Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes

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 a...

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Bibliographic Details
Published in:Human genetics 2018-03, Vol.137 (3), p.203-213
Main Authors: Liu, Chunyu, Fetterman, Jessica L., Liu, Poching, Luo, Yan, Larson, Martin G., Vasan, Ramachandran S., Zhu, Jun, Levy, Daniel
Format: Article
Language:English
Subjects:
Age
Aging
Alleles
Biomedical and Life Sciences
Biomedicine
Cytochrome oxidase
Cytochrome-c oxidase
Dehydrogenases
Gene Function
Genes
Genomes
Genomics
Heteroplasmy
Human Genetics
Metabolic Diseases
Mitochondrial DNA
Molecular Medicine
Mutation
NADH
NADH dehydrogenase
Original Investigation
RNA
rRNA 16S
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Summary: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 ( ND ) subunit 1, 4, 5 and 6 genes, n  = 7; cytochrome c oxidase I ( COI ), n  = 2; 16S rRNA, n  = 1; D-loop, n  = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p  
ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-018-1873-4