A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort

2003 ◽  
Vol 31 (2) ◽  
pp. 444-446 ◽  
Author(s):  
B. Zhang ◽  
S. Ye ◽  
A.A. Sayer ◽  
S.R. Hammans ◽  
S. Adio ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Somatic Mutation ◽  
Large Scale ◽  
Nuclear Genome ◽  
Epidemiological Studies ◽  
Elderly Subjects ◽  
Long Pcr ◽  
Peripheral Lymphocytes ◽  
Wide Range

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

scholarly journals Mitochondrial DNA Methylation and Human Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4594
Author(s):  
Andrea Stoccoro ◽  
Fabio Coppedè
Keyword(s):  
Dna Methylation ◽  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Nuclear Dna ◽  
Epigenetic Modification ◽  
Nuclear Genome ◽  
Epigenetic Modifications ◽  
Human Diseases ◽  
Loop Region ◽  
D Loop

Epigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases.

scholarly journals Mitochondrial DNA polymorphism and cardiovascular continuum diseases

2018 ◽  
pp. 9-13
Author(s):  
М.В. Голубенко ◽  
Р.Р. Салахов ◽  
Т.В. Шумакова ◽  
С.В. Буйкин ◽  
О.А. Макеева ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cardiovascular Diseases ◽  
Mitochondrial Genome ◽  
Dna Polymorphism ◽  
Nuclear Genome ◽  
Published Data ◽  
Human Populations ◽  
Mitochondrial Dna Polymorphism ◽  
Polymorphism Level ◽  
Cardiovascular Continuum

Митохондриальный геном кодирует жизненно важные белки субъединиц дыхательной цепи и характеризуется высоким уровнем полиморфизма в популяциях человека. Однако работы по поиску генов предрасположенности к многофакторным заболеваниям, в том числе сердечно-сосудистым, часто ограничиваются анализом ядерного генома. В то же время показано, что отдельные генотипы мтДНК могут отличаться более высокой или низкой эффективностью окислительного фосфорилирования. Выявлены ассоциации популяционного полиморфизма мтДНК с сердечно-сосудистыми заболеваниями. Согласно результатам наших исследований, а также опубликованных другими авторами результатам ассоциативных и функциональных исследований, можно говорить о том, что эффект полиморфизма мтДНК проявляется чаще не в предрасположенности к сердечно-сосудистым заболеваниям в целом, а в риске развития осложнений и коморбидных фенотипов в пределах синтропии сердечно-сосудистого континуума. Mitochondrial genome, encoding respiratory chain subunits, is characterized by high polymorphism level in human populations. In most studies for susceptibility genes for common diseases, including cardiovascular diseases, the analysis is limited to the nuclear genome. It was shown that particular mtDNA genotypes may differ by oxidative phosphorylation efficiency. Some associations of mtDNA polymorphisms with cardiovascular diseases have been found. According to our results and published data, we suggest that mtDNA effect on cardiovascular system does not manifest in predisposition to cardiovascular diseases themselves but rather in risk of complications and comorbidities in the cardiovascular continuum.

scholarly journals Are the Somatic Mutation and Tissue Organization Field Theories of Carcinogenesis Incompatible?

2013 ◽  
Vol 12 ◽  
pp. CIN.S13013 ◽  
Author(s):  
Simon Rosenfeld
Keyword(s):  
Somatic Mutation ◽  
Large Scale ◽  
Control Cell ◽  
Tissue Level ◽  
Dna Mutations ◽  
Tissue Organization ◽  
Tissue Organization Field Theory ◽  
Wide Range ◽  
Carcinogenic Agents ◽  
Successful Resolution

Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT). The essence of SMT is that cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations, and that those mutations occur on genes which control cell proliferation and cell cycle. Thus, according to SMT, neoplastic lesions are the results of DNA-level events. Conversely, according to TOFT, carcinogenesis is primarily a problem of tissue organization: carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity. Hence, in TOFT the DNA mutations are the effect, and not the cause, of the tissue-level events. Cardinal importance of successful resolution of the TOFT versus SMT controversy dwells in the fact that, according to SMT, cancer is a unidirectional and mostly irreversible disease; whereas, according to TOFT, it is curable and reversible. In this paper, our goal is to outline a plausible scenario in which TOFT and SMT can be reconciled using the framework and concepts of the self-organized criticality (SOC), the principle proven to be extremely fruitful in a wide range of disciplines pertaining to natural phenomena, to biological communities, to large-scale social developments, to technological networks, and to many other subjects of research.

scholarly journals Identification of Mitochondrial DNA (NUMTs) in the Nuclear Genome of Daphnia Magna

2020 ◽  
Author(s):  
Krzysztof Kowal ◽  
Angelika Tkaczyk ◽  
Mariusz Pierzchała ◽  
Adam Bownik ◽  
Brygida Ślaska
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Daphnia Magna ◽  
Sequence Homology ◽  
Nuclear Genome ◽  
Complete Information ◽  
Trna Genes ◽  
Entire Genome ◽  
Mtdna Sequence ◽  
D Loop

Abstract Background: This is the first study in which the Daphnia magna (D. magna) nuclear genome deposited in the GenBank data-base was analyzed for pseudogene sequences of mitochondrial origin. The first complete information about the genome of D. magna was published by Lee et al. in 2019. To date, there is no information about pseudogenes localized in the genome of D. magna . The aim of the present study was to identify NUMTs, their length, homology, and location for potential use in evolutionary studies and to check whether their occurrence causes co-amplification during mitochondrial genome analyses.Results: Bioinformatic analysis showed 1909 fragments of the mitochondrial genome of D. magna , of which 1630 fragments were located in ten linkage groups (LG) of the nuclear genome (nDNA). The most frequently occurring fragments of the mtDNA sequence in the nuclear genome included ND2 (115), ND3 (113), and TRNA-CYS (110)). However, the highest number of NUMTs was observed for the D-loop (147). 253 fragments showed 100% homology (from 16 to 46 bp) with mtDNA gene sequences. The sequence homology for TRNA-MET was 100% for all 6 NUMTs (from 16 to 18 bp). The overall length of NUMTs in the nDNA was 44.391 bp (from 16 to 182 bp), which accounted for 0.042% of the entire genome.Conclusions: The best-matched NUMTs covering more than 90% of the mtDNA gene sequence have been identified for the TRNA-ARG (95%), TRNA-GLU (97%), and TRNA-THR (95%) genes, and they may be included in the functional nuclear tRNA genes. Using the product of total DNA isolation in mtDNA studies, coamplification of nDNA fragments is unlikely in the case of amplification of the whole tRNA genes as well as fragments of other genes and the D-loop with a length exceeding 200 bp. It was observed that TRNA-MET fragments had the highest level of sequence homology, which means that they could be evolutionarily the youngest. The lowest degree of homology was found in the pseudogene derived from the mtDNA D-loop sequence. It may probably be the oldest element of mitochondrial DNA incorporated into the nuclear genome; however, further analysis is necessary.

scholarly journals Novel Lines of Evidence for the Asymmetric Strand Displacement Model of Mitochondrial DNA Replication

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Chih-Lin Hsieh
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Nuclear Genome ◽  
Strand Displacement ◽  
Single Stranded Dna ◽  
Quantitative Evidence ◽  
Qualitative And Quantitative ◽  
Mtdna Replication ◽  
Displacement Model

ABSTRACT The mitochondrial genome, which consists of 16,569 bp of DNA with a cytosine-rich light (L) strand and a heavy (H) strand, exists as a multicopy closed circular genome within the mitochondrial matrix. The machinery for replication of the mammalian mitochondrial genome is distinct from that for replication of the nuclear genome. Three models have been proposed for mitochondrial DNA (mtDNA) replication, and one of the key differences among them is whether extensive single-stranded regions exist on the H strand. Here, three different methods that can detect single-stranded DNA (ssDNA) are utilized to identify the presence, location, and abundance of ssDNA on mtDNA. Importantly, none of these newly described methods involve the complication of prior mtDNA fractionation. The H strand was found to have extensive single-stranded regions with a profile consistent with the strand displacement model of mtDNA replication, whereas single strandedness was predominantly absent on the L strand. These findings are consistent with the in vivo occupancy of mitochondrial single-stranded DNA binding protein reported previously and provide strong new qualitative and quantitative evidence for the asymmetric strand displacement model of mtDNA replication.

scholarly journals Optimization of Analytical Parameters for Inferring Relationships among Escherichia coli Isolates from Repetitive-Element PCR by Maximizing Correspondence with Multilocus Sequence Typing Data

2006 ◽  
Vol 72 (9) ◽  
pp. 6049-6052 ◽  
Author(s):  
Tony L. Goldberg ◽  
Thomas R. Gillespie ◽  
Randall S. Singer
Keyword(s):  
Escherichia Coli ◽  
Multilocus Sequence Typing ◽  
Large Scale ◽  
Repetitive Element ◽  
Phylogenetic Analyses ◽  
Epidemiological Studies ◽  
Genetic Distances ◽  
Accurate Information ◽  
Data Types ◽  
Wide Range

ABSTRACT Repetitive-element PCR (rep-PCR) is a method for genotyping bacteria based on the selective amplification of repetitive genetic elements dispersed throughout bacterial chromosomes. The method has great potential for large-scale epidemiological studies because of its speed and simplicity; however, objective guidelines for inferring relationships among bacterial isolates from rep-PCR data are lacking. We used multilocus sequence typing (MLST) as a “gold standard” to optimize the analytical parameters for inferring relationships among Escherichia coli isolates from rep-PCR data. We chose 12 isolates from a large database to represent a wide range of pairwise genetic distances, based on the initial evaluation of their rep-PCR fingerprints. We conducted MLST with these same isolates and systematically varied the analytical parameters to maximize the correspondence between the relationships inferred from rep-PCR and those inferred from MLST. Methods that compared the shapes of densitometric profiles (“curve-based” methods) yielded consistently higher correspondence values between data types than did methods that calculated indices of similarity based on shared and different bands (maximum correspondences of 84.5% and 80.3%, respectively). Curve-based methods were also markedly more robust in accommodating variations in user-specified analytical parameter values than were “band-sharing coefficient” methods, and they enhanced the reproducibility of rep-PCR. Phylogenetic analyses of rep-PCR data yielded trees with high topological correspondence to trees based on MLST and high statistical support for major clades. These results indicate that rep-PCR yields accurate information for inferring relationships among E. coli isolates and that accuracy can be enhanced with the use of analytical methods that consider the shapes of densitometric profiles.

scholarly journals Mitochondrial sequences or Numts – By-catch differs between sequencing methods

2019 ◽  
Author(s):  
Hannes Becher ◽  
Richard A Nichols
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Nuclear Genome ◽  
Short Read ◽  
Ancestral Sequences ◽  
Mtdna Sequence ◽  
Long Read ◽  
Data Yield ◽  
By Catch ◽  
Numt Sequence

AbstractNuclear inserts derived from mitochondrial DNA (Numts) encode valuable information. Being mostly non-functional, and accumulating mutations more slowly than mitochondrial sequence, they act like molecular fossils – they preserve information on the ancestral sequences of the mitochondrial DNA. In addition, changes to the Numt sequence since their insertion into the nuclear genome carry information about the nuclear phylogeny. These attributes cannot be reliably exploited if Numt sequence is confused with the mitochondrial genome (mtDNA). The analysis of mtDNA would be similarly compromised by any confusion, for example producing misleading results in DNA barcoding that used mtDNA sequence. We propose a method to distinguish Numts from mtDNA, without the need for comprehensive assembly of the nuclear genome or the physical separation of organelles and nuclei. It exploits the different biases of long and short-read sequencing. We find that short-read data yield mainly mtDNA sequences, whereas long-read sequencing strongly enriches for Numt sequences. We demonstrate the method using genome-skimming (coverage < 1x) data obtained on Illumina short-read and PacBio long-read technology from DNA extracted from six grasshopper individuals. The mitochondrial genome sequences were assembled from the short-read data despite the presence of Numts. The PacBio data contained a much higher proportion of Numt reads (over 16-fold), making us caution against the use of long-read methods for studies using mitochondrial loci. We obtained two estimates of the genomic proportion of Numts. Finally, we introduce “tangle plots”, a way of visualising Numt structural rearrangements and comparing them between samples.

scholarly journals Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

2019 ◽  
Author(s):  
Emi Ogasawara ◽  
Shun Katada ◽  
Takayuki Mito ◽  
Jun-Ichi Hayashi ◽  
Kazuto Nakada
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Large Scale ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Pathogenic Mutation ◽  
Physiological Status ◽  
Trna Genes ◽  
Diabetic Mice

AbstractMarked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion (ΔmtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying ΔmtDNA, diabetic mice carrying ΔmtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of ΔmtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.Author SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.

scholarly journals Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor

2016 ◽  
Vol 113 (32) ◽  
pp. 9099-9104 ◽  
Author(s):  
Richard G. Hunter ◽  
Ma’ayan Seligsohn ◽  
Todd G. Rubin ◽  
Brian B. Griffiths ◽  
Yildirim Ozdemir ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Acute Stress ◽  
Nuclear Genome ◽  
Brain Mitochondria ◽  
Male Rats ◽  
Chip Sequencing ◽  
Corticosterone Treatment ◽  
Stress Dependent

Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria.

scholarly journals Mitochondrial Fostering: The Mitochondrial Genome May Play a Role in Plant Orphan Gene Evolution

2020 ◽  
Vol 11 ◽  
Author(s):  
Seth O’Conner ◽  
Ling Li
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Gene Evolution ◽  
Nuclear Genome ◽  
Bioinformatic Analysis ◽  
Land Plants ◽  
Mitochondrial Genomes ◽  
Recombination Rates ◽  
Orphan Genes ◽  
Orphan Gene

Plant mitochondrial genomes exhibit unique evolutionary patterns. They have a high rearrangement but low mutation rate, and a large size. Based on massive mitochondrial DNA transfers to the nucleus as well as the mitochondrial unique evolutionary traits, we propose a “Mitochondrial Fostering” theory where the organelle genome plays an integral role in the arrival and development of orphan genes (genes with no homologs in other lineages). Two approaches were used to test this theory: (1) bioinformatic analysis of nuclear mitochondrial DNA (Numts: mitochondrial originating DNA that migrated to the nucleus) at the genome level, and (2) bioinformatic analysis of particular orphan sequences present in both the mitochondrial genome and the nuclear genome of Arabidopsis thaliana. One study example is given about one orphan sequence that codes for two unique orphan genes: one in the mitochondrial genome and another one in the nuclear genome. DNA alignments show regions of this A. thaliana orphan sequence exist scattered throughout other land plant mitochondrial genomes. This is consistent with the high recombination rates of mitochondrial genomes in land plants. This may also enable the creation of novel coding sequences within the orphan loci, which can then be transferred to the nuclear genome and become exposed to new evolutionary pressures. Our study also reveals a high correlation between the amount of mitochondrial DNA transferred to the nuclear genome and the number of orphan genes in land plants. All the data suggests the mitochondrial genome may play a role in nuclear orphan gene evolution in land plants.

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