Quantitative assessment of mitochondrial DNA copies from whole genome sequencing

Chu, Hsueh-Ting; Hsiao, William W. L.; Tsao, Theresa Tsun-Hui; Chang, Ching-Mao; Liu, Yen-Wenn; Fan, Chen-Chieh; Lin, Han; Chang, Hen-Hong; Yeh, Tze-Jung; Chen, Jen-Chih; Huang, Dun-Ming; Chen, Chaur-Chin; Kao, Cheng−Yan

doi:10.1186/1471-2164-13-s7-s5

Cited by 21 publications

(17 citation statements)

References 14 publications

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“…In accordance with our results, mtDNA copy number was recently reported to be lower in parents than in their children (Chu et al 2012). In addition, an age-related decline in mtDNA copy number has also been observed in the human pancreatic islet among pancreatic islet donors (Cree et al 2008) and in human muscletissue from muscle biopsy donors(Short KR 2005; Welle S et al 2003), as well as in liver and muscle cells from rats and several tissues from a short-lived fish(Barazzoni et al 2000; Hartmann et al 2011).…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

et al. 2014

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The role of the mitochondria in disease, general health and aging has drawn much attention over the years. Several attemptshave been made to describe how the numbersof mitochondriacorrelate with age, although with inconclusive results. In this study, the relativequantity of mitochondrial DNA compared to nuclear DNA,i.e. the mitochondrial DNA copy number, was measured by PCR technology and used as a proxy for the content of mitochondria copies. In 1,067 Danish twins and singletons (18-93 years of age), with the majority being elderly individuals, theestimated mean mitochondrial DNA copy numberin peripheral blood cells was similar for those 18-48 years of age (mean relative mtDNA content: 61.0; 95% CI [52.1; 69.9]), but declinedby −0.54 mtDNA 95%CI [−0.63; −0.45] every year for those older thanapproximately 50 years of age.However, the longitudinal, yearly decline within an individual was more than twice as steep as observed in the cross-sectional analysis (decline of mtDNA content: −1.27; 95%CI [−1.71; −0.82]). Subjects with low mitochondrial DNA copy numberhad poorer outcomes in terms of cognitive performance, physical strength, self-rated health, andhigher all-cause mortality than subjects with high mitochondrial DNA copy number, also when age was controlled for.The copy numbermortality associationcan contribute to the smaller decline in a cross-sectional sample of the population compared to the individual,longitudinal decline. This study suggests that high mitochondrial DNA copy number in blood is associated with betterhealth and survival among elderly.

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Section: Discussionsupporting

confidence: 93%

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

et al. 2014

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“…We note that a similar framework has been suggested by Chu and colleagues[ 16 ] to estimate copy number. However, their method identified only reads mapped to mtDNA and counted all the remaining reads as mapped to nuclear DNA.…”

Section: Methodsmentioning

confidence: 63%

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

et al. 2015

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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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“…To address these concerns, we employed next-generation sequencing (NGS) to measure mutations in both total genomic extract (unpurified) and purified mtDNA from the same tissue to evaluate the effect of purification on mtDNA mutation indices. We also used NGS to confirm the accuracy of our qPCR measurements of mtDNA copy number, as has been done previously [17,18]. Finally, we implemented a novel method of mtDNA purification that can be used to reduce sequencing costs and increase mtDNA coverage across a wide range of applications.…”

Section: Introductionmentioning

confidence: 95%

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

et al. 2020

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The mitochondrial theory of aging attributes much of the aging process to mitochondrial DNA damage. The polymerase gamma (PolG) mutant mouse was designed to evaluate this theory and thus carries a mutated proofreading region of polymerase gamma (D257A) that exclusively transcribes the mitochondrial genome. As a result, PolG D257A mice accumulate mitochondrial DNA (mtDNA) mutations that lead to premature aging, as evidenced by hair loss, weight loss, kyphosis, increased rates of apoptosis, organ damage, and an early death, occurring around 12 months of age. Research has shown that exercise decreases skeletal muscle mtDNA mutations and normalizes protein levels in PolG mice. However, brain mtDNA changes with exercise in PolG mice have not been studied. We found no effects of exercise on mtDNA mutations or copy number in either the brain or liver of PolG mice, despite changes to body mass. Our results suggest that mitochondrial mutations play little role in exercise-brain interactions in the PolG model of accelerated aging. In addition to evaluating the effect of exercise on mtDNA outcomes, we also implemented novel methods for both extracting mtDNA and measuring mtDNA mutations, with aims for improving the efficiency and accuracy of these methods.

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Quantitative assessment of mitochondrial DNA copies from whole genome sequencing

Cited by 21 publications

References 14 publications

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly

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

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

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