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PubMed1993

Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures.

We report on the variant phenotypic expression of mitochondrial genotypes in cultured skin fibroblasts and Epstein-Barr virus-transformed lymphocyte cultures from a patient with Pearson syndrome (McKusick no. 260560). Both cell types harbored a heteroplasmic population of normal and deleted mtDNA molecules. The deletion encompassed five tRNA genes and seven genes encoding subunits of cytochrome c oxidase, complex I, and ATPase. Patient skin fibroblasts and lymphocytes harbored 60 and 80% of deleted mtDNA molecules, respectively, and initially displayed defective respiratory chain activities. In both cases, there was a progressive recovery of respiratory chain activities during in vitro cell proliferation. In cultured skin fibroblasts, the loss of the deleted mtDNA molecules accounted for the recovery of normal respiratory chain activities. These features were prevented by allowing respiratory chain-deficient cells to grow in the presence of uridine (200 microM). In Epstein-Barr virus-transformed lymphocytes containing 60% of deleted mtDNA, the recovery of respiratory chain activities was attributable to an increase in the mtRNA translation efficiency rather than to an increased content in mtDNA or mtRNA. The present study suggests that the variant cellular responses to abnormal mitochondrial genotypes might contribute to the tissue-specific expression of mitochondrial disorders in vivo.

Cell Line, Transformed↗
PubMed2004

Genetic structure of Hmong-Mien speaking populations in East Asia as revealed by mtDNA lineages.

Hmong-Mien (H-M) is a major language family in East Asia, and its speakers distribute primarily in southern China and Southeast Asia. To date, genetic studies on H-M speaking populations are virtually absent in the literature. In this report, we present the results of an analysis of genetic variations in the mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS1) region and diagnostic variants in the coding regions in 537 individuals sampled from 17 H-M populations across East Asia. The analysis showed that the haplogroups that are predominant in southern East Asia, including B, R9, N9a, and M7, account for 63% (ranging from 45% to 90%) of mtDNAs in H-M populations. Furthermore, analysis of molecular variance (AMOVA), phylogenetic tree analysis, and principal component (PC) analysis demonstrate closer relatedness between H-M and other southern East Asians, suggesting a general southern origin of maternal lineages in the H-M populations. The estimated ages of the mtDNA lineages that are specific to H-M coincide with those based on archeological cultures that have been associated with H-M. Analysis of genetic distance and phylogenetic tree indicated some extent of difference between the Hmong and the Mien populations. Together with the higher frequency of north-dominating lineages observed in the Hmong people, our results indicate that the Hmong populations had experienced more contact with the northern East Asians, a finding consistent with historical evidence. Moreover, our data defined some new (sub-)haplogroups (A6, B4e, B4f, C5, F1a1, F1a1a, and R9c), which will direct further efforts to improve the phylogeny of East Asian mtDNAs.

Asia, Southeastern↗
PubMed2003

A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress.

We have previously reported a changed mitochondrial (mt) gene expression in brain from patients with schizophrenia [Schizophr. Res. 14 (1995) 203]; now, we describe the distribution in the mtDNA from lymphocytes of a heteroplasmic sequence variation that was originally found in the mtDNA from the postmortem brain of a patient with schizophrenia. The variant is m.12027T>C and results in the change from isoleucine to threonine at position 423 of the ND4 subunit of NADH-ubiquinone reductase. Using a PCR-RFLP method, we have determined the heteroplasmy as the ratio of variant to total (variant ratio) at m.12027 in 184 controls and 181 patients with schizophrenia as well as 24 postmortem brain samples. The distribution of variants is bimodal having peaks at variant ratios of 0.262 and 0.732. The variant-rich fraction is very significantly associated with schizophrenia in males (47%), while there is only 18% in control males. There are significantly more variant-rich control females (36%) than control males (18%), suggesting that the female population is less sensitive to the presence of a variant in terms of liability to schizophrenia. In variant-rich samples from postmortem brain originating from both sexes, there is an increased superoxide production, suggesting that the variation contributes to oxidative stress. Antioxidant glycosides, such as quercetin rutoside, quench the superoxide production without (in contrast to neuroleptic drugs) interfering with the electron transfer activity of the reductase.

Adult↗
PubMed2004

Linear versus circular mitochondrial genomes: intraspecies variability of mitochondrial genome architecture in Candida parapsilosis.

The yeast species Candida parapsilosis, an opportunistic pathogen, exhibits genetic and genomic heterogeneity. To assess the polymorphism at the level of mitochondrial DNA (mtDNA), the organization of the mitochondrial genome in strains belonging to the three variant groups of this species was investigated. Although these analyses revealed a group-specific restriction fragment pattern of mtDNA, strains belonging to different groups appear to have similar genes in the same gene order. An extensive survey of C. parapsilosis isolates uncovered surprising alterations in the molecular architecture of their mitochondrial genome. A screening strategy for strains harbouring mtDNA with rearranged architecture showed that nearly all strains from groups I and III possess linear mtDNA molecules terminating with arrays of tandem repeat units, while most of the group II strains have a circular mitochondrial genome. In addition, it was found that linear genophores in mitochondria of strains from different groups differ in the sequence of the mitochondrial telomeric repeat unit. The occurrence of altered forms of mtDNA among C. parapsilosis strains opens up the unique possibility to address questions concerning the evolutionary origin and replication strategy of linear and circular genomes in mitochondria.

Candida↗
PubMed1999

Interspecies transfer of female mitochondrial DNA is coupled with role-reversals and departure from neutrality in the mussel Mytilus trossulus.

Mussels of the genus Mytilus have distinct and highly diverged male and female mitochondrial DNA (mtDNA) genomes with separate routes of inheritance. Previous studies of European populations of Mytilus trossulus demonstrated that 33% of males are heteroplasmic for a second mtDNA genome of increased length and that hybridization with Mytilus edulis does not block mtDNA introgression, in contrast to reports for American populations. Here, we demonstrate that the female mtDNA type of M. edulis has replaced the resident female mtDNA type of European M. trossulus. This is supported by COIII sequence data indicating that the female mtDNA of European M. trossulus is very similar to that of M. edulis and that in phylogenetic trees, the mtDNAs of these two species cluster together but separately from American M. trossulus sequences, the latter not being disturbed by introgressive hybridization. We also provide evidence that the mtDNA genome of increased length found in heteroplasmic males of European M. trossulus derives from a recent partition of an introgressed M. edulis female type into the male route of transmission. Neutrality tests reveal that European populations of M. trossulus display an excess of replacement polymorphism within the female mtDNA type with respect to conspecific American populations, as well as a significant excess of rare variants, of a similar magnitude to those previously reported for the invading European M. edulis mtDNA. Results are consistent with a nearly neutral model of molecular evolution and suggest that selection acting on European M. trossulus mtDNA is largely independent of the nuclear genetic background.

Americas↗
PubMed2006

Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients.

PURPOSE: Oxidative phosphorylation is under dual genetic control of the nuclear and the mitochondrial DNA (mtDNA). Oxidative phosphorylation disorders are clinically and genetically heterogeneous, which makes it difficult to determine the genetic defect, and symptom-based protocols which link clinical symptoms directly to a specific gene or mtDNA mutation are falling short. Moreover, approximately 25% of the pediatric patients with oxidative phosphorylation disorders is estimated to have mutations in the mtDNA and a standard screening approach for common mutations and deletions will only explain part of these cases. Therefore, we tested a new CHIP-based screening method for the mtDNA. METHODS: MitoChip (Affymetrix) resequencing was performed on three test samples and on 28 patient samples. RESULTS: Call rates were 94% on average and heteroplasmy detection levels varied from 5-50%. A genetic diagnosis can be made in almost one-quarter of the patients at a potential output of 8 complete mtDNA sequences every 4 days. Moreover, a number of potentially pathogenic unclassified variants (UV) were detected. CONCLUSIONS: The availability of long-range PCR protocols and the predominance of single nucleotide substitutions in the mtDNA make the resequencing CHIP a very fast and reliable method to screen the complete mtDNA for mutations.

Child↗
PubMed2002

Rapid screening mitochondrial DNA mutation by using denaturing high-performance liquid chromatography.

AIM: To optimize conditions of DHPLC and analyze the effectiveness of various DNA polymerases on DHPLC resolution, and evaluate the sensitivity of DHPLC in the mutation screening of mitochondrial DNA (mtDNA). METHODS: Two fragments of 16s gene of mitochondrial DNA (one of them F2 is a mutant fragment) and an A3243G mutated fragment were used to analyze the UV detection limit and determine the minimum percentage of mutant PCR products for DHPLC and evaluate effects of DNA polymerases on resolution of DHPLC. Under the optimal conditions, we analyzed the mtDNA mutations from muscle tissues of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and screened blindly for variances in D-loop region of mtDNA from human gastric tumor specimen. RESULTS: Ten A3243G variants were detected in 12 cases of MELAS, no alterations were detected in controls and these results were consistent with the results obtained by analysis of RFLP with ApaI. We also identified 26 D-loop variances in 46 cases of human gastric cancer tissues and 38 alterations in 13 gastric cancer cell lines. The mutation of mtDNA at 80 ng PCR products containing a minimum of 5% mutant sequences could be detected by using DHPLC with UV detector. Moreover, Ampli-Taq Gold polymerase was equally as good as the proofreading DNA polymerase (e.g., Pfu) in eliminating the false positive produced by Taq DNA polymerases. CONCLUSION: DHPLC is a powerful, rapid and sensitive mutation screening method for mtDNA. Proofreading DNA polymerase is more suitable for DHPLC analysis than Taq polymerase.

Case-Control Studies↗
PubMed1995

[Polymorphism of mitochondrial DNA region V in native and migrant inhabitants of Northeast Asia].

Data on polymorphism of the V region of mitochondrial DNA (mtDNA) in eastern Slavs from Magadan (N = 108), Asian Eskimos (N = 21), and coastal Chukchi (N = 10) are presented. The region V insertion-deletion polymorphism was shown to be absent in the samples of native and immigrant population of northeastern Asia. The Hae III-Ava II restriction polymorphism of the 8249-8254 bp part of this mtDNA region was found only in eastern Slavs. In them, the variant Hae III(-)/Ava II(+) and the novel type of polymorphism Hae III(-)/Ava II(-) were recorded at frequencies 2.8% and 1.85%, respectively. The low level of diversity of mtDNA types in Arctic populations of the world is discussed. A hypothesis is advanced that the low level of mtDNA diversity in Arctic population of humans is determined by several factors. These include an initially low number of mtDNA types in forming ancestral populations, genetic drift, isolation, and continuous adaptation of the populations. The latter is associated with selection of genotypes optimal for living in the extreme climatic and geographic conditions of the North; some of these genotypes control a low level of free oxygen radicals in the cell.

Adaptation, Physiological↗
PubMed1997

Postglacial genetic differentiation of reproductive ecotypes of kokanee Oncorhynchus nerka in Okanagan Lake, British Columbia.

Okanagan Lake, south-central interior of BC, contains two reproductive ecotypes of kokanee Oncorhynchus nerka; individuals spawn in tributary streams ('stream-spawners') as well as on shoreline gravel areas ('beach-spawners'). We tested the hypothesis that these sympatric ecotypes comprise a single panmictic population by assaying variation in morphological traits and at allozyme, mitochondrial and minisatellite DNA loci in fish collected from three stream-spawning and two beach-spawning sites. No morphological traits consistently distinguished the reproductive ecotypes with the exception of the number of anal fin rays which was greater in stream-spawning kokanee. Four of 18 allozyme loci screened were polymorphic, but no significant allele frequency differences were detected among populations within ecotypes or between ecotypes. Similarly, allele frequencies at two minisatellite DNA loci were not significantly different among populations or between ecotypes. By contrast, significant differences in the frequencies of mitochondrial DNA restriction fragment length polymorphism (mtDNA RFLP) haplo-types were detected between stream- and beach-spawners, but not among populations within ecotypes. Further, two RFLPs that distinguished stream- and beach-spawning adults were found in juvenile kokanee sampled from the limnetic zone of Okanagan Lake. The two mtDNA RFLPs and a d-loop sequence variant appear to be unique to Okanagan Lake Kokanee because we did not observe these haplotypes in sockeye salmon and kokanee sampled outside of Okanagan Lake. Our data suggest that: (i) there is restricted female-mediated gene flow between stream- and beach-spawning kokanee in Okanagan Lake, (ii) the forms have diverged within the lake basin since the retreat of the Wisconsinian glaciers (< approximately equal to 11 000 years ago), and (iii) distinct reproductive niches may promote divergence in north temperate freshwater fish faunas.

Animals↗
PubMed2002

Population genetics of shortnose sturgeon Acipenser brevirostrum based on mitochondrial DNA control region sequences.

Shortnose sturgeon is an anadromous North American acipenserid that since 1973 has been designated as federally endangered in US waters. Historically, shortnose sturgeon occurred in as many as 19 rivers from the St. John River, NB, to the St. Johns River, FL, and these populations ranged in census size from 10(1) to 10(4), but little is known of their population structure or levels of gene flow. We used the polymerase chain reaction (PCR) and direct sequence analysis of a 440 bp portion of the mitochondrial DNA (mtDNA) control region to address these issues and to compare haplotype diversity with population size. Twenty-nine mtDNA nucleotide-substitution haplotypes were revealed among 275 specimens from 11 rivers and estuaries. Additionally, mtDNA length variation (6 haplotypes) and heteroplasmy (2-5 haplotypes for some individuals) were found. Significant genetic differentiation (P < 0.05) of mtDNA nucleotide-substitution haplotypes and length-variant haplotypes was observed among populations from all rivers and estuaries surveyed with the exception of the Delaware River and Chesapeake Bay collections. Significant haplotype differentiation was even observed between samples from two rivers (Kennebec and Androscoggin) within the Kennebec River drainage. The absence of haplotype frequency differences between samples from the Delaware River and Chesapeake Bay reflects a probable current absence of spawning within the Chesapeake Bay system and immigration of fish from the adjoining Delaware River. Haplotypic diversity indices ranged between 0.817 and 0.641; no relationship (P > 0.05) was found between haplotype diversity and census size. Gene flow estimates among populations were often low (< 2.0), but were generally higher at the latitudinal extremes of their distribution. A moderate level of haplotype diversity and a high percentage (37.9%) of haplotypes unique to the northern, once-glaciated region suggests that northern populations survived the Pleistocene in a northern refugium. Analysis of molecular variance best supported a five-region hierarchical grouping of populations, but our results indicate that in almost all cases populations of shortnose sturgeon should be managed as separate units.

Animals↗
PubMed1997

Neuromyelitis optica (Devic's syndrome): no association with the primary mitochondrial DNA mutations found in Leber hereditary optic neuropathy.

Devic's neuromyelitis optica is a rare syndrome characterised by the combination of acute or subacute optic neuritis and transverse myelitis, in some cases considered to be a variant of multiple sclerosis. Mutations of mitochondrial DNA (mtDNA) associated with Leber hereditary optic neuropathy (LHON) have been identified in some patients with multiple sclerosis in whom optic neuritis is a prominent early feature. Using restriction enzyme digestion of mtDNA products amplified by the polymerase chain reaction, the primary LHON mtDNA mutations at positions 3460 bp, 11,778 bp, and 14,484 bp have been excluded in four women with Devic's neuromyelitis optica. A mutation at 4160 bp associated in some LHON families with more widespread neurological disease was also not detected. It is concluded that the primary mtDNA mutations currently associated with LHON are not responsible for the prominence of optic nerve disease in Devic's neuromyelitis optica.

Adult↗
PubMed1991

Population variation of human mtDNA control region sequences detected by enzymatic amplification and sequence-specific oligonucleotide probes.

A method for detecting sequence variation of hypervariable segments of the mtDNA control region was developed. The technique uses hybridization of sequence-specific oligonucleotide (SSO) probes to DNA sequences that have been amplified by PCR. The nucleotide sequences of the two hypervariable segments of the mtDNA control region from 52 individuals were determined; these sequences were then used to define nine regions suitable for SSO typing. A total of 23 SSO probes were used to detect sequence variants at these nine regions in 525 individuals from five ethnic groups (African, Asian, Caucasian, Japanese, and Mexican). The SSO typing revealed an enormous amount of variability, with 274 mtDNA types observed among these 525 individuals and with diversity values, for each population, exceeding .95. For each of the nine mtDNA regions significant differences in the frequencies of sequence variants were observed between these five populations. The mtDNA SSO-typing system was successfully applied to a case involving individual identification of skeletal remains; the probability of a random match was approximately 0.7%. The potential useful applications of this mtDNA SSO-typing system thus include the analysis of individual identity as well as population genetic studies.

Base Sequence↗
PubMedDate not supplied

[Cytoplasmic male sterility-associated structural variation of the mitochondrial genome regions containing rps3 and orf215 in sugar beet Beta vulgaris L].

Several 5'-degenerate primers were selected by computer analysis and used for mtDNA typing in sugar beet cultivars with cytoplasms of the S (typical for cytoplasmic male sterility) or N (normal) type. A number of N- or S-specific markers were found to correspond to transcribed mitochondrial genes. One was from the orf215 region of the N-type mtDNA. A physical map of the corresponding region was constructed for the S-type mtDNA, and a substantial difference observed for the two genome types. One N-specific marker proved to contain a rearranged rps3 region and a truncated atp9 copy. With the known nucleotide sequence of this marker, three-primer PCR was designed and showed that both variants of the rps3 region simultaneously take place in the mtDNA pool, the new one occurring in a substochiometric proportion.

Base Sequence↗
PubMed1983

Assignment of a polymorphic polypeptide to the human mitochondrial DNA unidentified reading frame 3 gene by a new peptide mapping strategy.

A new method of peptide analysis is presented which allows assignment of unknown proteins to coding regions of genomes which have been sequenced. This approach involves comparison of the molecular weights of peptides generated by partial proteolytic digestion with those predicted for a protein whose primary amino acid sequence is deduced from a corresponding nucleotide sequence. The proteolytic digestions are accomplished in situ in the stacking gel of a two-dimensional polyacrylamide gel system. We have used this system to show that two variant proteins of the human mitochondrial DNA, MV-1 and MV-2, are allelic and encoded by the unidentified reading frame 3 (URF 3) gene. This assignment was supported by sequence analysis of a clone of this mtDNA region from a HeLa cell line which expresses the uncommon variant MV-2. Four nucleotide changes were found in HeLa URF 3, relative to the reported sequence from human placenta. Two of these changes alter the primary amino acid sequence of the encoded protein. It is proposed that one of those amino acid changes may account for the observed molecular weight variation in MV-1 and MV-2 by proteolytic cleavage, conformational change, or secondary modification. We have used this method to also assign a mitochondrially translated protein to URF 6. These are the first assignments of mitochondrially synthesized polypeptides to human URF genes and prove conclusively that at least some of these genes are expressed in human cells.

Amino Acid Sequence↗
PubMed2006

Profiling of length heteroplasmies in the human mitochondrial DNA control regions from blood cells in the Korean population.

The length heteroplasmies in the hypervariable (HV) regions of mitochondrial DNA (mtDNA) from blood cells were examined in 57 healthy Korean donors. Interestingly, all the healthy Korean subjects displayed length heteroplasmies in both the HV1 and HV2 regions. Closer examination of the HV2 length heteroplasmies indicated that most of these donors (84%) exhibited a minimal 303-315 homopolymeric C (poly-C) tract frameshift of 1 bp (mixture of one major and minor mtDNA type). Sixteen percent of the donors however had poly-C tract frameshifts of 2 bp or more. The donor group with major length variants (two or more frameshifts) had about a two-fold decrease in mtDNA copy number compared with the group exhibiting only a 1 bp frameshift. This result supports the possibility that a severe frameshift in the 303-315 poly-C tract may also cause the impairment of mtDNA replication in hematopoietic tissue.

Adolescent↗
PubMed2006

An enhanced MITOMAP with a global mtDNA mutational phylogeny.

The MITOMAP (http://www.mitomap.org) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial DNA (mtDNA) phylogenetic tree of approximately 3000 mtDNA coding region sequences plus expanded pathogenic mutation tables and a nuclear-mtDNA pseudogene (NUMT) data base. The phylogeny reconstructs the entire mutational history of the human mtDNA, thus defining the mtDNA haplogroups and differentiating ancient from recent mtDNA mutations. Pathogenic mutations are classified by both genotype and phenotype, and the NUMT sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis. These additions position MITOMAP for the implementation of our automated mtDNA sequence analysis system, Mitomaster.

DNA, Mitochondrial↗
PubMed2001

Barth's syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation).

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.

3-Hydroxybutyric Acid↗
PubMed2006

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

Adenine Nucleotide Translocator 1↗