Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

Poole, Jason C.; Procaccio, Vincent; Brandon, Martin; Merrick, G.S.; Wallace, Douglas C.

doi:10.1515/bc.2010.125

Cited by 9 publications

(9 citation statements)

References 72 publications

(89 reference statements)

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“…Following digestion, the relative levels of the fragments was determined by capillary electrophoresis, and the ratio of the two mtDNAs normalized using a standard curve. As an independent validation of this method, in some experiments the proportion of NZB and 129 mtDNAs was also determined using SNaPshot primer extension method with the latter also normalized by comparison with a standard curve (Poole et al, 2010). Supporting SNaPshot data are provided in Figures S1and S2.…”

Section: Resultsmentioning

confidence: 99%

Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Sharpley

Marciniak

Eckel‐Mahan

et al. 2012

Cell

336

312

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SUMMARY Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homo-plasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.

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Section: Resultsmentioning

confidence: 99%

Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Sharpley

Marciniak

Eckel‐Mahan

et al. 2012

Cell

336

312

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“…Using Phylotree, a comprehensive phylogenetic tree of global mitochondrial DNA variation (van Oven and Kayser 2009), as well as an extensive literature search on PubMed for prior studies with haplogroup classification (Herrnstadt et al 2002; van der Walt et al 2003; Poole et al 2010; Paneto et al 2011), a total of 63 mitochondrial SNPs (mtSNPs) were selected for genotyping to classify the major self-identified racial/ethnic groups within NHANES (non-Hispanic white, non-Hispanic black, and Mexican American) into haplogroups (Table S1). European (H, I, J, K, T, U, V, W, & X), African (L0, L1, L2, L3, & L4), and Native American/Asian (A, B, C, & D) mitochondrial haplogroup-defining SNPs were chosen.…”

Section: Methodsmentioning

confidence: 99%

Characterization of mitochondrial haplogroups in a large population-based sample from the United States

et al. 2014

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Mitochondrial DNA (mtDNA) haplogroups are valuable for investigations in forensic science, molecular anthropology, and human genetics. In this study, we developed a custom panel of 61 mtDNA markers for high-throughput classification of European, African, and Native American/Asian mitochondrial haplogroup lineages. Using these mtDNA markers we constructed a mitochondrial haplogroup classification tree and classified 18,832 participants from the National Health and Nutrition Examination Surveys (NHANES). To our knowledge, this is the largest study to date characterizing mitochondrial haplogroups in a population-based sample from the United States, and the first study characterizing mitochondrial haplogroup distributions in self-identified Mexican Americans separately from Hispanic Americans of other descent. We observed clear differences in the distribution of maternal genetic ancestry consistent with proposed admixture models for these subpopulations, underscoring the genetic heterogeneity of the United States Hispanic population. The mitochondrial haplogroup distributions in the other self-identified racial/ethnic groups within NHANES were largely comparable to previous studies. Mitochondrial haplogroup classification was highly concordant with self-identified race/ethnicity (SIRE) in non-Hispanic whites (94.8%), but was considerably lower in admixed populations including non-Hispanic blacks (88.3%), Mexican Americans (81.8%), and other Hispanics (61.6%), suggesting SIRE does not accurately reflect maternal genetic ancestry, particularly in populations with greater proportions of admixture. Thus, it is important to consider inconsistencies between SIRE and genetic ancestry when performing genetic association studies. The mitochondrial haplogroup data that we have generated, coupled with the epidemiologic variables in NHANES, is a valuable resource for future studies investigating the contribution of mtDNA variation to human health and disease.

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“…mtDNA sequencing and haplogroup assignment were performed as previously described (25,47) and reported as differences from the revised Cambridge Reference Sequence (48). Clinical data were collected during routine office visits over a median of 6 (range, 4-16) y, but we restricted statistical analyses for Table 1 …”

Section: Methodsmentioning

confidence: 99%

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

Strauss

DuBiner

Simon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mutations of both nuclear and mitochondrial DNA (mtDNA)-encoded mitochondrial proteins can cause cardiomyopathy associated with mitochondrial dysfunction. Hence, the cardiac phenotype of nuclear DNA mitochondrial mutations might be modulated by mtDNA variation. We studied a 13-generation Mennonite pedigree with autosomal recessive myopathy and cardiomyopathy due to an SLC25A4 frameshift null mutation (c.523delC, p.Q175RfsX38), which codes for the heart-muscle isoform of the adenine nucleotide translocator-1. Ten homozygous null (adenine nucleotide translocator-1) patients monitored over a median of 6 years had a phenotype of progressive myocardial thickening, hyperalaninemia, lactic acidosis, exercise intolerance, and persistent adrenergic activation. Electrocardiography and echocardiography with velocity vector imaging revealed abnormal contractile mechanics, myocardial repolarization abnormalities, and impaired left ventricular relaxation. End-stage heart disease was characterized by massive, symmetric, concentric cardiac hypertrophy; widespread cardiomyocyte degeneration; overabundant and structurally abnormal mitochondria; extensive subendocardial interstitial fibrosis; and marked hypertrophy of arteriolar smooth muscle. Substantial variability in the progression and severity of heart disease segregated with maternal lineage, and sequencing of mtDNA from five maternal lineages revealed two major European haplogroups, U and H. Patients with the haplogroup U mtDNAs had more rapid and severe cardiomyopathy than those with haplogroup H. ANT1 | oxidative stress | mitochondrial disease | variable penetrance | oxidative phosphorylation

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Multiplex analysis of mitochondrial DNA pathogenic and polymorphic sequence variants

Cited by 9 publications

References 72 publications

Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Heteroplasmy of Mouse mtDNA Is Genetically Unstable and Results in Altered Behavior and Cognition

Characterization of mitochondrial haplogroups in a large population-based sample from the United States

Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup

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