title: Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA.
abstract: Mitochondrial point heteroplasmy is a common event observed not only in patients with mitochondrial diseases but also in healthy individuals. We here report a comprehensive investigation of heteroplasmy occurrence in human including the whole mitochondrial control region from nine different tissue types of 100 individuals. Sanger sequencing was used as a standard method and results were supported by cloning, minisequencing, and massively parallel sequencing. Only 12% of all individuals showed no heteroplasmy, whereas 88% showed at least one heteroplasmic position within the investigated tissues. In 66% of individuals up to 8 positions were affected. The highest relative number of heteroplasmies was detected in muscle and liver (79%, 69%), followed by brain, hair, and heart (36.7%-30.2%). Lower percentages were observed in bone, blood, lung, and buccal cells (19.8%-16.2%). Accumulation of position-specific heteroplasmies was found in muscle (positions 64, 72, 73, 189, and 408), liver (position 72) and brain (partial deletion at position 71). Deeper analysis of these specific positions in muscle revealed a non-random appearance and position-specific dependency on age. MtDNA heteroplasmy frequency and its potential functional importance have been underestimated in the past and its occurrence is ubiquitous and dependent at least on age, tissue, and position-specific mutation rates.
authors.affiliation: Institute of Legal Medicine, Freiburg University Medical Center, Albertstrasse 9, D-79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, D-79104 Freiburg, Germany. Electronic address: jana.naue@uniklinik-freiburg.de.
authors.forename: Jana
authors.initials: J
authors.lastname: Naue
authors.affiliation: Institute of Legal Medicine, Freiburg University Medical Center, Albertstrasse 9, D-79104 Freiburg, Germany. Electronic address: steffen.hoerer@uniklinik-freiburg.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hörer
authors.affiliation: Institute of Legal Medicine, Freiburg University Medical Center, Albertstrasse 9, D-79104 Freiburg, Germany. Electronic address: timo.saenger@uniklinik-freiburg.de.
authors.forename: Timo
authors.initials: T
authors.lastname: Sänger
authors.affiliation: Institute of Legal Medicine, Innsbruck Medical University, Muellerstrasse 44, A-6020 Innsbruck, Austria. Electronic address: christina.strobl@i-med.ac.at.
authors.forename: Christina
authors.initials: C
authors.lastname: Strobl
authors.affiliation: Institute of Legal Medicine, Innsbruck Medical University, Muellerstrasse 44, A-6020 Innsbruck, Austria. Electronic address: petra.hatzer-grubwieser@i-med.ac.at.
authors.forename: Petra
authors.initials: P
authors.lastname: Hatzer-Grubwieser
authors.affiliation: Institute of Legal Medicine, Innsbruck Medical University, Muellerstrasse 44, A-6020 Innsbruck, Austria; Penn State Eberly College of Science, University Park, PA, USA. Electronic address: walther.parson@i-med.ac.at.
authors.forename: Walther
authors.initials: W
authors.lastname: Parson
authors.affiliation: Institute of Legal Medicine, Freiburg University Medical Center, Albertstrasse 9, D-79104 Freiburg, Germany. Electronic address: sabine.lutz-bonengel@uniklinik-freiburg.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lutz-Bonengel
mesh_terms: D004272:DNA, Mitochondrial / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial
keywords: Control region; Mitochondrial DNA; Point heteroplasmy; Sanger sequencing