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PubMed2000

MtDNA substitution rate and segregation of heteroplasmy in coding and noncoding regions.

The mitochondrial DNA (mtDNA) substitution rate and segregation of heteroplasmy were studied for the non-coding control region (D-loop) and 500 bp of the coding region between nucleotide positions 5550 and 6050, by sequence analysis of blood samples from 194 individuals, representing 33 maternal lineages. No homoplasmic nucleotide substitutions were detected in a total of 292 transmissions. The estimated substitution rate per nucleotide per million years for the control region (micro>0.21, 95% CI 0-0.6) was not significantly different from that for the coding region (micro>0.54, 95% CI 0-1.0). Variation in the length of homopolymeric C streches was observed at three sites in the control region (positions 65, 309 and 16,189), all of which were in the heteroplasmic state. Segregation of heteroplasmic genotypes between generations was observed in several maternal pedigrees. At position 309, a longer poly C tract length was strongly associated with a higher probability for heteroplasmy and rapid segregation between generations. The length heteroplasmy at positions 65 and 16,189 was found at low frequency and was confined to a few families.

Alleles↗

PubMed1996

Geographic homogeneity and non-equilibrium patterns of mtDNA sequences in Tuscany, Italy.

The geographical distribution of 49 mtDNA sequences from 22 localities in Southern Tuscany, Italy, was studied by molecular analysis of variance, by a new spatial autocorrelation statistic specifically designed for sequence data and by reconstructing genealogies of haplotypes. All these methods indicated a high homogeneity of populations. Nevertheless, genetic variability showed significant departure from equilibrium expectations, in agreement with the predicted effects of a population expansion. We suggest that a past population expansion that was probably associated with a migrational wave and with local gene flow between localities prevented spatial structuring in Southern Tuscany.

Analysis of Variance↗

PubMed2005

Genetic history of some western Mediterranean human isolates through mtDNA HVR1 polymorphisms.

The existence of a genetic gradient across continents has often been highlighted. Comparisons among several genetic markers have suggested that most genes of current Europeans are descended from the Near East. During the Paleolithic period, populations were confined in refuges by the last glaciation. At the end of the Paleolithic period, European migrations began from these refuges. Our objective was to highlight these various flows, starting from well-defined isolated populations, originating mainly from western Mediterranean islands. We investigated polymorphisms in the hypervariable 1 (HVR1) zone of mitochondrial DNA (mtDNA) in many Mediterranean isolates: Andalusia, Balearic Islands, southern Corsica, Morocco, Sant' Antioco Island, San Pietro Island, Gallura, Nuoro and Trexenta (Sardinia) and Tuscany. We have compared our findings with those from other Mediterranean populations. Occupation of the Mediterranean area from the Middle East began in the Upper Paleolithic period around 40,000 years ago, with a population diversity determined by geographical and historical factors. Of the isolates studied, the population of the Balearic Islands show genetic characteristics correlated with various European flows initiated about 5,000 years ago. The island of San Pietro, in southwest Sardinia, still preserves the genetic traces of settlement by Ligurian migrants in 1736.

Base Sequence↗

PubMed2000

Combination of mtDNA mutations in a patient with a mitochondrial multisystem syndrome.

We report a patient who manifested a heterogeneous clinical presentation, including hypertrophic cardiomyopathy and hypothyroidism, with initially limited central nervous system involvement, and who harbored the mitochondrial (mt)DNA A3243G mutation. MtDNA analysis also revealed deleted genomes in muscle and blood. This atypical molecular combination may have influenced the clinical phenotype.

Amino Acid Substitution↗

PubMed2005

Introducing a novel human mtDNA mutation into the Paracoccus denitrificans COX I gene explains functional deficits in a patient.

We identified a novel mutation (S142F) in the human mtDNA CO I gene in a patient with a clinical phenotype resembling mitochondrial cardioencephalomyopathy. To substantiate pathogenicity, we modeled the identified mutation in the homologous gene in Paracoccus denitrificans and analyzed the biochemical consequences. We observed a deleterious effect on enzyme activity, with a lack of heme a3. Taking advantage of the extensive structural homology between the bacterial enzyme and the mammalian core complex, we conclude that the novel S142F mutation is disease-related. This approach can be used in other cases to support the pathogenicity of novel variants in the mitochondrial genome.

Adult↗

PubMed2006

Genetic relationship of Chinese and Japanese gamecocks revealed by mtDNA sequence variation.

Cockfighting has a very long history dating back to as early as 2500 years ago in China. Cockfighting was intertwined with human cultural traditions, helped disperse chickens across the world, and influenced the subsequent breed selection. Therefore, tracing the origin of gamecocks could mirror the distribution of the cockfighting culture. In this study, we compared the available mtDNA control region sequences in Chinese and Japanese gamecocks to test the recently proposed hypothesis behind the dual origin of the Japanese cockfighting culture (from China and Southeast Asia independently). We assigned gamecock mtDNAs to different matrilineal components (or phylogenetic clades) that emerged from the phylogenetic tree and network profile, and compared the frequency differences between Chinese and Japanese gamecocks. Among the six clades (A-F) identified, Japanese gamecocks were most frequently found in clades C and D (74%, 32/43), whereas more than half of the Chinese gamecock samples (69%, 35/51) were grouped in clades A and B. Haplotypes in Japanese gamecocks assigned to clades A, B, and E were either shared with those of the Chinese samples or differed from the close Chinese types by no more than a three-mutation distance. This genetic pattern is in accordance with the proposed dual origin of Japanese gamecocks but has left room for single origin of Japanese gamecocks from China. The genetic structure of gamecocks in China and Japan might also be influenced by subsequent breed selection and conservation after the initial gamecock introduction.

Animals↗

PubMed2005

mtDNA single macrodeletions associated with myopathies: absence of haplogroup-related increased risk.

As for any non-recombining genome, any mutation at mtDNA, if not recurrent, appears on a particular haplotype background, allowing its detection by haplogroup association studies. It has been shown that the propensity for occurrence of single macrodeletions at a level beyond the pathological threshold is associated with super-haplogroup U/K. However, in this report, we present evidence for the absence of preferential haplogroup backgrounds for single macrodeletions. We have analysed how haplogroup diagnostic polymorphisms could disrupt direct repeats usually flanking the deleted segment, and we have concluded that for the Common Deletion, no such polymorphisms are observed in humans, but they do occur in other primates. Furthermore, we also report five new single macrodeletions.

Adolescent↗

PubMed1986

Structure of a Cephalosporium acremonium mtDNA replicator.

We have investigated the ARS (autonomously replicating sequence) activity of a 1.94 kb mitochondrial DNA fragment of Cephalosporium acremonium and found that several subfragments of this piece of mtDNA conferred the ARS phenotype. The nucleotide sequence of the fragment shows: (i) a high A + T content (72.5%); (ii) a perfect consensus ARS sequence (ATTTATATTTA) in the subfragment with the highest ARS activity; (iii) a large number of ARS consensus-related sequences in the other subfragments, even in one lacking ARS activity; (iv) several potential hairpin structures. One of them contains the perfect consensus ARS sequence.

Acremonium↗

PubMed1996

Leber's hereditary optic neuropathy with the 11 778 mtDNA mutation and white matter disease resembling multiple sclerosis: clinical, MRI and MRS findings.

A mother and her son are reported who suffer from Leber's hereditary optic neuropathy (LHON) with the 11778 mtDNA mutation. In both subjects additional clinical and paraclinical evidence of a cerebral demyelinating disease was found. This combination has been reported incidentally in females, rarely in males. Magnetic resonance imaging and proton spectroscopy findings are reported. These findings are compatible with multiple sclerosis.

Adult↗

PubMed1985

Anomalous electrophoretic mobility of mouse mtDNA restriction fragments.

Analysis of the electrophoretic mobilities of mouse mtDNA restriction fragments revealed a high incidence of anomalous migration in polyacrylamide slab gels. Relative to the mobility predicted by the sequence, 6 of 29 200- to 700-bp fragments had deviations of 5-12%. Three of these fragments migrated more slowly than predicted while three were faster. There was little, if any, correlation between electrophoretic mobility and base composition. The anomalous restriction fragments mapped throughout the mitochondrial genome.

Animals↗

PubMed1995

Modelling the effects of age-related mtDNA mutation accumulation; complex I deficiency, superoxide and cell death.

Deleterious mitochondrial mutations accumulate during normal human aging in postmitotic tissues. How these mutations affect aging cells is currently unknown. This issue has been addressed in two ways. The first is to determine the likeliest effect of random mutations in the mitochondrial genome, and of the 4977 bp deletion and MELAS point mutation that rise in frequency with age. The results indicate that Complex I is statistically much more likely to be affected than any other product of the mitochondrial genome. We have also attempted to model Complex I deficiency in animals with the drug MPTP, a specific inhibitor of Complex I. We find that MPTP causes massive damage in brains of mice with a genetic deficiency in the mitochondrial superoxide dismutase, MnSOD, but less in mice that overexpress the enzyme. We conclude from these data that MPTP-induced cell death must be mediated through an increase in the steady-state concentration of superoxide anion in mitochondria. Since the likeliest target of mitochondrial mutation is Complex I, deficiency of which causes MnSOD-inhibitable lethality, we propose that rising mtDNA mutations with age will cause an increase in superoxide-mediated cell death. Such a mechanism for age-related cell death has the potential to explain several age-related phenotypes.

Aging↗

PubMed1992

The evolutionary history of the sinica-group of macaque monkeys as revealed by mtDNA restriction site analysis.

We estimated the phylogenetic relationships of mitochondrial DNA haplotypes within the sinica-group of macaques, which includes Macaca sinica, M. radiata, M. thibetana, M. assamensis, and possibly M. arctoides. Some effort was made to detect intraspecific variation by sampling individuals from different parts of the species' range or from different matrilines. In the case of M. assamensis, individuals were sampled from both subspecies (M. assamensis assamensis and M. assamensis pelops). Total genomic DNA was extracted from blood samples and cut with a battery of 16 restriction endonucleases. A total of 97 restriction sites were mapped for these enzymes in the sinica-group and M. nemestrina, which was used as an outgroup. Phylogenetic trees constructed by both the maximum parsimony method and the neighbor-joining method were highly congruent. A bootstrap analysis of the maximum parsimony tree indicated a high degree of confidence to the association of particular haplotypes within the 80% majority rule consensus tree. An exhaustive search of all possible trees also supported this topology, although one haplotype had to be eliminated from this analysis to save computer time. The results were also unaffected by weighting the character state changes in favor of site gains over site losses. The mtDNA phylogeny produced here differs from trees based on morphology and allozymes in three ways: M. sinica and M. radiata sit in two different branches of the tree; the two subspecies of M. assamensis are separated from one another; and M. arctoides consistently fell outside the rest of the sinica-group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

The 7472insC mtDNA mutation impairs 5' and 3' processing of tRNA(Ser(UCN)).

The deafness-associated 7472insC mtDNA mutation was previously shown to decrease the steady-state level of tRNA(Ser(UCN)) post-transcriptionally. To identify the affected tRNA maturation step(s) we analysed the effects of the mutation on processing in vivo and in vitro. tRNA(Ser(UCN)) from cybrid cells homoplasmic for 7472insC contained a high frequency (>11%) of molecules misprocessed at one or both termini. In vitro assays using partially purified HeLa cell RNase P and mitochondrial tRNA 3' processing endonuclease (tRNase Z) confirmed that the efficiency of both 5' and 3' processing was impaired. A mutant precursor not already processed at the 5' end was poorly processed in vitro by tRNase Z. Misprocessing at the 3' end further impaired the efficiency and accuracy of 5' processing of the mutant substrate. The mutation thus appears to affect several distinct, but interdependent, RNA processing steps, with the predicted outcome dependent on the exact processing pathway operating in vivo.

5' Untranslated Regions↗

PubMed2005

A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family.

Leber's hereditary optic neuropathy (LHON) is a frequent cause of inherited blindness. A routine screening for common mtDNA mutations constitutes an important first in its diagnosis. However, a substantial number of LHON patients do not harbor known variants, both pointing to the genetic heterogeneity of LHON and bringing into question its genetic diagnosis. We report a familial case that exhibited typical features of LHON but lacked any of the common mutations. Genetic analysis revealed a novel pathogenic defect in the ND6 gene at 14279A that was not detected in any haplogroup-matched controls screened for it, nor has it been previously reported. This mutation causes a substantial conformational change in the secondary structure of the polypeptide matrix coil and may explain the LHON expression. Thus, it expands the spectrum of deleterious changes affecting ND6-encoding subunit and further highlights the functional significance of this gene, providing additional clues to the disease pathogenesis.

Adolescent↗

PubMed2005

Application of ES cells for generation of respiration-deficient mice carrying mtDNA with a large-scale deletion.

In a previous study, we used mouse zygotes as recipients of mtDNA with a large-scale deletion mutation (DeltamtDNA) and generated respiration-deficient mice (mito-mice) carrying DeltamtDNA. In this study, we used mouse ES cells as recipients of DeltamtDNA, and generated mito-mice with DeltamtDNA only when the ES cells carried 17% DeltamtDNA. No chimera mice or their F(1) progenies were obtained from ES cells carrying more than 61% DeltamtDNA. These observations suggest that respiratory defects of ES cells inhibit their normal differentiation into chimera mice and mito-mice, and that ES cells are more effective than zygotes for generation of mito-mice carrying mtDNAs without significant pathogenic mutations.

Animals↗

PubMed2006

High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients.

For identifying mutation(s) that are potentially pathogenic it is essential to determine the entire mitochondrial DNA (mtDNA) sequences from patients suffering from a particular mitochondrial disease, such as Leber hereditary optic neuropathy (LHON). However, such sequencing efforts can, in the worst case, be riddled with errors by imposing phantom mutations or misreporting variant nucleotides, and moreover, by inadvertently regarding some mutations as novel and pathogenic, which are actually known to define minor haplogroups. Under such circumstances it remains unclear whether the disease-associated mutations would have been determined adequately. Here, we re-analyse four problematic LHON studies and propose guidelines by which some of the pitfalls could be avoided.

Artifacts↗

PubMed2006

Complete mitochondrial genome of Chinese big-headed turtle, Platysternon megacephalum, with a novel gene organization in vertebrate mtDNA.

The mitochondrial genome of the Chinese big-headed turtle, Platysternon megacephalum, was obtained using polymerase chain reaction (PCR). The entire mtDNA sequence, the longest mitochondrial genome in turtles reported so far, is 19161 bp. This mitochondrial genome exhibits a novel gene order, which greatly differs from that of any other vertebrates. It is characterized by four distinctive features: 1) the translocation of a gene cluster including three tRNA genes (tRNAHis, tRNASer, tRNALeu(CUN)) and ND5 gene, 2) two tRNAThr pseudogenes, 3) a duplication of pseudo tRNAThr/tRNAPro/D-loop region and 4) 3 non-coding spacers. These unique identities represent a new mitogenomic gene order in vertebrates. The TDRL model was proposed to account for the generation of the gene order in P. megacephalum.

Animals↗

PubMed2005

Congenital or late-onset myopathy in patients with the T14709C mtDNA mutation.

Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis.

Cysteine↗