to determine the nature and extent of mitochondrial DNA (mtDNA) disease in Africa. The mtDNA is maternally inherited, encodes essential energy genes, and has a very high mutation rate. This high mutation rate has resulted in the accumulation of high levels of normal continent-specific sequence polymorphisms, and is also the cause of the high prevalence of mtDNA disease. Recently, mtDNA disease has been extensively characterized in North America, Europe, and Asia; but on Africans have been very limited. Analysis of the normal mtDNA variation in native populations has revealed that 2/3 of all African mtDNAs fall into a coherent group of related mtDNA haplotypes known as macro-haplogroup L*. The other 1/3 of African mtDNAs gave rise to the nine European-specific mtDNA haplogroups, including haplogroup J; and to the two Asian macrohaplogroups. Studies on the phenotypes associated with specific pathogenic mtDNA mutations (eg. the 14484 mutation), have revealed that certain European haplogroups, particularly J, enhance the severity of mitochondrial disease; but suggest that African macro-haplogroup L* mtDNAs may be protective. Therefore, to understand the molecular basis of African mtDNA disease, they will characterize both the pathogenic mtDNA mutations and the background mtDNA variation. To accomplish these goals, the investigators will pursue three specific aims. First, they will continue to characterize the normal mtDNA variation among native South Africans. Second, they will identify and characterize South African patients likely to harbor mtDNA disease. Third, they will determine the mtDNA background and pathogenic mtDNA mutation of each patient. Fourth, they will compare patients with the same pathogenic mtDNA mutation, but different background mtDNA haplogroups, to determine in macro- haplogroup L* does modulate the severity of mtDNA disease in Africans. By the end of this study, they hope to have a better understanding of the molecular basis of African mtDNA disease, and to have established a permanent mitochondrial disease center in South Africa to serve the future needs of the African population.
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|Mishmar, Dan; Ruiz-Pesini, Eduardo; Golik, Pawel et al. (2003) Natural selection shaped regional mtDNA variation in humans. Proc Natl Acad Sci U S A 100:171-6|