The mutation rate in the human mtDNA control region

The mutation rate of the mitochondrial control region has been widely used to calibrate human population history. However, estimates of the mutation r ate in this region have spanned two orders of magnitude. To readdress this rate, we sequenced the mtDNA control region in 272 individuals, who were re lated by a total of 705 mtDNA transmission events, from 26 large Icelandic pedigrees. Three base substitutions were observed, and the mutation rate ac ross the two hypervariable regions was estimated to be 3/705 = .0043 per ge neration (95% confidence interval [CI] .00088-.013), or .32/site/1 million years (95% CI.065-.97). This study is substantially larger than others publ ished, which have directly assessed mtDNA mutation rates on the basis of pe digrees, and the estimated mutation rate is intermediate among those derive d from pedigree-based studies. Our estimated rate remains higher than those based on phylogenetic comparisons. We discuss possible reasons for-and con sequences of-this discrepancy. The present study also provides information on rates of insertion/deletion mutations, rates of heteroplasmy, and the re liability of maternal links in the Icelandic genealogy database.