Inheritance of Mitochondrial DNA Recombinants in Double-Heteroplasmic Families: Potential Implications for Phylogenetic Analysis

• Published in: American journal of human genetics Vol. 80; no. 2; pp. 298 - 305
• Main Authors: Zsurka, Gábor, Hampel, Kevin G., Kudina, Tatiana, Kornblum, Cornelia, Kraytsberg, Yevgenia, Elger, Christian E., Khrapko, Konstantin, Kunz, Wolfram S.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.02.2007; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; DNA, Mitochondrial - genetics; DNA, Recombinant - genetics; Extrachromosomal Inheritance; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic recombination; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Medical genetics; Medical sciences; MELAS Syndrome - genetics; MERRF Syndrome - genetics; Mitochondrial DNA; Molecular and cellular biology; Molecular Sequence Data; Molecules; Musculoskeletal system; Mutation; Pedigree; Phylogeny; Human; Family study; Phylogenetic tree; Inheritance; Family environment; Genetics; Mitochondrial DNA; Recombinant DNA; Inheritance(genetics); Double
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/511282

Recently, somatic recombination of human mitochondrial DNA (mtDNA) was discovered in skeletal muscle. To determine whether recombinant mtDNA molecules can be transmitted through the germ line, we investigated two families, each harboring two inherited heteroplasmic mtDNA mutations. Using allele-specific polymerase chain reaction and single-cell and single-molecule mutational analyses, we discovered, in both families, all four possible allelic combinations of the two heteroplasmic mutations (tetraplasmy), the hallmark of mtDNA recombination. We strongly suggest that these recombinant mtDNA molecules were inherited rather than de novo generated somatically, because they (1) are highly abundant and (2) are present in different tissues of maternally related family members, including young individuals. Moreover, the comparison of the complete mtDNA sequence of one of the families with database sequences revealed an irregular, nontreelike pattern of mutations, reminiscent of a reticulation. We therefore propose that certain reticulations of the human mtDNA phylogenetic tree might be explained by recombination of coexisting mtDNA molecules harboring multiple mutations.