title: Heteroplasmic mitochondrial DNA mutations in normal and tumour cells.
abstract: The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype.
authors.affiliation: The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21231, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.forename: Devin C
authors.initials: DC
authors.lastname: Dressman
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D015179:Colorectal Neoplasms / Q000473:pathology*; D004272:DNA, Mitochondrial / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial