The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree rates

Abstract

We have extended our previous analysis of the pedigree rate of control-region divergence in the human mitochondrial genome. One new germline mutation in the mitochondrial DNA (mtDNA) control region was detected among 185 transmission events (generations) from five Leber hereditary optic neuropathy (LHON) pedigrees. Pooling the LHON pedigree analyses yields a control-region divergence rate of 1.0 mutation/bp/10(6) years (Myr). When the results from eight published studies that used a similar approach were pooled with the LHON pedigree studies, totaling >2,600 transmission events, a pedigree divergence rate of 0.95 mutations/bp/Myr for the control region was obtained with a 99.5% confidence interval of 0.53-1.57. Taken together, the cumulative results support the original conclusion that the pedigree divergence rate for the control region is approximately 10-fold higher than that obtained with phylogenetic analyses. There is no evidence that any one factor explains this discrepancy, and the possible roles of mutational hotspots (rate heterogeneity), selection, and random genetic drift and the limitations of phylogenetic approaches to deal with high levels of homoplasy are discussed. In addition, we have extended our pedigree analysis of divergence in the mtDNA coding region. Finally, divergence of complete mtDNA sequences was analyzed in two tissues, white blood cells and skeletal muscle, from each of 17 individuals. In three of these individuals, there were four instances in which an mtDNA mutation was found in one tissue but not in the other. These results are discussed in terms of the occurrence of somatic mtDNA mutations.

Figure 1

The matrilineal pedigree of the USA2 11778 family with LHON. Filled symbols indicate that the family member is visually affected.

Figure 2

A partial matrilineal pedigree of the ENG1 11778 family with LHON. The complete pedigree contains too many members to be conveniently shown. As a result, the numbers used to denote individual family members are not consecutive within a generation. When the family member numbers are underlined and italicized, the mtDNA control region from these family members was analyzed. Filled symbols indicate that the family member is visually affected.

Figure 3

Pedigree of the “A” branch of the ENG1 family with LHON. Although this pedigree cannot be definitively linked genealogically to the main ENG1 pedigree, sequencing analyses of coding region polymorphisms (described in the text) show that this is an authentic branch of the pedigree. When the family member numbers are underlined and italicized, the control region was analyzed. Filled symbols indicate that the family member is visually affected.