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MtDNA next generation sequencing

Gráinne S Gorman, Patrick F Chinnery, Salvatore DiMauro, Michio Hirano, Yasutoshi Koga, Robert McFarland, Anu Suomalainen, David R Thorburn, Massimo Zeviani, Douglass M Turnbull
Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis...
October 20, 2016: Nature Reviews. Disease Primers
Auke B C Otten, Alphons P M Stassen, Michiel Adriaens, Mike Gerards, Richard G J Dohmen, Adriana J Timmer, Sabina J V Vanherle, Rick Kamps, Iris B W Boesten, Jo M Vanoevelen, Marc Muller, Bert Smeets
Of all pathogenic mitochondrial DNA (mtDNA) mutations in humans, ~25% is de novo, although the occurrence in oocytes has never been directly assessed. We used next generation sequencing to detect point mutations directly in the mtDNA of 3-15 individual mature oocytes and three somatic tissues from eight zebrafish females. Various statistical and biological filters allowed reliable detection of de novo variants with heteroplasmy ≥1.5%. In total, we detected 38 de novo base substitutions, but no insertions or deletions...
October 21, 2016: Genetics
Bing Xu, Xiyuan Li, Miaomiao Du, Chao Zhou, Hezhi Fang, Jianxin Lyu, Yanling Yang
By using next-generation sequencing targeted to MitoExome including the entire mtDNA and exons of 1033 genes encoding the mitochondrial proteome, we described here a novel m.11240C>T mutation in the mitochondrial ND4 gene from a patient with Leigh syndrome. High mutant loads of m.11240C>T were detected in blood, urinary epithelium, oral mucosal epithelium cells, and skin fibroblasts of the patient. Decreased mitochondrial complex I activity was found in transmitochondrial cybrids containing the m.11240C>T mutation with biochemical analysis...
October 20, 2016: Journal of Human Genetics
Anton M F Kalsbeek, Eva F K Chan, Judith Grogan, Desiree C Petersen, Weerachai Jaratlerdsiri, Ruta Gupta, Ruth J Lyons, Anne-Maree Haynes, Lisa G Horvath, James G Kench, Phillip D Stricker, Vanessa M Hayes
Prostate cancer management is complicated by extreme disease heterogeneity, which is further limited by availability of prognostic biomarkers. Recognition of prostate cancer as a genetic disease has prompted a focus on the nuclear genome for biomarker discovery, with little attention given to the mitochondrial genome. While it is evident that mitochondrial DNA (mtDNA) mutations are acquired during prostate tumorigenesis, no study has evaluated the prognostic value of mtDNA variation. Here we used next-generation sequencing to interrogate the mitochondrial genomes from prostate tissue biopsies and matched blood of 115 men having undergone a radical prostatectomy for which there was a mean of 107 months clinical follow-up...
October 5, 2016: Aging
Charlotte L Alston, Mariana C Rocha, Nichola Z Lax, Doug M Turnbull, Robert W Taylor
Mitochondria are double membrane-bound organelles that are present in all nucleated eukaryotic cells and responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control - the 16.6 kb mitochondrial genome encoding just 37 genes with the remaining ~1300 proteins of the mitoproteome encoded by nuclear genes. Mitochondrial dysfunction can arise due to defects in either mtDNA or nuclear mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity with symptoms affecting a single organ or tissue, or multisystem involvement...
September 23, 2016: Journal of Pathology
Maria Lopopolo, Claus Børsting, Vania Pereira, Niels Morling
OBJECTIVES: The Greenlandic population history is characterized by a number of migrations of people of various ethnicities. In this work, the analysis of the complete mtDNA genome aimed to contribute to the ongoing debate on the origin of current Greenlanders and, at the same time, to address the migration patterns in the Greenlandic population from a female inheritance demographic perspective. METHODS: We investigated the maternal genetic variation in the Greenlandic population by sequencing the whole mtDNA genome in 127 Greenlandic individuals using the Illumina MiSeq(®) platform...
August 24, 2016: American Journal of Physical Anthropology
Ester Perales-Clemente, Alexandra N Cook, Jared M Evans, Samantha Roellinger, Frank Secreto, Valentina Emmanuele, Devin Oglesbee, Vamsi K Mootha, Michio Hirano, Eric A Schon, Andre Terzic, Timothy J Nelson
Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high-quality biorepositories. Beyond inter-person variability, the root cause of intra-person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next-generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non-mitochondrial patients...
September 15, 2016: EMBO Journal
Scott V Edwards, Sally Potter, C Jonathan Schmitt, Jason G Bragg, Craig Moritz
Phylogeography, and its extensions into comparative phylogeography, have their roots in the layering of gene trees across geography, a paradigm that was greatly facilitated by the nonrecombining, fast evolution provided by animal mtDNA. As phylogeography moves into the era of next-generation sequencing, the specter of reticulation at several levels-within loci and genomes in the form of recombination and across populations and species in the form of introgression-has raised its head with a prominence even greater than glimpsed during the nuclear gene PCR era...
July 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
Angela D Bhalla, Alireza Khodadadi-Jamayran, Yanjie Li, David R Lynch, Marek Napierala
OBJECTIVE: Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat expansion disorder caused by epigenetic silencing of the frataxin gene (FXN). Current research suggests that damage and variation of mitochondrial DNA (mtDNA) contribute to the molecular pathogenesis of FRDA. We sought to establish the extent of the mutation burden across the mitochondrial genome in FRDA cells and investigate the molecular mechanisms connecting FXN downregulation and the acquisition of mtDNA damage...
July 2016: Annals of Clinical and Translational Neurology
Michelle A Peck, Michael D Brandhagen, Charla Marshall, Toni M Diegoli, Jodi A Irwin, Kimberly Sturk-Andreaggi
Sanger-type sequencing (STS) of mitochondrial DNA (mtDNA), specifically the control region (CR), is routinely employed in forensics in human identification and missing persons scenarios. Yet next-generation sequencing (NGS) has the potential to overcome some of the major limitations of STS processing, permitting reasonable paths forward for full mitochondrial genome (mtGenome) sequencing, while also offering higher-throughput and higher sensitivity capabilities. To establish the accuracy and reproducibility of NGS for the development of mtDNA data, 90 DNA extracts that were previously used to generate forensic quality full mtGenomes using STS were sequenced using Nextera XT library preparation and the Illumina MiSeq...
September 2016: Forensic Science International. Genetics
Hong Li, Rui Bi, Yu Fan, Yong Wu, Yanqing Tang, Zongchang Li, Ying He, Jun Zhou, Jinsong Tang, Xiaogang Chen, Yong-Gang Yao
Although monozygotic (MZ) twins have theoretically identical nuclear DNA sequences, there may be phenotypic differences between them caused by somatic mutations and epigenetic changes affecting each genome. In this study, we collected eight families of MZ twins discordant for schizophrenia with the aim of investigating the potential role of mitochondrial DNA (mtDNA) heteroplasmy in causing the phenotypic differences between the twin pairs. Next-generation sequencing (NGS) technology was used to screen the whole mitochondrial genome of the twin pairs and their parents...
June 24, 2016: Molecular Neurobiology
Jake G Hoekstra, Michael J Hipp, Thomas J Montine, Scott R Kennedy
Mitochondrial dysfunction and oxidative damage are commonly associated with early stage Alzheimer disease (AD). The accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been hypothesized to be a driver of these phenotypes, but the detection of increased mutation loads has been difficult due to a lack of sensitive methods. We used an ultrasensitive next generation sequencing technique to measure the mutation load of the entire mitochondrial genome. Here, we report a significant increase in the mtDNA mutation frequency in the hippocampus of early stage AD, with the cause of these mutations being consistent with replication errors and not oxidative damage...
August 2016: Annals of Neurology
Elmira Mohandesan, Camilla F Speller, Joris Peters, Hans-Peter Uerpmann, Margarethe Uerpmann, Bea De Cupere, Michael Hofreiter, Pamela A Burger
The performance of hybridization capture combined with next generation sequencing (NGS) has seen limited investigation with samples from hot and arid regions until now. We applied hybridization capture and shotgun sequencing to recover DNA sequences from bone specimens of ancient-domestic dromedary (Camelus dromedarius) and its extinct ancestor, the wild dromedary from Jordan, Syria, Turkey and the Arabian Peninsula, respectively. Our results show that hybridization capture increased the percentage of mitochondrial DNA (mtDNA) recovery by an average 187-fold and in some cases yielded virtually complete mitochondrial (mt) genomes at multi-fold coverage in a single capture experiment...
June 11, 2016: Molecular Ecology Resources
David Ballard
The analysis of mitochondrial DNA (mtDNA) is an established forensic tool and has been used extensively to aid with both the identification of human remains and evidence recovered from scenes of crime. The biology of mtDNA confers both advantages and disadvantages when using it as a tool for identification. It benefits from a high copy number, which facilitates analysis from samples with highly degraded DNA or trace amounts of DNA, but the maternal mode of inheritance restricts its power of discrimination. With Next Generation Sequencing being used in research and some forensic casework laboratories the scope of mtDNA analysis in forensic casework may expand in the near future...
2016: Methods in Molecular Biology
Massimo Ancora, Massimiliano Orsini, Alessia Colosimo, Maurilia Marcacci, Valentina Russo, Maria De Santo, Marco D'Aurora, Liborio Stuppia, Barbara Barboni, Cesare Cammà, Valentina Gatta
Mitochondrial DNA (mtDNA) plays a key role in the development of a competent oocyte. In this study, the complete mtDNA sequence obtained for the first time by multiple displacement amplification approach in combination with next-generation sequencing from a single human oocyte is reported (GenBank accession no. KT364276). The analysis of oocyte mitochondrial mutations could provide a better understanding of the genetic variants correlated with the oocyte quality.
February 24, 2016: Mitochondrial DNA. Part A. DNA Mapping, Sequencing, and Analysis
Hansi Weissensteiner, Lukas Forer, Christian Fuchsberger, Bernd Schöpf, Anita Kloss-Brandstätter, Günther Specht, Florian Kronenberg, Sebastian Schönherr
Next generation sequencing (NGS) allows investigating mitochondrial DNA (mtDNA) characteristics such as heteroplasmy (i.e. intra-individual sequence variation) to a higher level of detail. While several pipelines for analyzing heteroplasmies exist, issues in usability, accuracy of results and interpreting final data limit their usage. Here we present mtDNA-Server, a scalable web server for the analysis of mtDNA studies of any size with a special focus on usability as well as reliable identification and quantification of heteroplasmic variants...
July 8, 2016: Nucleic Acids Research
Esita Chattopadhyay, Navonil De Sarkar, Richa Singh, Anindita Ray, Roshni Roy, Ranjan Rashmi Paul, Mousumi Pal, Sandip Ghose, Subhrendu Ghosh, Debajyoti Kabiraj, Raja Banerjee, Bidyut Roy
Several studies reported that mtDNA mutations may play important roles in carcinogenesis although the mechanism is not clear yet. Most of the studies compared mtDNA sequences in a tumor with those in normal tissues from different individuals ignoring inter-individual variations. In this study, 271 SNPs, 7 novel SNPs (or SNVs), and 15 somatic mutations were detected in mtDNA of 8 oral cancer tissues with respect to reference (rCRS) and adjacent normal tissues, respectively, using Ion PGM next generation sequencing method...
April 7, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Andrea Legati, Aurelio Reyes, Alessia Nasca, Federica Invernizzi, Eleonora Lamantea, Valeria Tiranti, Barbara Garavaglia, Costanza Lamperti, Anna Ardissone, Isabella Moroni, Alan Robinson, Daniele Ghezzi, Massimo Zeviani
Next Generation Sequencing (NGS) technologies are revolutionizing the diagnostic screening for rare disease entities, including primary mitochondrial disorders, particularly those caused by nuclear gene defects. NGS approaches are able to identify the causative gene defects in small families and even single individuals, unsuitable for investigation by traditional linkage analysis. These technologies are contributing to fill the gap between mitochondrial disease cases defined on the basis of clinical, neuroimaging and biochemical readouts, which still outnumber by approximately 50% the cases for which a molecular-genetic diagnosis is attained...
August 2016: Biochimica et Biophysica Acta
Andrea Mignarri, Anna Rubegni, Alessandra Tessa, Stefano Stefanucci, Alessandro Malandrini, Elena Cardaioli, Maria Chiara Meschini, Maria Laura Stromillo, Stefano Doccini, Antonio Federico, Filippo Maria Santorelli, Maria Teresa Dotti
Mutations in DDHD1 cause the SPG28 subtype of hereditary spastic paraplegia (HSP). Recent studies suggested that mitochondrial dysfunction occurs in SPG28. Here we describe two siblings with SPG28, and report evidence of mitochondrial impairment in skeletal muscle and skin fibroblasts. Patient 1 (Pt1) was a 35-year-old man with spastic paraparesis and urinary incontinence, while his 25-year-old brother (Pt2) had gait spasticity and motor axonal neuropathy. In these patients we identified the novel homozygous c...
March 15, 2016: Journal of the Neurological Sciences
Shengyu Ni, Mark Stoneking
BACKGROUND: Minor allele detection in very high coverage sequence data (>1000X) has many applications such as detecting mtDNA heteroplasmy, somatic mutations in cancer or tumors, SNP calling in pool sequencing, etc., where reads with low frequency are not necessarily sequence error but may instead convey biological information. However, the suitability of common base quality recalibration tools for such applications has not been investigated in detail. RESULTS: We show that the widely used tool GATK BaseRecalibration has several limitations in minor allele detection...
2016: BMC Genomics
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