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At least 379 records · Page 21Linked to original sources
PubMed2003

A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes.

Historical inferences from genetic data increasingly depend on assumptions about the genealogical process that shapes the frequencies of alleles over time. Yet little is known about the structure of human genealogies over long periods of time and how they depart from expectations of standard demographic models, such as that attributed to Wright and Fisher. To obtain such information and to examine the recent evolutionary history of mtDNA and Y-chromosome haplotypes in the Icelandic gene pool, we traced the matrilineal and patrilineal ancestry of all 131,060 Icelanders born after 1972 back to two cohorts of ancestors, one born between 1848 and 1892 and the other between 1798 and 1742. This populationwide coalescent analysis of Icelandic genealogies revealed highly positively skewed distributions of descendants to ancestors, with the vast majority of potential ancestors contributing one or no descendants and a minority of ancestors contributing large numbers of descendants. The expansion and loss of matrilines and patrilines has caused considerable fluctuation in the frequencies of mtDNA and Y-chromosome haplotypes, despite a rapid population expansion in Iceland during the past 300 years. Contrary to a widespread assumption, the rate of evolution caused by this lineage-sorting process was markedly faster in matrilines (mtDNA) than in patrilines (Y chromosomes). The primary cause is a 10% shorter matrilineal generation interval. Variance in the number of offspring produced within each generation was not an important differentiating factor. We observed an intergenerational correlation in offspring number and in the length of generation intervals in the matrilineal and patrilineal genealogies, which was stronger in matrilines and thus contributes to their faster evolutionary rate. These findings may have implications for coalescent date estimates based on mtDNA and Y chromosomes.

Alleles↗
PubMed2005

Infection with HIV-1 induces a decrease in mtDNA.

Cross-sectional studies have suggested that infection with human immunodeficiency virus (HIV) type 1 could reduce the mitochondrial DNA (mtDNA) content of blood cells. We investigated mtDNA content in peripheral blood mononuclear cells (PBMCs) obtained from 36 antiretroviral therapy-naive documented HIV-1 seroconverters, before and after seroconversion. mtDNA content statistically significantly decreased 1 year after seroconversion and showed a nonsignificant decrease during the subsequent 4 years. These findings confirm that infection with HIV-1 may, itself, reduce mtDNA content, at least within PBMCs. This could have implications for the subsequent development of mitochondrial toxicities associated with the use of nucleoside analogue reverse-transcriptase inhibitors.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Functional and structural features of a tandem duplication of the human mtDNA promoter region.

An approximately 260-bp tandem duplication of the human mtDNA regulatory region has been identified in patients with mitochondrial disorders and in a specific Caucasian haplogroup. The functional significance of this mtDNA duplication was difficult to assess, because it was present at very low levels in human tissues. We have isolated several transmitochondrial cybrid lines harboring this mutation, one of which (clone CA17.1) was essentially homoplasmic for the duplication. Oxidative-phosphorylation function was not impaired in clone CA17.1, suggesting that this mtDNA alteration is not pathogenic. mtDNA copy number and steady-state levels of heavy- and light-strand transcripts were unaltered in clone CA 17.1. The steady-state levels of RNAs made from the two promoters (either from the heavy-strand or from the light-strand) were also similar, indicating that oppositely oriented promoters did not interfere with each other.

Base Sequence↗
PubMed1996

The effect of zidovudine on skeletal muscle mtDNA in HIV-1 infected patients with mild or no muscle dysfunction.

Zidovudine (ZDV), a nucleoside analogue which inhibits viral replication, is currently used in the treatment of type 1 human immunodeficiency virus (HIV-1) infection. It has been considered to be the cause of an acquired form of myopathy associated with a depletion of mitochondrial DNA (mtDNA) in muscle fibres, although the fact that the patients previously studied were clearly symptomatic, and the theoretical difficulty in differentiating on HIV-related myopathy from the effects of ZDV, led to a controversy on the possible deleterious effect of ZDV on muscle fibres. We studied the muscle biopsy taken from 42 HIV-1 infected patients, regardless of their medical complaints, and two series of controls: 12 HIV-negative patients suffering from diverse neuromuscular diseases and 10 normal patients who underwent orthopaedic surgery. Whole DNA was extracted following standard procedures and analysed by means of Southern blotting and polymerase chain reaction (PCR). We found that mtDNA was only depleted in HIV-1 infected patients treated with ZDV, but not in controls or patients untreated with this antiretroviral drug. Moreover, the depletion was more marked in patients who either presented weakness, myalgia, raised serum creatine kinase (CK), or ragged-red fibres. Mitochondrial DNA deletions were found in low proportion in all groups of patients, regardless of their HIV infection or ZDV status, but not in normal controls. We conclude that ZDV treatment in HIV-1 positive patients produces depletion of muscle mtDNA. The depletion can be demonstrated even in asymptotic patients, but is more marked in patients with clinical symptoms or abnormalities in their muscle biopsies. Other mtDNA abnormalities such as deletions seemed to be more related to other circumstances concurring in HIV-1 infected patients than to the effects of ZDV.

Adult↗
PubMed1987

Temporal and spatial heterogeneity of mtDNA polymorphisms in natural populations of Drosophila mercatorum.

Restriction endonuclease analysis of mtDNA was used to examine the genetic relatedness of several geographically separated isolines of the Drosophila mercatorum subgroup. In addition, we examined the temporal and spatial distribution of two mtDNA restriction site polymorphisms produced by the enzymes BstEII and BstNI at a single locality--Kamuela, Hawaii. Due to small sample sizes of some collections and the undesirable dependance of the estimation of polymorphism frequency on its variance, an arcsin square root transformation of the frequency data was used. We also use an Fst estimator of our transformed frequencies to demonstrate considerable spatial and temporal differentiation within the Kamuela population. In contrast, isozyme data from the same population reveals no pattern of differentiation. The temporal and geographic heterogeneity and population subdivision detected with mtDNA analysis also is consistent with the known dispersal behavior and ecological constraints of this species. The mtDNA data in conjunction with the isozyme data show that the population structure of the Kamuela D. mercatorum is close to the boundary line separating panmixia from subdivision, a conclusion that could not be made from isozyme data alone.

Alleles↗
PubMed1988

Natural selection with nuclear and cytoplasmic transmission. III. Joint analysis of segregation and mtDNA in Drosophila melanogaster.

Despite the widespread use of mitochondrial DNA by evolutionary geneticists, relatively little effort has been spent assessing the magnitude of forces maintaining mtDNA sequence diversity. In this study the influence of cytoplasmic variation on viability in Drosophila was examined by analysis of second chromosome segregation. A factorial experiment with balancer chromosomes permitted the effects of cytoplasma and reciprocal crosses to be individually distinguished. The first test used six lines of diverse geographic origin, testing the segregation of all six second chromosomes in all six cytoplasms. The second and third tests were also factorial designs, but used flies from one population in central Pennsylvania. The fourth test was a large chain cross, using 28 lines from the same Pennsylvania population. Only the first test detected a significant nuclear-cytoplasmic effect. Restriction site variation in the mtDNA of all of these lines was assayed by Southern blotting, and statistical tests were performed in an effort to detect an influence of mtDNA type on fitness components. Posterior linear contrasts revealed an effect of mtDNA on segregation only among lines of diverse geographic origin. Within a population, no such influence was detected, even though the experiment was sufficiently large to have revealed statistical significance of a 0.5% segregation difference with a 57% probability.

Animals↗
PubMed1994

Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy.

We studied the cellular distribution of both deleted (delta) and wild-type (wt) mitochondrial DNAs (mtDNAs) in 'normal' and respiration-deficient muscle fibers from four patients with mitochondrial myopathy. PCR-based methods were used to quantitate both relative and absolute amounts of delta- and wt-mtDNAs in microdissected fiber segments. Although delta-mtDNAs were present in normal fibers (31% +/- 26), their percentages were much higher in affected fibers (95% +/- 2). Absolute levels of delta-mtDNA were also increased in affected fibers, whereas levels of wt-mtDNA were significantly reduced in these fibers. These results indicate that a threshold ratio of delta-/wt-mtDNA must be achieved before an impairment of respiration is observed in muscle. Moreover, the marked reduction in wt-mtDNA observed in affected fibers suggests that absolute amounts of mtDNA may play a role in the pathogenesis of mitochondrial myopathies.

Adolescent↗
PubMed1994

The relationship between mitochondrial genotype and mitochondrial phenotype in lymphoblasts with a heteroplasmic mtDNA deletion.

The relationship between mitochondrial genotype and mitochondrial phenotype was investigated in lymphoblasts derived from a patient with the Pearson syndrome. In 70% of the mtDNA of this Pearson cell line a deletion from within the COX II gene to within the ND5 gene was present. The deletion led to a reduced expression of the deleted genes, but the severely lowered synthesis of e.g. subunit II of cytochrome c oxidase was not reflected in a significant decrease in the cytochrome c oxidase activity. Moreover, there were no obvious differences between control cells and Pearson cells regarding the capacity for oxidative phosphorylation. Analysis of the synthesis and assembly of both nuclearly and mitochondrially encoded subunits of cytochrome c oxidase showed that normally mtDNA-encoded polypeptides are produced in excess. This overproduction fully explained the discrepancy between the severe defect in the expression of the mitochondrial genome and the normal mitochondrial function in the Pearson cells. These data demonstrate that the expression of one or more mitochondrial genes can be reduced specifically at intermediate percentages of deleted mtDNA. However, the data also suggest that whether or not a lower expression of mitochondrial genes encoding subunits of enzymes involved in oxidative phosphorylation influences the normal function of these enzymes depends on the relative abundance of the mitochondrial subunits in tissues or cells with deleted mtDNA.

Cells, Cultured↗
PubMed1997

Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease.

Mitochondrial (mt)DNA haplogroups in a German control group (n = 67) were characterized by screening mitochondrial coding regions encompassing most of the ND, tRNA and cyt b genes. We used a PCR-SSCP screening approach followed by direct sequencing of polymorphic mtDNA fragments. Five major mtDNA lineages, diverging in at least nine different haplogroups, could be defined by characteristic polymorphic sites in mitochondrial genes. Additional sequencing of two hypervariable segments (HVS-I and II) of the non-coding displacement (D) loop in all control subjects revealed that certain D loop variants were strongly correlated with lineages and haplogroups, while others represented hotspots occurring frequently in different haplogroups. The existence of identified lineages and haplogroups received support from data in the literature, obtained by use of different approaches. Subsequently, we investigated four disease groups for association with these haplogroups: (i) LHON patients (n = 55) carrying at least one of the primary/intermediate LHON mutations at nt 3460, 11778, 14484 and/or 15257; (ii) patients suffering from Wolfram or DIDMOAD syndrome (n = 8); (iii) MELAS patients (n = 9); (iv) a group of children, who died from 'sudden infant death syndrome' (SIDS) (n = 9). The distribution patterns among the haplogroups of the disease groups (LHON, DIDMOAD and SIDS) differed considerably from the control population. LHON and DIDMOAD were significantly under-represented in the most frequent German haplogroup DC, but were concentrated in a mtDNA lineage defined by polymorphisms at nt 4216 + 11251 + 16126. As this lineage diverged into two precisely defined haplogroups, LHON and DIDMOAD could be assigned to the two haplogroups separately. Strikingly, SIDS was often found in association with two rare German haplogroups. MELAS patients were equally distributed among German haplogroups and, moreover, did not reveal any accumulation of specific D loop variants. We conclude that certain European mtDNA haplogroups define a genetic susceptibility basis for various disorders.

Child↗
PubMed2000

A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome.

We report on a novel frameshift mutation in the mtDNA gene encoding cytochrome c oxidase (COX) subunit III. The proband is an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she has developed a progressive spastic paraparesis associated with ophthalmoparesis and moderate mental retardation. The presence of severe lactic acidosis and Leigh-like lesions of putamina prompted us to perform muscle and skin biopsies. In both, a profound, isolated defect of COX was found by histochemical and biochemical assays. Sequence analysis of muscle mtDNA resulted in the identification of a virtually homoplasmic frameshift mutation in the COIII gene, due to the insertion of an extra C at nucleotide position 9537 of mtDNA. Although the 9537C(ins) does not impair transcription of COIII, no full-length COX III protein was detected in mtDNA translation assays in vivo. Western blot analysis of two-dimensional blue-native electrophoresis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of patient's cultured fibroblasts. Taken together, the data indicate a role for COX III in the incorporation and maintenance of smaller COX subunits within the complex.

Base Sequence↗
PubMed2000

Human mtDNA sublimons resemble rearranged mitochondrial genoms found in pathological states.

Sublimons, originally identified in plant mitochondria, are defined as rearranged mtDNA molecules present at very low levels. We have analysed the primary structures of sublimons found in human cells and tissues and estimated their abundance. Each tissue of a given individual contains a wide range of different sublimons and the most abundant species differ between tissues in a substantially systematic manner. Sublimons are undetectable in rho(0) cells, indicating that they are bona fide derivatives of mtDNA. They are most prominent in post-mitotic tissue subject to oxidative stress. Rearrangement break-points, often defined by short direct repeats, are scattered, but hotspot regions are clearly identifiable, notably near the end of the D-loop. The region between the replication origins is therefore frequently eliminated. One other hotspot region is located adjacent to a known site of protein binding, suggesting that recombination may be facilitated by protein-protein interactions. For a given primary rearrangement, both deleted and partially duplicated species can be detected. Although each sublimon is typically present at a low level, at most a few copies per cell, sublimon abundance in a given tissue can vary over three orders of magnitude between healthy individuals. Collectively, therefore, they can represent a non-negligible fraction of total mtDNA. Their structures are very similar to those of the rearranged molecules found in pathological states, such as adPEO and MNGIE; therefore, we propose that, as in plants, human mtDNA sublimons represent a pool of variant molecules that can become amplified under pathological conditions, thus contributing to cellular dysfunction.

Adult↗
PubMed2003

Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria.

Human mtDNA is transcribed from both strands, producing polycistronic RNA species that are immediately processed. Discrete RNA units are matured by the addition of nucleotides at their 3' termini: -CCA trinucleotide is added to mt-tRNAs, whilst mt-rRNAs and mt-mRNAs are oligo- or polyadenylated, respectively. The cis-acting elements, enzymes and indeed the mechanisms involved in these processes are still largely uncharacterized. Further, the function of polyadenylation in promoting stability, translation or decay of human mt-mRNA is unclear. A microdeletion has been identified in a patient presenting with mtDNA disease. Loss of these two residues removes the termination codon for MTATP6 and sets MTCO3 immediately in frame. Accurate processing at this site still occurs, but there is a markedly decreased steady-state level of RNA14, the ATPase 8- and 6-encoding bi-cistronic mRNA unit, establishing that an mtDNA mutation can cause dysregulation of mRNA stability. Analysis of the polyadenylation profile of the processed RNA14 at steady state revealed substantial abnormalities. The majority of mutated RNA14 terminated with short poly (A) extensions and a second, partially truncated population, was also present. Initial maturation of mutated RNA14 was unaffected, but deadenylation occurred rapidly. Inhibition of mitochondrial protein synthesis showed that the deadenylation was dependent on translation. Finally, deadenylation was shown to enhance mRNA decay, explaining the decrease in steady-state RNA14. An hypothesis is presented to describe how an mtDNA mutation that results in the loss of a termination codon causes enhanced mt-mRNA decay by translation-dependent deadenylation.

Adenosine Triphosphatases↗
PubMedDate not supplied

Turkish honeybees: genetic variation and evidence for a fourth lineage of Apis mellifera mtDNA.

The mtDNA of bees from 84 colonies of Turkish honeybees (Apis mellifera) was surveyed for variation at four diagnostic restriction sites and the sequence of a noncoding intergenic region. These colonies came from 16 locations, ranging from European Turkey and the western Mediterranean coast to the Caucasus Mountains along the Georgian border, the eastern Lake Van region, and the extreme south. Combined restriction site and sequence data revealed four haplotypes. Three haplotypes belonged to the eastern Mediterranean mtDNA lineage. The fourth haplotype, which had a novel restriction site pattern and noncoding sequence, was found in samples from the extreme south, near the Syrian border. We found two different noncoding sequences among the eastern Mediterranean haplotypes. The "Caucasian" sequence matches that described from A. m. caucasica, and the "Anatolian" sequence matches that of A. m. carnica. The frequency of the "Caucasian" sequence was highest (98-100%) in sites near the Georgian border and decreased steeply to the south and west. Elsewhere the Anatolian sequence was found. In European Turkey (Thrace) a restriction site polymorphism previously reported from A. m. carnica in Austria and the Balkans was present at high frequency. A novel mtDNA haplotype with a unique restriction site pattern and noncoding sequence was found among bees from Hatay, in the extreme south near the Syrian border. This haplotype differed from the three previously known lineages of honeybee mtDNA--African, western European, and eastern Mediterranean-and may represent a fourth mitochondrial lineage.

Animals↗
PubMedDate not supplied

Analysis of the complete human mtDNA genome: methodology and inferences for human evolution.

The analysis of mitochondrial DNA (mtDNA) sequences has been a potent tool in our understanding of human evolution. However, almost all studies of human evolution based on mtDNA sequencing have focused on the control region, which constitutes less than 7% of the mitochondrial genome. The rapid development of technology for automated DNA sequencing has made it possible to study the complete mtDNA genomes in large numbers of individuals, opening the field of mitochondrial population genomics. Here we describe a suitable methodology for determining the complete human mitochondrial sequence and the global mtDNA diversity in humans. Also, we discuss the implications of the results with respect to the different hypotheses for the evolution of modern humans.

Biological Evolution↗
PubMed2004

Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia.

It has been often stated that the overall pattern of human maternal lineages in Europe is largely uniform. Yet this uniformity may also result from an insufficient depth and width of the phylogenetic analysis, in particular of the predominant western Eurasian haplogroup (Hg) H that comprises nearly a half of the European mitochondrial DNA (mtDNA) pool. Making use of the coding sequence information from 267 mtDNA Hg H sequences, we have analyzed 830 mtDNA genomes, from 11 European, Near and Middle Eastern, Central Asian, and Altaian populations. In addition to the seven previously specified subhaplogroups, we define fifteen novel subclades of Hg H present in the extant human populations of western Eurasia. The refinement of the phylogenetic resolution has allowed us to resolve a large number of homoplasies in phylogenetic trees of Hg H based on the first hypervariable segment (HVS-I) of mtDNA. As many as 50 out of 125 polymorphic positions in HVS-I were found to be mutated in more than one subcluster of Hg H. The phylogeographic analysis revealed that sub-Hgs H1*, H1b, H1f, H2a, H3, H6a, H6b, and H8 demonstrate distinct phylogeographic patterns. The monophyletic subhaplogroups of Hg H provide means for further progress in the understanding of the (pre)historic movements of women in Eurasia and for the understanding of the present-day genetic diversity of western Eurasians in general.

Asia↗
PubMed2002

Complete mtDNA sequences of two millipedes suggest a new model for mitochondrial gene rearrangements: duplication and nonrandom loss.

We determined the complete mitochondrial DNA (mtDNA) sequences of the millipedes Narceus annularus and Thyropygus sp. (Arthropoda: Diplopoda) and identified, in both genomes, all 37 genes typical for metazoan mtDNA. The arrangement of these genes is identical in the two millipedes, but differs from others found in arthropod mtDNAs in the location of at least four genes or gene blocks. This novel gene arrangement is unusual for animal mtDNA in that genes with identical transcriptional polarities are clustered in the genome, and the two clusters are separated by two noncoding regions. The only exception to this pattern is the gene for cysteine tRNA, which is located in the part of the genome that otherwise contains all genes with the opposite transcriptional polarity. We suggest that a mechanism involving complete mtDNA duplication followed by the loss of genes, predetermined by their transcriptional polarity and location in the genome, could generate this gene arrangement from the one ancestral for arthropods. The proposed mechanism has important implications for phylogenetic inferences that are drawn on the basis of gene arrangement comparisons.

Animals↗
PubMed1994

Contrasting population structure from nuclear intron sequences and mtDNA of humpback whales.

Powerful analyses of population structure require information from multiple genetic loci. To help develop a molecular toolbox for obtaining this information, we have designed universal oligonucleotide primers that span conserved intron-exon junctions in a wide variety of animal phyla. We test the utility of exon-primed, intron-crossing amplifications by analyzing the variability of actin intron sequences from humpback, blue, and bowhead whales and comparing the results with mitochondrial DNA (mtDNA) haplotype data. Humpback actin introns fall into two major clades that exist in different frequencies in different oceanic populations. It is surprising that Hawaii and California populations, which are very distinct in mtDNAs, are similar in actin intron alleles. This discrepancy between mtDNA and nuclear DNA results may be due either to differences in genetic drift in mitochondrial and nuclear genes or to preferential movement of males, which do not transmit mtDNA to offspring, between separate breeding grounds. Opposing mtDNA and nuclear DNA results can help clarify otherwise hidden patterns of structure in natural populations.

Animals↗
PubMed2003

Transcript mapping and genome annotation of ascidian mtDNA using EST data.

Mitochondrial transcripts of two ascidian species were reconstructed through sequence assembly of publicly available ESTs resembling mitochondrial DNA sequences (mt-ESTs). This strategy allowed us to analyze processing and mapping of the mitochondrial transcripts and to investigate the gene organization of a previously uncharacterized mitochondrial genome (mtDNA). This new strategy would greatly facilitate the sequencing and annotation of mtDNAs. In Ciona intestinalis, the assembled mt-ESTs covered 22 mitochondrial genes ( approximately 12,000 bp) and provided the partial sequence of the mtDNA and the prediction of its gene organization. Such sequences were confirmed by amplification and sequencing of the entire Ciona mtDNA. For Halocynthia roretzi, for which the mtDNA sequence was already available, the inferred mt transcripts allowed better definition of gene boundaries (16S rRNA, ND1, ATP6, and tRNA-Ser genes) and the identification of a new gene (an additional Phe-tRNA). In both species, polycistronic and immature transcripts, creation of stop codons by polyadenylation, tRNA signal processing, and rRNA transcript termination signals were identified, thus suggesting that the main features of mitochondrial transcripts are conserved in Chordata.

Animals↗