Heteroplasmic point mutations in the human mtDNA control region

As part of an investigation of the fixation mechanisms of mtDNA mutations in humans, we sequenced the first hypervariable segment of the control region in 180 twin pairs and found evidence of site heteroplasmy in 4 pairs. Significant levels of two mitochondrial haplotypes differing by a single point mutation were found in two MZ pairs, and within each pair, both members had similar levels of heteroplasmy. Two DZ pairs were found in which the predominant mitochondrial haplotype differed within the pair. We measured proportions of mitochondrial haplotypes within two twin pairs and their maternal relatives, using primer extension. In both maternal lineages, most family members were heteroplasmic, and the proportions of each genotype varied widely in different individuals. We used the changes in haplotype proportions within mother-offspring pairs to calculate the size range of potential bottlenecks in mitochondrial numbers occurring during development of the offspring. In most individuals, the most likely effective bottleneck sizes ranged from 3 to 20 segregating units, though in two individuals a small bottleneck was very unlikely and there was no upper limit on its possible size. We also used the data from this study, together with unpublished data from other populations, to estimate the frequency of site heteroplasmy in normal human populations. From this, we calculated that the rate of mutation and fixation in the first hypervariable segment of the human mtDNA control region is between 1.2 x 10(-6) and 2.7 x 10(-5) per site per generation. This range is in good agreement with published estimates calculated by other methods.