Phylogenetic and familial estimates of mitochondrial substitution rates: Study of control region mutations in deep-rooting pedigrees

We studied mutations in the mtDNA control region (CR) using deep-rooting Fr ench-Canadian pedigrees. In 508 maternal transmissions, we observed four su bstitutions (0.0079 per generation per 673 bp, 95% CI 0.0023-0.186). Combin ed with other familial studies, our results add up to 18 substitutions in 1 ,729 transmissions (0.0104), confirming earlier findings of much greater mu tation rates in families than those based on phylogenetic comparisons. Only 12 of these mutations occurred at independent sites, whereas three positio ns mutated twice each, suggesting that pedigree studies preferentially reve al a fraction of highly mutable sites. Fitting the data through use of a no nuniform rate model predicts the presence of 40 (95% CI 27-54) such fast si tes in the whole CR, characterized by the mutation rate of 274 per site per million generations (95% CI 138-410). The corresponding values for hyperva riable regions I (HVI; 1,729 transmissions) and II (HVII; 1,956 transmissio ns), are 19 and 22 fast sites, with rates of 224 and 274, respectively. Bec ause of the high probability of recurrent mutations, such sites are expecte d to be of no or little informativity for the evaluation of mutational dist ances at the phylogenetic time scale. The analysis of substitution density in the alignment of 973 HVI and 650 HVII unrelated European sequences revea ls that the bulk of the sites mutate at relatively moderate and slow rates. Assuming a star-like phylogeny and an average time depth of 250 generation s, we estimate the rates for HVI and HVII at 23 and 24 for the moderate sit es and 1.3 and 1.0 for the slow sites. The fast, moderate, and slow sites, at the ratio of 1:2:13, respectively, describe the mutation-rate heterogene ity in the CR. Our results reconcile the controversial rate estimates in th e phylogenetic and familial studies; the fast sites prevail in the latter, whereas the slow and moderate sites dominate the phylogenetic-rate estimati ons.