HETEROPLASMIC POINT MUTATIONS IN THE HUMAN MTDNA CONTROL REGION

As part of an investigation of the fixation mechanisms of mtDNA mutati ons in humans, we sequenced the first hypervariable segment of the con trol region in 180 twin pairs and found evidence of site heteroplasmy in 4 pairs. Significant levels of two mitochondrial haplotypes differi ng by a single point mutation were found in two MZ pairs, and within e ach pair, both members had similar levels of heteroplasmy. Two DZ pair s 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 exten sion. In both maternal lineages, most family members were heteroplasmi c, and the proportions of each genotype varied widely in different ind ividuals. We used the changes in haplotype proportions within mother-o ffspring 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 bot tleneck was very unlikely and there was no upper limit on its possible size. We also used the data from this study, together with unpublishe d data from other populations, to estimate the frequency of site heter oplasmy in normal human populations. From this, we calculated that the rate of mutation and fixation in the first hypervariable segment of t he 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 publish ed estimates calculated by other methods.