Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools

DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a g...

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Vydáno v:PLoS genetics Ročník 11; číslo 7; s. e1005306
Hlavní autoři: Ding, Jun, Sidore, Carlo, Butler, Thomas J., Wing, Mary Kate, Qian, Yong, Meirelles, Osorio, Busonero, Fabio, Tsoi, Lam C., Maschio, Andrea, Angius, Andrea, Kang, Hyun Min, Nagaraja, Ramaiah, Cucca, Francesco, Abecasis, Gonçalo R., Schlessinger, David
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Public Library of Science 01.07.2015
Public Library of Science (PLoS)
Témata:
Age
Aging
Algorithms
Base Sequence
Body Fat Distribution
Body Mass Index
Deoxyribonucleic acid
DNA
DNA Copy Number Variations - genetics
DNA, Mitochondrial - genetics
Female
Gene Dosage - genetics
Genes
Genomes
High-Throughput Nucleotide Sequencing
Humans
Lymphocytes
Lymphocytes - cytology
Male
Metabolism
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial DNA
Obesity - genetics
Population
Sequence Analysis, DNA
Sex Factors
Studies
Waist Circumference - genetics
Waist-Hip Ratio
ISSN:1553-7404, 1553-7390, 1553-7404
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Shrnutí:DNA sequencing identifies common and rare genetic variants for association studies, but studies typically focus on variants in nuclear DNA and ignore the mitochondrial genome. In fact, analyzing variants in mitochondrial DNA (mtDNA) sequences presents special problems, which we resolve here with a general solution for the analysis of mtDNA in next-generation sequencing studies. The new program package comprises 1) an algorithm designed to identify mtDNA variants (i.e., homoplasmies and heteroplasmies), incorporating sequencing error rates at each base in a likelihood calculation and allowing allele fractions at a variant site to differ across individuals; and 2) an estimation of mtDNA copy number in a cell directly from whole-genome sequencing data. We also apply the methods to DNA sequence from lymphocytes of ~2,000 SardiNIA Project participants. As expected, mothers and offspring share all homoplasmies but a lesser proportion of heteroplasmies. Both homoplasmies and heteroplasmies show 5-fold higher transition/transversion ratios than variants in nuclear DNA. Also, heteroplasmy increases with age, though on average only ~1 heteroplasmy reaches the 4% level between ages 20 and 90. In addition, we find that mtDNA copy number averages ~110 copies/lymphocyte and is ~54% heritable, implying substantial genetic regulation of the level of mtDNA. Copy numbers also decrease modestly but significantly with age, and females on average have significantly more copies than males. The mtDNA copy numbers are significantly associated with waist circumference (p-value = 0.0031) and waist-hip ratio (p-value = 2.4×10-5), but not with body mass index, indicating an association with central fat distribution. To our knowledge, this is the largest population analysis to date of mtDNA dynamics, revealing the age-imposed increase in heteroplasmy, the relatively high heritability of copy number, and the association of copy number with metabolic traits.
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Conceived and designed the experiments: JD FC GRA DS. Performed the experiments: FB AM AA RN FC GRA. Analyzed the data: JD CS TJB YQ OM. Contributed reagents/materials/analysis tools: MKW LCT HMK. Wrote the paper: JD CS RN FC GRA DS.
The authors have declared that no competing interests exist.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005306