We have studied the genetic characteristics of a homopolymeric tract length heteroplasmy associated with the 16189C variant in the mtDNA D-loop control region to identify the factor(s) involved in the generation of the length heteroplasmy. The relative proportion of the various lengths of the polycytosines (i.e., the pattern of the length heteroplasmy) is maintained in an individual, and previous evidence shows that it is regenerated de novo following cell divisions. The pattern is maintained in maternally related individuals, suggestive of mtDNA determinants. Of the 38 individuals with the 16189C variant studied, 39% were found to exhibit the (16180)AAACCCCCCCCCCC(16193) variant associated with A16183C polymorphism [(11C)-group], while 53% showed the (16180)AACCCCCCCCCCCC(16193) variant associated with a further A16182C polymorphism [(12C)-group]. Haplotype analysis of the mtDNA revealed a specific association of the longer mean length of the poly[C] in the (12C)-group with haplogroup B. A similar association was also observed in the (11C)-group, but with a novel haplogroup. Cybrid constructions revealed that the involvement of nuclear factor(s) in the generation of the length heteroplasmy is prominent in homopolymeric tract of eight cytosines. The nuclearly coded factor(s) is/are presumably related to the fidelity of the nuclearly coded components of the mitochondrial DNA replication machinery.
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