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PubMed2001

mtDNA disease in the primary care setting.

Disorders of mitochondrial DNA (mtDNA) may commonly present to primary care physicians but go undiagnosed. A 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss and a family history of diabetes mellitus and heart disease presented to our hospital without a unifying diagnosis. Physiologic, biochemical, and genetic testing revealed deficient aerobic metabolism, a defect in mitochondrial electron transport, and the presence of an A-to-G point mutation at position 3243 of the mitochondrial leucine-transfer RNA gene, establishing the diagnosis of mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome (MELAS). Diagnosing mtDNA disorders requires a careful integration of clinical signs and symptoms with pedigree analysis and multidisciplinary testing. Diagnosis is important to provide genetic counseling, avoid unnecessary evaluation, and facilitate therapy for symptomatic relief.

Adult↗

PubMed1999

Multiple origins of the mtDNA 9-bp deletion in populations of South India.

The origins and genetic affinities of the more than 500 tribal populations living in South Asia are widely disputed. This may reflect differential contributions that continental populations have made to tribal groups in South Asia. We assayed for the presence of the intergenic COII/tRNALys 9-bp deletion in human mtDNA in 646 individuals from 12 caste and 14 tribal populations of South India and compared them to individuals from Africa, Europe, and Asia. The 9-bp deletion is observed in four South Indian tribal populations, the Irula, Yanadi, Siddi, and Maria Gond, and in the Nicobarese. Length polymorphisms of the 9-bp motif are present in the Santal, Khonda Dora, and Jalari, all of whom live in a circumscribed region on the eastern Indian coast. Phylogenetic analyses of mtDNA control region sequence from individuals with the 9-bp deletion indicate that it has arisen independently in some Indian tribal populations. Other 9-bp deletion haplotypes are likely to be of Asian and African origin, implying multiple origins of the 9-bp deletion in South India. These results demonstrate varying genetic affinities of different South Indian tribes to continental populations and underscore the complex histories of the tribal populations living in South Asia.

Africa↗

PubMed2000

mtDNA lineage analyses: origins and migrations of Micronesians and Polynesians.

The islands of Micronesia and Polynesia collectively comprise the last major region of the globe to be settled by humans. Both of these groups of islands were colonized within the last 4,000 years by Austronesian-speaking agriculturists. Based on biogeographic and linguistic patterns, central-eastern Micronesia and Polynesia are included by many in a single category called Remote Oceania. Similarities of biologic, linguistic, and cultural traits within Remote Oceania highlight a question central to Oceanic studies: Are similarities among islands due to a common origin of isolated communities, to ongoing interactions among islands, or both? Analyses of mitochondrial DNA (mtDNA) sequences reveal that most remote Oceanic populations are polyphyletic. These polyphyletic populations violate the assumptions of many genetic distance and population demography models and so are problematic to interpret. The majority of mtDNA sequences from Micronesian and Polynesian populations are derived from Asia, whereas others are inferred to have originated in New Guinea. These data support an Island Southeast Asian origin and a colonization route along the north coast of New Guinea. The Marianas and Yap proper (main island) appear to have been independently settled directly from Island Southeast Asia, and both have received migrants from Central-Eastern Micronesia since then. Palau clearly demonstrates a complex prehistory including a significant influx of lineages from New Guinea. Thus genetic similarities among Micronesian and Polynesian populations result, in some cases, from a common origin, and in others, from extensive gene flow.

DNA, Mitochondrial↗

PubMed2001

mtDNA analysis of Leber hereditary optic neuropathy associated with spondyloepiphyseal dysplasia.

A patient was diagnosed in 1974 with the unique combination of Leber hereditary optic neuropathy (LHON) and spondyloepiphyseal dysplasia. The entire mitochondrial DNA (mtDNA) sequence from this patient was determined in order to identify candidate pathogenic mutations. The patient's mtDNA carried the LHON mutation at nucleotide 14484, thus elucidating the etiology of his optic neuropathy. We also identified another ND6 mutation at nucleotide 14420. This latter mutation is probably a clinically benign private polymorphism, although a pathogenic role in his skeletal abnormalities or in his optic neuropathy cannot yet be ruled out.

DNA Mutational Analysis↗

PubMed2002

Genetic relationship of Chinese ethnic populations revealed by mtDNA sequence diversity.

The origin and demographic history of the ethnic populations of China have not been clearly resolved. In this study, we examined the hypervariable segment I sequences (HVSI) of the mitochondrial DNA control region in 372 individuals from nine Chinese populations and one northern Thai population. A relatively high percentage of individuals was found to share sequences with those from other populations of the same ethnogenesis. In general, the populations of southern or Pai-Yuei tribal origin showed high haplotype diversity and nucleotide diversity compared with the populations of northern or Di-Qiang tribal origin. Mismatch distributions from these populations showed concordant features. All except the northern groups Nu, Lisu, Tibetan, and Mongolian showed typical signatures of ancient population expansions in the mismatch distributions and neutrality tests. Episodes of extreme size reduction in the past are one of the likely explanations for the absence of evidence of expansion in northern populations. Small sample sizes as well as samples from isolated subpopulations contributed to the bumpy mismatch distributions observed. Phylogenetic analysis and haplotype sharing among populations suggest that current mtDNA variation in these ethnic populations could reveal their ethnohistory to some extent, but in general, linguistic and geographic classifications of the populations did not agree well with classification by mtDNA variation.

Adult↗

PubMed2004

Early population differentiation in extinct aborigines from Tierra del Fuego-Patagonia: ancient mtDNA sequences and Y-chromosome STR characterization.

Ancient mtDNA was successfully recovered from 24 skeletal samples of a total of 60 ancient individuals from Patagonia-Tierra del Fuego, dated to 100-400 years BP, for which consistent amplifications and two-strand sequences were obtained. Y-chromosome STRs (DYS434, DYS437, DYS439, DYS393, DYS391, DYS390, DYS19, DYS389I, DYS389II, and DYS388) and the biallelic system DYS199 were also amplified, Y-STR alleles could be characterized in nine cases, with an average of 4.1 loci per sample correctly typed. In two samples of the same ethnic group (Aonikenk), an identical and complete eight-loci haplotype was recovered. The DYS199 biallelic system was used as a control of contamination by modern DNA and, along with DYS19, as a marker of American origin. The analysis of both mtDNA and Y-STRs revealed DNA from Amerindian ancestry. The observed polymorphisms are consistent with the hypothesis that the ancient Fuegians are close to populations from south-central Chile and Argentina, but their high nucleotide diversity and the frequency of single lineages strongly support early genetic differentiation of the Fuegians through combined processes of population bottleneck, isolation, and/or migration, followed by strong genetic drift. This suggests an early genetic diversification of the Fuegians right after their arrival at the southernmost extreme of South America.

Argentina↗

PubMed2005

Shipwrecks and founder effects: divergent demographic histories reflected in Caribbean mtDNA.

During the period of the Atlantic slave trade (15th-19th centuries), millions of people were forced to move from Africa to many American destinations, changing dramatically the human landscape of the Americas. Here, we analyze mitochondrial DNA from two different American populations with African ancestry, with hitherto unknown European and Native American components. On the basis of historical records, African-Americans from Chocó (Colombia) and the Garífunas (or "Black Carib") of Honduras are likely to have had very different demographic histories, with a significant founder effect in the formation of the latter. Both the common features and differences are reflected in their mtDNA composition. Both show a minor component (approximately 16%) from Native Central/South Americans and a larger component (approximately 84%) from sub-Saharan Africans. The latter component is very diverse in the African-Americans from Chocó, similar to that of sub-Saharan Africans, but much less so in the Garífunas, with several mtDNA types elevated to high frequency, suggesting the action of genetic drift.

Africa↗

PubMed2006

mtDNA microevolution in Southern Chile's archipelagos.

The genetic variability of four predominantly Indian populations of southern Chile's archipelagos was examined by determining the frequencies of four mitochondrial DNA haplogroups that characterize the American Indian populations. Over 90% of the individuals analyzed presented Native American mtDNA haplogroups. By means of an unweighted group pair method with arithmetic mean (UPGMA) dendrogram, a principal component analysis (PCA) derived from a distance matrix of mtDNA, and the exact test of population differentiation, we are able to prove the existence of a North-South cline. The populations in the northern part of the archipelagos are genetically similar to the Huilliche tribe, while the groups from the South are most closely related to the Fueguino tribe from the extreme South of Chile, and secondarily to the Pehuenche and Mapuche, who are found to the North and East of Chiloé archipelago. These results are consistent with a colonization of the southern archipelagos from Tierra del Fuego. We evaluate the evolutionary relationships of the population of the Chiloé area to groups from other geographic areas of Chile, using analysis of molecular variance (AMOVA). Three Amerindian clusters are identified: one formed by the Aymará and Atacameño, a second by the Huilliche, and a third including the Mapuche, Pehuenche, and Fueguino tribes, and the population inhabiting the South of the Chiloé arcipelago. These groups exhibit a North-South gradient in the frequency of haplogroup B, confirmed by F(ST) tests.

Chile↗

PubMed2006

mtDNA variation in Inuit populations of Greenland and Canada: migration history and population structure.

We examined 395 mtDNA control-region sequences from Greenlandic Inuit and Canadian Kitikmeot Inuit with the aim of shedding light on the migration history that underlies the present geographic patterns of genetic variation at this locus in the Arctic. In line with previous studies, we found that Inuit populations carry only sequences belonging to haplotype clusters A2 and D3. However, a comparison of Arctic populations from Siberia, Canada, and Greenland revealed considerable differences in the frequencies of these haplotypes. Moreover, large sample sizes and regional information about birthplaces of maternal grandmothers permitted the detection of notable differences in the distribution of haplotypes among subpopulations within Greenland. Our results cast doubt on the prevailing hypothesis that contemporary Inuit trace their all of their ancestry to so-called Thule groups that expanded from Alaska about 800-1,000 years ago. In particular, discrepancies in mutational divergence between the Inuit populations and their putative source mtDNA pool in Siberia/Alaska for the two predominant haplotype clusters, A2a and A2b, are more consistent with the possibility that expanding Thule groups encountered and interbred with existing Dorset populations in Canada and Greenland.

Canada↗

PubMed2002

The A8296G mtDNA mutation associated with several mitochondrial diseases does not cause mitochondrial dysfunction in cybrid cell lines.

Transmitochondrial cybrid cell lines homoplasmic for the A8296G mtDNA transition, a mutation associated with several mitochondrial diseases, have a normal oxidative phosphorylation function, as shown by oxygen consumption, lactate production, respiratory enzyme activities, and growth using galactose as the only source of energy. The synthesis of mitochondrial proteins is also similar in mutant and wild-type cybrids. Our results suggest that the A8296G mutation is a polymorphism and reinforce the necessity of performing functional studies to assess the pathogenicity of mtDNA mutations.

Adenine↗

PubMed1994

A new mtDNA mutation in the tRNA(Leu(UUR)) gene associated with maternally inherited cardiomyopathy.

We report a new mutation, a C to T transition at nt 3303 of mtDNA, in seven members of a family with cardiomyopathy and myopathy: the proband and two siblings had fatal infantile cardiomyopathy, whereas in three maternal relatives the disease manifested later in life as sudden cardiac death or as mitochondrial myopathy with cardiomyopathy. The mutation was homoplasmic in all tissues (including blood) from the proband and her brother, but heteroplasmic in blood from five oligosymptomatic or asymptomatic maternal relatives. This mutation disrupts a conserved base pair in the aminoacyl stem of the tRNA(Leu(UUR)). None of 70 controls carried the mutation. Our data indicate that this mutation is the genetic cause of the disorder in this family, and confirm that the tRNA(Leu(UUR)) is a "hot spot" for mutations in mtDNA.

Adolescent↗

PubMed2005

Aberrant heteroplasmic transmission of mtDNA in cloned pigs arising from double nuclear transfer.

Double nuclear transfer begins with the transfer of nuclear DNA from a donor cell into an enucleated recipient oocyte. This reconstructed oocyte is allowed to develop to the pronuclear stage, where the pronuclei are transferred into an enucleated zygote. This reconstructed zygote is then transferred to a surrogate sow. The genetic integrity of cloned offspring can be compromised by the transmission of mitochondrial DNA from the donor cell, the recipient oocyte and the recipient zygote. We have verified through the use of sequence analysis, restriction fragment length polymorphism analysis, allele specific PCR and primer extension polymorphism analysis that following double nuclear transfer the donor cell mtDNA is eliminated. However, it is likely that the recipient oocyte and zygote mitochondrial DNA are transmitted to the offspring, indicating bimaternal mitochondrial DNA transmission. This pattern of mtDNA inheritance is similar to that observed following cytoplasmic transfer and violates the strict unimaternal inheritance of mitochondrial DNA to offspring. This form of transmission raises concerns regarding the genetic integrity of cloned offspring and their uses in studies that require metabolic analysis or a stable genetic environment where only one variable is under analysis, such as in knockout technology.

Animals↗

PubMed1995

Accumulation of deletions in MtDNA during tissue aging: analysis by long PCR.

Multiple deletions of mtDNA have not only been implicated in aging, but also in a wide variety of pathological conditions. The enzyme system used in long-PCR makes it possible to synthesize the entire mitochondrial genome (16.5 kb), exposing the multiple deletions in mtDNAs implicated in and, at least partially, responsible for these pathologies. But it is not the number or type of anomalous mtDNA that is crucial, rather it is their frequency relative to the number of intact copies of the mitochondrial genome. Our work exposes the necessity of quantitating the number of normal mitochondrial DNAs. The accuracy of the technique and the small sample size required permit one to detect multiple deletions, located in a specific organ, and simultaneously measure the fraction of intact molecules. This fraction can then be correlated with mitochondrial dysfunction to serve both as an indicator of tissue aging and a monitor of an impending myopathy.

Aged↗

PubMed1997

Bcl-2 completely blocks Fas-mediated apoptosis in mtDNA-depleted HeLa cells.

Bcl-2 inhibits apoptosis induced by a variety of death stimuli but does not completely inhibit Fas-mediated apoptosis. We have previously shown that a HeLa-derived cell line lacking mitochondrial DNA (mtDNA) expresses Fas at a high level and apoptosis is easily induced using a low concentration of an anti-Fas antibody. In this study, overexpression of Bcl-2 in the mtDNA-less cells completely blocked Fas-mediated apoptosis, and this was not due to a depression of the enhanced Fas expression. These findings suggest that the Fas-mediated apoptotic pathway is directly linked to Bcl-2 protection in the cells with an accompanying mitochondrial dysfunction.

Antibodies↗

PubMed2000

Comparison of Y chromosome and mtDNA phylogenies leads to unique inferences of macaque evolutionary history.

We report here the results of one of the first analyses to use male-specific nuclear markers in elucidating primate phylogenetic relationships at the intrageneric level. Two closely linked Y chromosome markers, TSPY and SRY, were sequenced for a total of 3100 bases. Forty-four macaques, representing 18 of the 19 recognized species, were sequenced for the full 3.1 kb, as was 1 individual from each of the following outgroup genera: Papio, Theropithecus, Mandrillus, Allenopithecus,Cercopithecus, Trachypithecus, Presbytis, and Homo. In contrast to recent mtDNA phylogenies, Y chromosome loci support four monophyletic species groups, including a sinica group containing M. arctoides-a classification largely congruent with those of Fooden and Delson. Comparison of mtDNA and Y chromosome phylogenies highlight (1) a potential hybrid origin of Macaca arctoides from M. fascicularis and proto-M. assamensis/thibetana and (2) cases of mitochondrial paraphyly in macaque species whose Y chromosome lineages are monophyletic-a probable evolutionary consequence of philopatric females vs dispersing males. These results raise the question of whether a phylogenetic tree should be a topology of species origins or a depiction of more current species relationships, including subsequent episodes of introgression.

Animals↗

PubMed2002

Phylogeny and character evolution in the Empidonax group of tyrant flycatchers (Aves: Tyrannidae): a test of W. E. Lanyon's hypothesis using mtDNA sequences.

We sequenced mitochondrial DNA from four protein-coding genes for 26 taxa to test W. E. Lanyon's hypothesis of intergeneric relationships and character evolution in the Empidonax group of tyrant flycatchers. Three genera in this group (Empidonax, Contopus, and Sayornis) successfully occupy north temperate habitats for breeding, while the remaining genera (Mitrephanes, Cnemotriccus, Aphanotriccus, Lathrotriccus, and Xenotriccus) are restricted to neotropical latitudes. Lanyon hypothesized two major clades in the group based on differences in syringeal morphology and proposed relationships among genera using a combination of morphologic, behavioral, and allozymic characters. The mtDNA data strongly support Lanyon's division of genera into two clades. In addition, the molecular and nonmolecular data sets agree in uniting Aphanotriccus and Lathrotriccus as sister taxa, with Cnemotriccus as basal to these genera. Species of Aphanotriccus, Lathrotriccus, and Cnemotriccus form a clade that exploits a distinctive nesting niche relative to other members of the Empidonax group. Within the second major clade, mtDNA sequences support a reconstruction based on allozymes that places Contopus and Empidonax as sister taxa. This hypothesis contradicts that of Lanyon, who allied Contopus with Mitrephanes on the basis of similarity in foraging mode. Genera in the Empidonax group are members of a larger assemblage that radiated in South America. Occupancy of temperate habitats by certain genera in this group is coincident with their evolution of migratory behavior and with independent diversification in foraging modes that reduces potential competition in sympatry.

Cytochrome b Group↗

PubMed1994

A DNA-polymerase-related reading frame (pol-r) in the mtDNA of Secale cereale.

Mitochondrial (mt)DNA of Secale cereale contains an open reading frame (pol-r), the potential translation product of which shows significant homology to the type-B DNA polymerase encoded by the S1 plasmid of Zea mays; it contains the highly-conserved domains IIa to V of family B polymerases. The pol-r ORF is transcribed, as proven by RT-PCR, but the transcript is not edited. Upstream of the putative start codon a potential promoter motif was detected, fitting well into the postulated consensus sequence of the transcription initiation regions of Z. mays and Triticum aestivum. The pol-r ORF occurs in mtDNA of the fertile rye variety "Halo" and the cytoplasmic male-sterile (CMS) line "Pampa". Both ORFs are almost identical, apart from the 3' terminus; pol-r from Halo can code for 289 amino acids, pol-r from Pampa for 312 amino acids. Based on codon usage and the lack of editing, pol-r is considered to be a "young" gene, probably introduced in the mtDNA of rye by recombination with an mt plasmid.

Amino Acid Sequence↗

PubMed2006

De novo double mutation in PAX6 and mtDNA tRNA(Lys) associated with atypical aniridia and mitochondrial disease.

We report on the clinical, molecular and biochemical findings of a patient with the rare event (<4.02 x 10(-9) per generation) of coinciding de novo mutations in the nuclear PAX6 (c.1252-1267del16) and the mitochondrial mt.RNA (Lys) (8347A-->G) genes. The boy suffers from exercise intolerance, ptosis, nystagmus, macular hypoplasia and anterior segment abnormalities evocative of Axenfeld-Rieger anomaly. The PAX6 mutation is predicted to cause haploinsufficiency. The novel mt.RNA (Lys) mutation is located close to the classic myoclonic epilepsy with ragged-red-fibers mutation, but the patient exhibits neither myoclonic epilepsy nor ragged-red-fibers. The degree of mutant mtDNA heteroplasmy, as determined by a very accurate pyrosequencing assay, varies between 31% (muscle) and 38% (fibroblasts). We discuss a potential effect of the PAX6 mutation on the mtDNA mutation rate.

Adolescent↗