title: Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations.
abstract: Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at ∼3,500× average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different nucleotide positions (nps) exhibit high frequencies of heteroplasmy in different tissues, and, moreover, heteroplasmy is strongly dependent on the specific consensus allele at an np. All of these tissue-related and allele-related heteroplasmies show a significant age-related accumulation, suggesting positive selection for specific alleles at specific positions in specific tissues. We also find a highly significant excess of liver-specific heteroplasmies involving nonsynonymous changes, most of which are predicted to have an impact on protein function. This apparent positive selection for reduced mitochondrial function in the liver may reflect selection to decrease damaging byproducts of liver mitochondrial metabolism (i.e., "survival of the slowest"). Overall, our results provide compelling evidence for positive selection acting on some somatic mtDNA mutations.
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D04103 Leipzig, Germany; Fondation Mérieux, Lyon 69002, France; and.
authors: Mingkun
authors: M
authors: Li
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D04103 Leipzig, Germany;
authors: Roland
authors: R
authors: Schröder
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D04103 Leipzig, Germany;
authors: Shengyu
authors: S
authors: Ni
authors: Institut für Rechtsmedizin, Universitätsklinikum Bonn, D53111 Bonn, Germany.
authors: Burkhard
authors: B
authors: Madea
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, D04103 Leipzig, Germany; stoneking@eva.mpg.de.
authors: Mark
authors: M
authors: Stoneking
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics*; D012641:Selection, Genetic; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial
keywords: heteroplasmy; human; mtDNA; selection; tissue variation