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PubMed1995

Introgression of Luxilus cornutus mtDNA into allopatric populations of Luxilus chrysocephalus (Teleostei: Cyprinidae) in Missouri and Arkansas.

The cyprinid fishes Luxilus cornutus and Luxilus chrysocephalus hybridize extensively in a zone extending through the Great Lakes region with extensive introgression of L. cornutus mtDNA occurring in populations of L. chrysocephalus south of the present hybrid zone in Ohio. Western populations of these two species occur adjacent to one another in Missouri but hybridization has never been observed. In order to determine if hybridization has occurred historically in Missouri, allopatric populations of L. chrysocephalus were analysed for mtDNA introgression. Extensive introgression of L. cornutus mtDNA was observed in most populations of L. chrysocephalus in Missouri resulting in the elimination of L. chrysocephalus mtDNA in many populations. Luxilus cornutus mtDNA in L. chrysocephalus is found approximately 300 km south of extant L. cornutus populations in Missouri. Luxilus chrysocephalus mtDNA was replaced by four unique L. cornutus mtDNA haplotypes, with one particular haplotype becoming fixed in several L. chrysocephalus populations. The pattern of introgression suggests that historically L. cornutus occupied a more southern distribution in Missouri bringing it into contact with western populations of L. chrysocephalus and resulting in a hybrid zone.

Animals↗
PubMed2004

Most of the extant mtDNA boundaries in south and southwest Asia were likely shaped during the initial settlement of Eurasia by anatomically modern humans.

BACKGROUND: Recent advances in the understanding of the maternal and paternal heritage of south and southwest Asian populations have highlighted their role in the colonization of Eurasia by anatomically modern humans. Further understanding requires a deeper insight into the topology of the branches of the Indian mtDNA phylogenetic tree, which should be contextualized within the phylogeography of the neighboring regional mtDNA variation. Accordingly, we have analyzed mtDNA control and coding region variation in 796 Indian (including both tribal and caste populations from different parts of India) and 436 Iranian mtDNAs. The results were integrated and analyzed together with published data from South, Southeast Asia and West Eurasia. RESULTS: Four new Indian-specific haplogroup M sub-clades were defined. These, in combination with two previously described haplogroups, encompass approximately one third of the haplogroup M mtDNAs in India. Their phylogeography and spread among different linguistic phyla and social strata was investigated in detail. Furthermore, the analysis of the Iranian mtDNA pool revealed patterns of limited reciprocal gene flow between Iran and the Indian sub-continent and allowed the identification of different assemblies of shared mtDNA sub-clades. CONCLUSIONS: Since the initial peopling of South and West Asia by anatomically modern humans, when this region may well have provided the initial settlers who colonized much of the rest of Eurasia, the gene flow in and out of India of the maternally transmitted mtDNA has been surprisingly limited. Specifically, our analysis of the mtDNA haplogroups, which are shared between Indian and Iranian populations and exhibit coalescence ages corresponding to around the early Upper Paleolithic, indicates that they are present in India largely as Indian-specific sub-lineages. In contrast, other ancient Indian-specific variants of M and R are very rare outside the sub-continent.

Asia↗
PubMed1997

Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease.

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients' tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3-24.3 in a Finnish family and one on 3p 14.1-21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.

Adult↗
PubMed1999

Nonrandom tissue distribution of mutant mtDNA.

Heteroplasmic mitochondrial DNA (mtDNA) defects are an important cause of inherited human disease. On a cellular level, the percentage of mutant mtDNA is the principal factor behind the expression of the genetic defect. Marked variation in the level of mutant mtDNA among tissues is thought to be responsible for the diverse clinical phenotypes associated with the same pathogenic mtDNA mutation. This study was designed to determine whether the percentage level of a pathogenic mtDNA molecule is determined by a purely random process. The tissue distribution of the A3243G MELAS point mutation was analyzed in five individuals who were members of a family with maternally inherited diabetes and deafness. The level of mutant mtDNA was measured in four tissues in three individuals and three tissues in two individuals. The highest level of mutant mtDNA occurred in skeletal muscle, followed by hair follicles, and then buccal mucosa, with the lowest levels in blood (leucocyte/platelet fraction). The probability of observing any strict hierarchy in family is 4.82 x 10(-5). These results indicate that the distribution of the A3243G mutation is not solely determined by random processes.

Adult↗
PubMed2000

[The role of mtDNA deletion in the sensitivity to aminoglycoside antibiotic induced deafness].

OBJECTIVE: To establish an animal model of mitochondrial DNA (mtDNA) deletion and investigate the possible role of mtDNA deletion in aminoglycoside antibiotic induced deafness. METHODS: Thirty wistar rats (4 months) were randomly divided into group A and B. Doxorubicin (DOX) was subcutaneously injected at doses of 2 mg/kg twice per week for 3 months in group A and then kanamycin (KM) was intraperitoneally injected 500 mg/kg per day for 10 consecutive days. The treatments of group B were identical to group A, except normal saline was substituted for DOX. The thresholds of auditory brainstem response (ABR) were measured before and after the drug administrations. The inner ear membranous labyrinthine tissue was harvested and mtDNA was amplified to identify 4,834 bp deletion by PCR technique. RESULTS: The elevation of the mean ABR thresholds in group A(67.08 +/- 8.59) dB peSPL was significantly higher than that in group B (12.71 +/- 4.42) dB peSPL after KM administration (P < 0.001). In group A, 9 of the 15 rats demonstrated 4,834 bp mtDNA deletion. However, mtDNA 4,834 bp deletion was negative in group B animals. CONCLUSION: DOX can induce mtDNA deletion in the inner ear tissue of the rat. mtDNA deletion in the inner ear may play an important role in the hypersensitivity to aminoglycoside antibiotic ototoxicity.

Animals↗
PubMed2004

[mtDNA mutations in mouse tumors].

OBJECTIVE: To investigate variations of mtDNA in mouse tumors and to explore the relationship between mtDNA mutations and murine carcinogenesis. METHODS: Variations of D-loop, ND3 and tRNAIle + Glu + Met gene fragments of mtDNA from six mouse tumor cell lines were analyzed by PCR-RFLP and PCR-SSCP techniques. RESULTS: ND3 and tRNAIle + Glu + Met gene fragments of mtDNA from the tumors showed no variations at 27 endonuclease sites. The D-loop of mtDNA from Hca-F demonstrated an additional endonuclease site of Hinf I in contrast to the inbred mouse. Upon PCR-SSCP analysis, the D-loop of mtDNA was found to possess mutations in 4 of 6 tumors. CONCLUSION: D-loop appears to be the hot spot for tumor mtDNA mutations, which may contribute to the carcinogenesis of murine tumors.

Animals↗
PubMed1997

High proportions of mtDNA duplications in patients with Kearns-Sayre syndrome occur in the heart.

Kearns-Sayre syndrome (KSS) is a sporadic multisystem mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, onset before age 20, and severe cardiac conduction defects that can lead to death. KSS patients harbor partial deletions of mitochondrial DNA (delta-mtDNA), sometimes associated with the corresponding mtDNA duplication (dup-mtDNA). As reports on the distribution of dup-mtDNAs among KSS tissues are scarce, we searched for the presence of dup-mtDNAs in different autopsy tissues of two such patients, one of whom carried the so-called "common deletion." Using a newly developed long polymerase chain reaction (PCR) protocol in conjunction with Southern blot analyses, we found dup-mtDNAs in most of the examined tissues from both patients. The proportion of dup-mtDNA in these tissues was much lower than the proportion of delta-mtDNA, with one notable exception: in both patients, we found an unusually high level of dup-mtDNA in the heart. These data suggest that dup-mtDNAs may be more stable in heart tissue of KSS patients than in other long-lived postmitotic tissues.

Adolescent↗
PubMed2000

Single-fiber PCR in MELAS(3243) patients: correlations between intratissue distribution and phenotypic expression of the mtDNA(A3243G) genotype.

We performed morphological, biochemical, and genetic studies, including single-fiber PCR (sf PCR), on muscle biopsies obtained from a mother and daughter with MELAS syndrome due to the A3243G transition of mitochondrial DNA (mtDNA). The severity of muscle involvement appeared quite distinct, in spite of the fact that both patients segregated similar mutant mtDNA levels on total muscle DNA. The daughter did not show any clinical muscle involvement: muscle biopsy revealed many ragged red fibers (RRFs) mostly positive for cytochrome-c oxidase (COX) activity. In contrast, her mother had developed a generalized myopathy without progressive external ophthalmoplegia (PEO), morphologically characterized by many COX-negative RRFs. Single-muscle fiber PCR demonstrated in both patients significantly higher percentages of wild-type mtDNA in normal fibers (daughter: 23.25 +/- 15.22; mother: 43.13 +/- 26.11) than in COX-positive RRFs (daughter: 11.25 +/- 5.22, P < 0.005; mother: 9.12 +/- 5.9, P < 0.001) and in COX-negative RRFs (daughter: 8.9 +/- 4.2, P < 0.001 mother: 4.8 +/- 2.8, P < 0.001). Wild-type mtDNA levels resulted higher also in COX-positive vs. COX-negative RRFs (daughter: P < 0.05; mother: P < 0.001). Our data confirm a direct correlation between A3243G levels and impairment of COX function at the single-muscle fiber level. Moreover, the evidence of a clinical myopathy in the patient with higher amounts of COX-negative RRFs bolsters the concept that a differential distribution of mutant mtDNAs at the cellular level may have effects on the clinical involvement of individual tissues. However, the occurrence of a similar morphological and biochemical muscle phenotype also in PEO(3243) patients suggests that other genetic factors involved in the interaction between mitochondrial and nuclear DNA, rather than the stochastic distribution of mtDNA genomes during embryogenesis, are primarily implicated in determining the various clinical expressions of the A3243G of mtDNA.

Adolescent↗
PubMed1996

Mutant mtDNA at 1555 A to G in 12S rRNA gene and hypersusceptibility of mitochondrial translation to streptomycin can be co-transferred to rho 0 HeLa cells.

Human skin fibroblast line 95-119, which had been isolated from the mother of a Japanese patient with aminoglycoside-induced deafness and a 1555 A to G mutation at 12S rRNA gene in mitochondrial DNA (mtDNA), was used to investigate the relationship between the 1555 mtDNA mutation and its pathogenicity. By the intercellular transfer of mtDNA with or without the 1555 mutation to mtDNA-less (rho 0) HeLa cells, we isolated cybrid clones and found that the mitochondrial translation in a cybrid clone repopulated with the homoplasmic 1555 mutation showed the highest susceptibility to streptomycin. These observations suggest that the genotype of the mutant mtDNA and the phenotype of hypersusceptibility to streptomycin observed in 95-119 fibroblasts were co-transferred simultaneously to rho 0 HeLa cells, supporting the idea that the homoplasmic 1555 mtDNA mutation is involved in the pathogenesis leading to aminoglycoside-induced hearing loss.

Aminoglycosides↗
PubMed1993

Comparison between the complete mtDNA sequences of the blue and the fin whale, two species that can hybridize in nature.

The sequence of the mitochondrial DNA (mtDNA) molecule of the blue whale (Balaenoptera musculus) was determined. The molecule is 16,402 bp long and its organization conforms with that of other eutherian mammals. The molecule was compared with the mtDNA of the congeneric fin whale (B. physalus). It was recently documented that the two species can hybridize and that male offspring are infertile whereas female offspring may be fertile. The present comparison made it possible to determine the degree of mtDNA difference that occurs between two species that are not completely separated by hybridization incompatibility. The difference between the complete mtDNA sequences was 7.4%. Lengths of peptide coding genes were the same in both species. Except for a small portion of the control region, disruption in alignment was usually limited to insertion/deletion of a single nucleotide. Nucleotide differences between peptide coding genes ranged from 7.1 to 10.5%, and difference at the inferred amino acid level was 0.0-7.9%. In the rRNA genes the mean transition difference was 3.8%. This figure is similar in degree to the difference (3.4%) between the 12S rRNA gene of humans and the chimpanzee. The mtDNA differences between the two whale species, involving both peptide coding and rRNA genes, suggest an evolutionary separation of > or = 5 million years. Although hybridization between more distantly related mammalian species may not be excluded, it is probable that the blue and fin whales are nearly as different in their mtDNA sequences as hybridizing mammal species may be.

Adenosine Triphosphatases↗
PubMed1992

Tissue segregation of a heteroplasmic mtDNA mutation in MERRF (myoclonic epilepsy with ragged red fibers) encephalomyopathy.

The distribution of the causal 8344A-->G mtDNA mutation has been examined in six tissues of a patient with myoclonic epilepsy with ragged red fibers (MERRF), to study the developmental genetics of this type of mitochondrial disorder, and to determine the pathophysiological importance of the mtDNA heteroplasmy generally observed in such patients. Heteroplasmy of the mtDNA was observed in all six tissues (cerebellum, cerebrum, pancreas, liver, muscle, and heart) suggesting that, whereas the mtDNA mutation is relatively new, the mutated population must have existed before the formation of the three primary embryonic layers. The tissue distribution reveals significant variations in the ratio between the mutated and the normal mtDNA species, indicating the randomness of mtDNA segregation during developmental cell division and differentiation events. The result suggests the existence of tissue-specific nuclear factor(s) that determines the expression of the 8344A-->G mutation in various tissues; in MERRF syndrome, expression is mainly in the central nervous system.

Adult↗
PubMed2006

Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing.

Analysis of mtDNA variation using Sanger sequencing does not allow accurate quantification of the components of mtDNA mixtures. An alternative method to determine the specific mixture ratios in samples displaying hetero-plasma, consisting of DNA contributions from several individuals, or containing contamination would therefore be valuable. A novel quantification system for mtDNA mixture analysis has been developed based on pyrosequencing technology, in which the linear relationship between incorporated nucleotides and released light allows quantification of the components of a sample. Within five polymerase chain reaction fragments, seven variable positions in the mtDNA control and coding region were evaluated using this quantification analysis. For all single nucleotide polymorphisms quantified in this study, a linear relationship was observed between the measured and expected mixture ratios. This mtDNA quantification assay is an easy to use, fast and accurate quantification system, with the ability to resolve and interpret major and minor mtDNA components in forensic mixture samples.

DNA Fingerprinting↗
PubMed2002

The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted form of blindness caused by mitochondrial DNA (mtDNA) mutations. Approximately 90% of LHON cases are caused by 3460A, 11778A, or 14484C mtDNA mutations. These are designated "primary" mutations because they impart a high risk for LHON expression. Although the 11778A and 14484C mutations unequivocally predispose carriers to LHON, they are preferentially associated with mtDNA haplogroup J, one of nine Western Eurasian mtDNA lineages, suggesting a synergistic and deleterious interaction between these LHON mutations and haplogroup J polymorphism(s). We report here the characterization of a new primary LHON mutation in the mtDNA ND4L gene at nucleotide pair 10663. The homoplasmic 10663C mutation has been found in three independent LHON patients who lack a known primary mutation and all of which belong to haplogroup J. This mutation has not been found in a large number of haplotype-matched or non-haplogroup-J control mtDNAs. Phylogenetic analysis with primarily complete mtDNA sequence data demonstrates that the 10663C mutation has arisen at least three independent times in haplogroup J, indicating that it is not a rare lineage-specific polymorphism. Analysis of complex I function in patient lymphoblasts and transmitochondrial cybrids has revealed a partial complex I defect similar in magnitude to the 14484C mutation. Thus, the 10663C mutation appears to be a new primary LHON mutation that is pathogenic when co-occurring with haplogroup J. These results strongly support a role for haplogroup J in the expression of certain LHON mutations.

Amino Acid Sequence↗
PubMed2006

Interpretation of mtDNA RFLP variability among Aspergillus tubingensis isolates.

Aspergillus tubingensis isolates collected from distant geographic areas were earlier classified into six groups on the basis of the mtDNA RFLP variability they exhibited (mtDNA types 2a-2f). In the present work, we investigated the reason for the intraspecific mtDNA variability and we describe here how this fungus, with a relatively small mitochondrial genome, can display intraspecific polymorphism due to intron acquisition and also sporadic point mutations affecting the recognition motifs of the restriction enzymes employed in the RFLP analysis. Three different LAGLI-DADG type group I introns were identified in the cox1 gene amongst the six mtDNA RFLP types. MtDNAs of types 2b and 2d contain all of the three introns, mtDNA of type 2f carries only one, and the other mtDNA types contain two introns each. Comparative analysis showed that the first and second introns of mtDNAs of types 2b and 2d are well distributed among fungi, indicating their active horizontal transfer capacity. The third intron occurs rarely among fungi and is restricted to a limited number of fungal species, namely to A. tubingensis and the yeast Candida stellata. It is interesting that this intron is present in a small mitochondrial genome such as that of A. tubingensis and, considering its rarity, its presence amongst black Aspergillus isolates is recommended to be considered as a tool to establish taxonomical unit(s) or to track down evolutionary divergence of closely related taxonomical units.

Aspergillus↗
PubMed1995

Altered properties of mitochondrial ATP-synthase in patients with a T-->G mutation in the ATPase 6 (subunit a) gene at position 8993 of mtDNA.

A family is described with a T-->G mutation at position 8993 of mtDNA. This mutation is located in the ATPase 6 gene of mtDNA which encodes subunit a of the ATP-synthase complex (FlFo-ATPase). Clinically, the patients showed severe infantile lactate acidosis and encephalomyopathy in a form that was different from the classical Leigh syndrome. In 3 affected boys, ranging in age from 3 months to 8 years, the mutation was found in 95-99% of the mtDNA population. The clinical symptoms correlated with the mtDNA heteroplasmy and in the healthy mother 50% of the mtDNA was mutated. The rate of mitochondrial ATP production by cultured skin fibroblasts containing 99% of mutated mtDNA was about 2-fold lower than that in normal fibroblasts. Native electrophoresis of the mitochondrial enzyme complexes revealed instability of the FlFo-ATPase in all the tissues of the patient that were investigated (heart, muscle, kidney, liver). Only a small portion of the ATP-synthase complex was present in the complete, intact form (620 kDa). Incomplete forms of the enzyme were present as subcomplexes with approx. molecular weights of 460, 390 and 150 kDa, respectively, which differed in the content of F1 and Fo subunits. Immunochemical analysis of the subunits of the FlFo-ATPase further revealed a markedly decreased content of the Fo subunit b in mitochondria from muscle and heart, and an increased content of the Fo subunit c in muscle mitochondria, respectively. These results indicate that in this family the T-->G point mutation at position 8993 in the mitochondrial ATPase 6 gene is accompanied by structural instability and altered assembly of the enzyme complex, that are both most likely due to changes in the properties of subunit a of the membrane sector part of the ATP-synthase.

Acidosis, Lactic↗
PubMed2006

mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese.

Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL.

Aminoglycosides↗
PubMed2006

Concomitant replacement of language and mtDNA in South Caspian populations of Iran.

The Gilaki and Mazandarani occupy the South Caspian region of Iran and speak languages belonging to the North-Western branch of Iranian languages . It has been suggested that their ancestors came from the Caucasus region, perhaps displacing an earlier group in the South Caspian . Linguistic evidence supports this scenario, in that the Gilaki and Mazandarani languages (but not other Iranian languages) share certain typological features with Caucasian languages . We analyzed patterns of mtDNA and Y chromosome variation in the Gilaki and Mazandarani. Based on mtDNA HV1 sequences, the Gilaki and Mazandarani most closely resemble their geographic and linguistic neighbors, namely other Iranian groups. However, their Y chromosome types most closely resemble those found in groups from the South Caucasus. A scenario that explains these differences is a south Caucasian origin for the ancestors of the Gilaki and Mazandarani, followed by introgression of women (but not men) from local Iranian groups, possibly because of patrilocality. Given that both mtDNA and language are maternally transmitted, the incorporation of local Iranian women would have resulted in the concomitant replacement of the ancestral Caucasian language and mtDNA types of the Gilaki and Mazandarani with their current Iranian language and mtDNA types. Concomitant replacement of language and mtDNA may be a more general phenomenon than previously recognized.

Chromosomes, Human, Y↗
PubMed2005

MtDNA point mutations are associated with deletion mutations in aged rat.

The age-dependent accumulation of point mutations in the control region of human mtDNA has been suggested to contribute to aging processes. We investigated whether mtDNA point mutations accumulate to detectable levels in this region of mtDNA from aged Fischer 344 X Brown Norway F(1) hybrid rats. The control region and a portion of the major arc region (nucleotides 4386-7707) of the mtDNA were PCR-amplified and directly sequenced from microdissected single cardiomyocytes and single skeletal muscle fibers of 36-month old rats. Point mutations were not observed in these regions of the full-length mtDNA. Point mutations were, however, associated with deletion mutations, especially in cardiac cells. Approximately 40% of the deletion mutations identified in heart contained a point mutation, whereas only 1.9% of deletion mutations in skeletal muscle contained a point mutation. Point mutations were located adjacent to the deletion breakpoints and each point mutation was unique. In aged rats, point mutations are clonally expanded only when associated with deletion events suggesting that there are important differences between rats and humans in the mechanisms that cause mtDNA abnormalities.

Aging↗