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African Y chromosome and mtDNA divergence provides insight into the history of click languages.

BACKGROUND: About 30 languages of southern Africa, spoken by Khwe and San, are characterized by a repertoire of click consonants and phonetic accompaniments. The Jumid R:'hoansi (!Kung) San carry multiple deeply coalescing gene lineages. The deep genetic diversity of the San parallels the diversity among the languages they speak. Intriguingly, the language of the Hadzabe of eastern Africa, although not closely related to any other language, shares click consonants and accompaniments with languages of Khwe and San. RESULTS: We present original Y chromosome and mtDNA variation of Hadzabe and other ethnic groups of Tanzania and Y chromosome variation of San and peoples of the central African forests: Biaka, Mbuti, and Lisongo. In the context of comparable published data for other African populations, analyses of each of these independently inherited DNA segments indicate that click-speaking Hadzabe and Jumid R:'hoansi are separated by genetic distance as great or greater than that between any other pair of African populations. Phylogenetic tree topology indicates a basal separation of the ancient ancestors of these click-speaking peoples. That genetic divergence does not appear to be the result of recent gene flow from neighboring groups. CONCLUSIONS: The deep genetic divergence among click-speaking peoples of Africa and mounting linguistic evidence suggest that click consonants date to early in the history of modern humans. At least two explanations remain viable. Clicks may have persisted for tens of thousands of years, independently in multiple populations, as a neutral trait. Alternatively, clicks may have been retained, because they confer an advantage during hunting in certain environments.

Africa, Eastern↗

Diversification of sympatric Sapromyza (Diptera: Lauxaniidae) from Madeira: six morphological species but only four mtDNA lineages.

A series of recent studies on speciation of insects within the Canary Islands have indicated considerable within-island diversification, similar to that described in the Hawaiian islands. Little work has yet been carried out on the neighboring Madeiran archipelago, which is also volcanic. This study examines relationships among all known Lauxaniid flies of the genus Sapromyza from Madeira (including six newly described morphological species) based on mitochondrial gene trees constructed from cytochrome c oxidase (subunit I) and 16S rRNA partial sequences. Phylogenies based on maximum likelihood distances, a Bayesian method based on Markov chain Monte Carlo sampling from the posterior probability distribution, and maximum parsimony show that eight of the nine Madeiran species comprise a single monophyletic group. This clade is also split into two subclades representing black- and yellow/orange-bodied forms. The latter mtDNA clade corresponds to only two species (Sapromyza imitans and Sapromyza indigena) which are not reciprocally monophyletic. Monophyly is strongly supported within four of the six black-bodied species but not for the species pair (Sapromyza inconspicua, Sapromyza laurisilvae). We discuss the double occurrence (at least) of introgressive hybridization/incomplete lineage sorting within this group and suggest that recent speciation is the most likely explanation. The remaining species on the island, Sapromyza madeirensis, is very divergent from the aforementioned group, occupying a more basal position in the tree than the other Atlantic island and continental Sapromyza that were included in the analysis. At least two speciation events for Madeiran Sapromyza appear to correspond to quite ancient periods relative to the age of the island, while others are more recent. This suggests that a combination of island colonization and within-island sympatric and/or vicariance-mediated speciation may explain the observed diversity.

Animals↗

Macroevolutionary relationships of species of Drosophila melanogaster group based on mtDNA sequences.

The phylogenetic relationships among the Drosophila melanogaster group species were analyzed using approximately 1700 nucleotide-long sequences of the mitochondrial DNA. Phylogenetic analysis was performed using this region consisting of a part of the cytochrome b (cytb) coding gene, the entire coding sequences of tRNA-Leu, tRNA-Ser and the first subunit of NADH dehydrogenase (NADH1), and a part of the 16S-rRNA gene. The study of these sequences showed that this region of mtDNA is very invariable, as regards with the type of the genes that it contains, as well as the order that they are located on it. The resulting phylogenetic trees reveal a topology that separates the species into three main ancestral lines, leading to the following subgroups: (a) ananassae subgroup, (b) montium subgroup, and (c) melanogaster and Oriental subgroups. The inferred topology complements and generally agrees with previously proposed classifications based on morphological and molecular data.

Animals↗

Restriction fragment analysis as a source of error in detection of heteroplasmic mtDNA mutations.

The transition from A to G at nt 5656 (5656A-->G) in mitochondrial DNA has been suggested to be a pathogenic mutation and, furthermore, a heteroplasmic one. We found that the mutation was present in 14 out of 83 healthy controls from northern Finland and that 5656A-->G was exclusively associated with mtDNA haplogroup U. Interestingly, 5656A-->G appeared to be heteroplasmic in NheI digestion of PCR fragments that were amplified by using a mismatched oligonucleotide primer creating a digestion site in the presence of the mutant variant. However, we did not detect the wild type genome in clones from such a sample and subsequent experiments revealed that the apparent heteroplasmy was due to inhibition of NheI by NaCl. Our results suggest that 5656A-->G is a polymorphism and it may be highly characteristic for Finns. Furthermore, new heteroplasmic mutations identified by restriction fragment analysis should be adequately controlled for any false positive results that may be due to incomplete digestion.

DNA↗

Mitochondrial Endonuclease G function in apoptosis and mtDNA metabolism: a historical perspective.

All mitochondria contain a single, major Mg2+-dependent nuclease capable of extensively degrading DNA and RNA in vitro. This nuclease activity and its gene now go by the name Endonuclease G. For many years, however, a number of different names for this mitochondrial nuclease have been used. This can lead to great deal of confusion for anyone searching the literature. The name Endonuclease G had originally been assigned to an endonuclease activity identified in nuclear extracts of chicken erythrocytes that was found to specifically nick within guanine (G) tracts in DNA in vitro. Subsequent studies however, established that this Endonuclease G activity was identical to the well known, major endonuclease activity isolated from mitochondria of several species. In addition, studies of the mammalian mitochondrial endonuclease showed that the endonuclease is not restricted to only attacking guanine tracts, although it does so avidly. The enzyme is also capable of avidly nicking within cytosine tracts, and at a large variety of sites, that fragments duplex DNA extensively. Despite this, the name Endonuclease G persists. One purpose of this review is to summarize the history of Endonuclease G that spans some 40 years, and review what we have learned about the enzyme's biochemical and biologic properties. Endonuclease G likely serves a role in repair and/or degradation of damaged mtDNA in vivo. Recently, genetic and biochemical evidence has emerged that Endonuclease G is released from the inter membrane space during early stages of programmed cell death, and translocates to the nucleus where it presumably facilitates degradation of chromatin. This exciting new potential role for the enzyme in apoptotic cell death will be discussed.

Journal Article↗

In vitro culture and mtDNA fate of ibex-rabbit nuclear transfer embryos.

Rabbit oocyte can be used as the recipient in interspecies somatic cell nuclear transfer (iSCNT). This work was undertaken in order to study the developmental competence of Capra ibex somatic cells reprogrammed by rabbit oocytes and the fate of mitochondria in iSCNT embryos. Metaphase II (MII) oocytes from superovulated rabbit were used as nuclear recipients. The nuclear donors were Capra ibex somatic cells with different proliferative status: population doubling time (PDL) = 15 +/- 2 (group 1), 35 +/- 2 (group 2), 55 +/- 2 (group 3) and 70 +/- 2 (group 4). Oocytes reconstructed with electrical pulses (2.1kV/cm, 10 micros, 2 times) were activated (1.4kV, 20 micros, 2 times) and then cultured in Medium199 containing 10% fetal bovine serum at 38.5 degrees C, 5% CO2 in air. In groups 1, 2, 3 and 4, the fusion rates were 35.83%, 66.03%, 65.40% and 35.35%, respectively. Similar cleavage rates were observed among the four groups. However, the developmental potential to morula/blastocyst from early nuclear donor embryos (16.42%/10.45%) was significantly higher (p < 0.05) than in terminal donor embryos (9.52%/3.81%). Polymerase chain reaction analysis of the mitochondrial (mt) DNA cytb gene demonstrated that mtDNAs from ibex and rabbit could be detected at various developmental stages before implantation. In conclusion, our results provide some original information about rescuing Capra ibex using the iSCNT technique. These results indicate that: (1) enucleated rabbit oocytes make Capra ibex fibroblast nuclei reprogramme; (2) the proliferative status of donor cells affects the efficiency of iSCNT; and (3) rabbit ooplasm rescues the donor-derived mtDNAs, resulting in mtDNA heteroplasmy before implantation.

Animals↗

Comparison of mtDNA variants among Mediterranean and New World introductions of the Mediterranean fruit fly Ceratitis capitata (Wied.).

Restriction enzyme cleavage sites of mitochondrial DNA (mtDNA) from the Mediterranean fruit fly (Ceratitis capitata) were found to vary among Mediterranean and New World populations. A restriction map for six populations (one from Greece and five from the New World) is constructed for the Mediterranean fruit fly. Six diagnostic restriction enzymes (EcoRI, EcoRV, HaeIII, HindIII, SstI, XbaI) are assigned three geographically distinct main types, CI, CII, and CIII.

Animals↗

Pearson syndrome and the role of deletion dimers and duplications in the mtDNA.

Pearson syndrome is an often fatal multisystem disease associated with mitochondrial DNA rearrangements. Here we report a patient with a novel mtDNA deletion of 3.4 kb ranging from nucleotides 6097 to 9541 in combination with deletion dimers. The mutation percentage in different tissues (blood, muscle and liver) varied between 64% and 95%. After a remission period of about a year, the patient suddenly died at the age of 3 years owing to a severe lactic acidosis. A second patient with a previously reported deletion of 8 kb and a milder phenotype was found to have mitochondrial duplications and died at the age of 10 years. From these data and data from previous reports, we hypothesize that duplications might be beneficial in the clinical course of the disease and in life expectancy.

Anemia↗

The A1555G mtDNA mutation in Danish hearing-impaired patients: frequency and clinical signs.

The A1555G mutation of the mtDNA is associated with both aminoglycoside-induced and non-syndromic hearing loss. The A1555G is relatively frequent in the Spanish and some Asian populations, but has only been reported rarely in other populations, possibly because of ascertainment bias. We studied 85 Danish patients with varying degrees of hearing impairment and found two patients with the A1555G mutation (2.4%). Neither had received aminoglycosides. Our study indicates that the mutation might not be uncommon in Danish patients with hearing impairment.

Adolescent↗

Visual recovery in a man with the rare combination of mtDNA 11778 LHON mutation and a MS-like disease after mitoxantrone therapy.

We describe a young man with prognostic unfavourable homoplasmatic mitochondrial DNA(mt DNA) 11778 Leber's hereditary optic neuropathy (LHON) point mutation and confirmed multiple sclerosis (MS). This combination of LHON and MS-like disease is rare in both sexes, and in men has been described in only a few case reports. In a 4-year follow-up during immunosuppressive therapy with mitoxantrone, we found a remarkable time delayed visual recovery 12 months after acute onset of rapid sequential bilateral subtotal visual loss followed by episodes of isolated acute demyelinative optic neuropathy. Visual recovery to such extent after this latency is uncommon in both mtDNA 11778 LHON mutation and optic neuritis (ON) in MS. Relapses in visual deterioration must be considered as extremely rare in LHON. This case might support the hypothesis of an immunological pathogenetic factor in combined LHON and MS, and possibly in LHON alone. We suggest a search for the LHON mutation in MS patients with predominant visual impairment, independent of patients' gender.

Adolescent↗

MtDNA mutation in MERRF syndrome causes defective aminoacylation of tRNA(Lys) and premature translation termination.

We have investigated the pathogenetic mechanism of the mitochondrial tRNA(Lys) gene mutation (position 8344) associated with MERRF encephalomyopathy in several mitochondrial DNA (mtDNA)-less cell transformants carrying the mutation and in control cells. A decrease of 50-60% in the specific tRNA(Lys) aminoacylation capacity per cell was found in mutant cells. Furthermore, several lines of evidence reveal that the severe protein synthesis impairment in MERRF mutation-carrying cells is due to premature termination of translation at each or near each lysine codon, with the deficiency of aminoacylated tRNA(Lys) being the most likely cause of this phenomenon.

Cell Line↗

MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.

Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.

Lysosomes↗

Polymorphisms in the coding region of mtDNA and effects on clinical outcome of unrelated bone marrow transplantation.

The entire protein-coding region was divided into 45 fragments, separately amplified and analyzed for polymorphism by the PCR-SSCP (single-strand conformation polymorphism) method. The effect of polymorphism mismatching on the clinical outcome of unrelated bone marrow transplantation was studied to clarify whether products from mtDNA become minor antigens. Variability in PCR-SSCP pattern combinations of the 45 fragments suggests that each individual has a different polymorphism combination in the protein-coding region if all the coding regions were compared at the nucleotide sequence level. Nonsynonymous polymorphisms were found at relatively high frequency in MTATP8 and MTND3. Both the polymorphisms with and without substitution matched the peptide-binding motifs of HLA-A*0201. The effects of the polymorphism matching were retrospectively analyzed in 340 recipients transplanted with HLA-A, -B, -DRB1 allele-matched bone marrow from unrelated donors. There were no effects of polymorphism matching on the incidence of acute GVHD and cumulative disease-free survival. These results suggest that polymorphisms which generate peptides, with and without substitutions, that bind the same HLA molecule hardly influence GVHD because the difference between the HLA-peptide complexes is minute.

Bone Marrow Transplantation↗

Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction.

Several mtDNA mutations have been reported in families with both syndromic and non-syndromic hearing loss. One such mutation is the heteroplasmic 7472insC in the tRNA(Ser(UCN)) gene which has been found in six families, all from Western Europe. However, it was not clear if this distribution was due to a common founder effect or chance sampling of several unrelated families, the 7472insC mutation having occurred multiple times. Haplotype analysis of all six families supports the latter notion. This confirms the pathogenicity of the 7472insC mutation and suggests it may exist in other populations where it may prove to be a small but significant cause of hearing loss, particularly when neurological symptoms are also present.

DNA, Mitochondrial↗

The evidence of mtDNA haplogroup F in a European population and its ethnohistoric implications.

Mitochondrial DNA polymorphism was analysed in a sample of 108 Croatians from the Adriatic Island isolate of Hvar. Besides typically European varieties of human maternal lineages, haplogroup F was found in a considerable frequency (8.3%). This haplogroup is most frequent in southeast Asia but has not been reported before in Europe. The genealogical analysis of haplogroup F cases from Hvar suggested founder effect. Subsequent field work was undertaken to sample and analyse 336 persons from three neighbouring islands (Brac, Korcula and Krk) and 379 more persons from all Croatian mainland counties and to determine if haplogroup F is present in the general population. Only one more case was found in one of the mainland cities, with no known ancestors from Hvar Island. The first published phylogenetic analysis of haplogroup F worldwide is presented, applying the median network method, suggesting several scenarios how this maternal lineage may have been added to the Croatian mtDNA pool.

DNA, Mitochondrial↗

An mtDNA mutation, 14453G-->A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome.

We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome. The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit. The patient was heteroplasmic for the mutation in both muscle and blood, but the mutation was not detected in the patient's mother. A marked reduction of complex I activity was found in the patient's muscular tissue. This is the first report of a mutation in the ND6 subunit causing MELAS. Our data confirm the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and confirms that MELAS can be caused by mutation in polypeptide-coding mtDNA genes.

Base Sequence↗

Ancient mtDNA analysis and the origin of the Guanches.

The prehistoric colonisation of the Canary Islands by the Guanches (native Canarians) woke up great expectation about their origin, since the Europeans conquest of the Archipelago. Here, we report mitochondrial DNA analysis (HVRI sequences and RFLPs) of aborigine remains around 1000 years old. The sequences retrieved show that the Guanches possessed U6b1 lineages that are in the present day Canarian population, but not in Africans. In turn, U6b, the phylogenetically closest ancestor found in Africa, is not present in the Canary Islands. Comparisons with other populations relate the Guanches with the actual inhabitants of the Archipelago and with Moroccan Berbers. This shows that, despite the continuous changes suffered by the population (Spanish colonisation, slave trade), aboriginal mtDNA lineages constitute a considerable proportion of the Canarian gene pool. Although the Berbers are the most probable ancestors of the Guanches, it is deduced that important human movements have reshaped Northwest Africa after the migratory wave to the Canary Islands.

Base Sequence↗

Population structure of African buffalo inferred from mtDNA sequences and microsatellite loci: high variation but low differentiation.

The African buffalo (Syncerus caffer) is widespread throughout sub-Saharan Africa and is found in most major vegetation types, wherever permanent sources of water are available, making it physically able to disperse through a wide range of habitats. Despite this, the buffalo has been assumed to be strongly philopatric and to form large aggregations that remain within separate home ranges with little interchange between units, but the level of differentiation within the species is unknown. Genetic differences between populations were assessed using mitochondrial DNA (control region) sequence data and analysis of variation at six microsatellite loci among 11 localities in eastern and southern Africa. High levels of genetic variability were found, suggesting that reported severe population bottlenecks due to outbreak of rinderpest during the last century did not strongly reduce the genetic variability within the species. The high level of genetic variation within the species was found to be evenly distributed among populations and only at the continental level were we able to consistently detect significant differentiation, contrasting with the assumed philopatric behaviour of the buffalo. Results of mtDNA and microsatellite data were found to be congruent, disagreeing with the alleged male-biased dispersal. We propose that the observed pattern of the distribution of genetic variation between buffalo populations at the regional level can be caused by fragmentation of a previous panmictic population due to human activity, and at the continental level, reflects an effect of geographical distance between populations.

Animals↗