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- Title
Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes.
- Authors
Liu, Chunyu; Fetterman, Jessica L.; Liu, Poching; Luo, Yan; Larson, Martin G.; Vasan, Ramachandran S.; Zhu, Jun; Levy, Daniel
- Abstract
Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic—the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic “hot” spots [NADH dehydrogenase (<italic>ND</italic>) subunit 1, 4, 5 and 6 genes, <italic>n</italic> = 7; cytochrome c oxidase I (<italic>COI</italic>), <italic>n</italic> = 2; 16S rRNA, <italic>n</italic> = 1; D-loop, <italic>n</italic> = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction <italic>p</italic> < 0.001). Four of these heteroplasmic mutations in <italic>ND</italic> and <italic>COI</italic> genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases.
- Subjects
NUCLEOTIDE sequencing; MITOCHONDRIAL DNA; NADH dehydrogenase; DEHYDROGENASE genetics; DNA mutational analysis; AGE factors in disease
- Publication
Human Genetics, 2018, Vol 137, Issue 3, p203
- ISSN
0340-6717
- Publication type
Article
- DOI
10.1007/s00439-018-1873-4