Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal)

We analyzed the control region of the mitochondrial DNA (mtDNA)from maternally related individuals originating from the AzoresIslands (Portugal) in order to estimate the mutation rate ofmtDNA and to gain insights into the process by which a new mutationarises and segregates into heteroplasmy. Length and/or pointheteroplasmies were found at least in one individual of 72%of the studied families. Eleven new point substitutions werefound, all of them in heteroplasmy, from which five appear tobe somatic mutations and six can be considered germinal, evidencingthe high frequency of somatic mutations in mtDNA in healthyyoung individuals. Different values of the mutation rate accordingto different assumptions were estimated. When considering allthe germinal mutations, the value of the mutation rate obtainedis one of the highest reported so far in family studies. However,when corrected for gender (assuming that the mutations presentin men have the same evolutionary weight of somatic mutationsbecause they will inevitably be lost) and for the probabilityof intraindividual fixation, the value for the mutation rateobtained for HVRI and HVRII (0.2415 mutations/site/Myr) wasin the upper end of the values provided by phylogenetic estimations.These results indicate that the discrepancy, that has been reportedpreviously, between the human mtDNA mutation rates observedalong evolutionary timescales and the estimations obtained usingfamily pedigrees can be minimized when corrections for genderproportions in newborn individuals and for the probability ofintraindividual fixation are introduced. The analyses performedsupport the hypothesis that (1) in a constant, tight bottleneckgenetic drift alone can explain different patterns of heteroplasmysegregation and (2) in neutral conditions, the destiny of anew mutation is strictly related to the initial proportion ofthe new variant. Another important point arising from the dataobtained is that, even in the absence of a paternal contributionof mtDNA, recombination may occur between mtDNA molecules presentin an individual, which is only observable if it occurs betweenmtDNA types that differ at two or more positions.