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In a patient with clinical features of myoclonus epilepsy with ragged red fibers (MERRF), molecular genetic analysis of mitochondrial DNA did not show either of the two point mutations typically associated with MERRF but did show multiple deletions by Southern blot. This case further illustrates the heterogeneity observed with mtDNA mutations.
To assess dysphagia, the authors examined 12 patients with Kearns-Sayre syndrome (KSS) or chronic progressive external ophthalmoplegia (CPEO) due to mitochondrial DNA (mtDNA) deletion by videofluoroscopy and manometry. Cricopharyngeal achalasia was documented in nine of 12 patients (75%), whereas deglutitive coordination problems were found in one patient. Cricopharyngeal myotomy may be an effective treatment in selected cases with severe cricopharyngeal obstruction.
The authors identified a novel mtDNA mutation (T9176G) in the ATPase 6 gene in a family in which a 10-year-old girl had a severe neurodegenerative disorder, her elder sister had died of Leigh syndrome (LS), and a maternal uncle had a spinocerebellar disorder. Biochemical studies disclosed a reduced rate of ATP synthesis in skin fibroblast cultures from the proposita as the likely explanation of her severe illness. The findings expand the genetic variants associated with LS.
Two sisters developed gastrointestinal malabsorption with pain and unsteady gait due to polyneuropathy at age 15. Both had ophthalmoplegia, neurogenic EMG, and COX-negative muscle fibers. One patient had low muscle complex I-IV activity, multiple mtDNA deletions, and depletion, but no thymidine phosphorylase (TP) or dNT-2 gene mutations. TP activity and brain MRI were normal. The condition resembles mitochondrial neurogastrointestinal encephalomyopathy, except for the absence of leukoencephalopathy, and is likely caused by a nuclear DNA mutation that disrupts intergenomic signaling.
mtDNA Amerindian polymorphisms were studied in 108 inhabitants of Montevideo, Uruguay, using PCR RFLP analysis. Amerindian haplogroups were found in 20.4% of the sample. The frequency of Amerindian polymorphisms in Montevideo differed significantly from that observed in Tacuarembó, a city about 400 km away, indicating the high level of variation within Uruguay. Results for mitochondrial markers indicate that admixture occurred primarily as a result of Amerindian females mating with European males.
The Mosuo, living in the Lugu Lake area in northwest Yunnan Province, China, is the only matriarchal population in China. The Mosuo was officially identified as Naxi nationality although its relationship with Naxi remains controversial. We studied the genetic relationship between the Mosuo and five other ethnic groups currently residing in northwest Yunnan, i.e. Naxi, Tibetan, Bai, Yi and Pumi, by typing the genetic variations in mtDNA HVS1 and 21 Y chromosome markers (13 SNPs & 8 STR markers). We showed that the maternal lineages of the Mosuo bear the strongest resemblance with those found in Naxi while its paternal lineages are more similar to those that are prevalent in Yunnan Tibetan. The marked difference between paternal and maternal lineages may be attributable to the genetic history, matriarchal structure, and visiting marriage.
Leber's hereditary optic neuropathy (LHON) is a maternally inherited form of retinal ganglion cell degeneration leading to optic atrophy in young adults. Several mutations in different genes can cause LHON (heterogeneity). The ND6 gene is one of the mitochondrial genes that encodes subunit 6 of complex I of the respiratory chain. This gene is a hot spot gene. Fourteen Persian LHON patients were analyzed with single-strand conformational polymorphism and DNA sequencing techniques. None of these patients had four primary mutations, G3460A, G11788A, T14484C, and G14459A, related to this disease. We identified twelve nucleotide substitutions, G13702C, T13879C, T14110C, C14167T, G14199T, A14233G, G14272C, A14290G, G14365C, G14368C, T14766C, and T14798C. Eleven of twelve nucleotide substitutions had already been reported as polymorphism. One of the nucleotide substitutions (A14290G) has not been reported. The A14290G nucleotide substitution does not change its amino acid (glutamic acid). We looked for base conservation using DNA star software (MEGALIGN program) as a criterion for pathogenic or nonpathogenic nucleotide substitution in A14290G. The results of ND6 gene alignment in humans and in other species (mouse, cow, elegans worm, and Neurospora crassa mold) revealed that the 14290th base was not conserved. Fifty normal controls were also investigated for this polymorphism in the Iranian population and two had A14290G polymorphism (4%). This study provides evidence that the mtDNA A14290G allele is a new nonpathogenic polymorphism. We suggest follow-up studies regarding this polymorphism in different populations.
The Japanese dormouse, Glirulus Japonicus, is the only extant lineage that represents this genus and it has been classified as a single species distributed on the three main islands of Japan, namely Honshu, Shikoku and Kyushu. However, individuals collected from Fukui, Wakayama and Kochi Prefectures (southwestern part of Japan) yielded distinctly different profiles of restriction fragments of the nuclear ribosomal DNA (rDNA) spacer from those collected from Yamanashi and Nagano Prefectures (central Japan). The estimated sequence divergence between the two groups was 2.8% on average, which corresponds to a putative divergence some two million years ago. Representing mitochondrial DNA (mtDNA) sequences, 402 bases of cytochrome b gene were determined by direct sequencing and the estimated extent of the sequence divergence between the two groups was 6.5-7%. Differences between the two geographic groups were also substantial in the sequences of about 300 base-fragments from the Y-linked, sex-determining locus, Sry. To assess the phylogenetic relationships between the Japanese dormouse and members of the family Myoxidae, we compared sequences of mitochondrial 12S rRNA gene of Japanese dormice with those of the forest dormouse (Dryomys nitedula) and the common dormouse (Muscardinus avellanarins), two continental genera thought to be closely related to the genus Glirulus. The results showed that the sequences from Japanese dormice were distinct from any sequences of the two continental species and the extent of the differences were somewhat similar to that between the rat (Rattus norvegicus) and the hamster (mesocricetus auratus).
A molecular phylogenetic survey was conducted using mtDNA sequences of 12S and 16S rRNA, and cyt-b genes to examine taxonomic relationships among populations of the Pan-Oriental microhylid, Microhyla ornata, from India, Bangladesh, Thailand, Laos, China, Taiwan, and the Ryukyu Archipelago of Japan. Two discrete clades are recognized within this species, one consisting of populations from India and Bangladesh, and the other encompassing the remaining populations. In the latter clade, populations from the Ryukyu Archipelago are clearly split from the rest (populations from Taiwan and the continent) with considerable degrees of genetic differentiations. Each of the three lineages is judged to represent a good species, and the name Microhyla ornata is restricted to the South Asian populations. For the populations from Taiwan and a wide region from China to Southeast Asia, the name Microhyla fissipes should be applied, whereas the Ryukyu populations are most appropriately referred to as Microhyla okinavensis, although further substantial genetic differentiations are recognized among some island group populations within this last species.
A 50-year-old woman with subacute dementia and brain atrophy on CT showed periodic synchronous discharge (PSD) on electroencephalogram (EEG) and myoclonus. She was initially suspected of suffering from Creutzfeldt-Jakob disease (CJD), but dramatically recovered over 5 months. Based on further investigations, the final diagnosis was mitochondrial encephalomyopathy with an A-to-G substitution at nucleotide position 3243 in mitochondrial DNA (mtDNA), commonly seen in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This case suggests that patients suspected of suffering from CJD should be evaluated for mitochondrial encephalomyopathy.
Single large mitochondrial DNA deletions (DeltamtDNA) are usually spontaneously occurring and cause a wide variety of symptoms, ranging from severe infantile multisystem disorders to adult onset progressive external ophthalmoplegia (PEO). There is always heteroplasmy with a mixture of normal and mutant mtDNA and the levels usually vary widely between tissues. There is at present insufficient scientific basis for accurate genetic counselling of women with DeltamtDNA, but it is reasonable to assume that DeltamtDNA can be transmitted if it is present in the female germ cells. Here, we present the results of prenatal analysis in a woman with DeltamtDNA and PEO. No DeltamtDNA was detected by Southern blot and PCR analyses of chorionic villi from the first trimester of pregnancy, in cord blood obtained at birth or in peripheral blood from the child at six months of age. This makes it unlikely that the child will develop a severe infantile mitochondrial disorder due to transmission of high levels of DeltamtDNA. However, the complex mitochondrial genetics and the limited access to human tissues makes it impossible to exclude transmission of low levels of DeltamtDNA that possibly could cause disease later in life.
New research into variation in mutation rates across nucleotide positions in human mitochondrial DNA (mtDNA) calls into question population genetics models that assume a constant mutation rate for all sites in a sequence, particularly for hypervariable control region segments I and II. Related to this research is discovering the extent to which highly polymorphic sites are really mutational "hot spots" rather than "old" sites rooted early in the phylogenetic tree. This issue is addressed through the analysis of linkage disequilibrium patterns in the mtDNAs of 10 human populations. Hot spots can be expected to show little or no disequilibrium since they can be interpreted as having randomly expressed patterns. In fact, the results suggest that many highly polymorphic sites are not old sites, but instead are hot spots. Suspected hot spots are listed and compared with hypervariable sites given by Wakeley (1993) and Hasegawa et al. (1993).
The mtDNA Cyt b sequences (432 bp) were analyzed in 10 individuals from 8 different families of Acridoidea in China. The homologous sequences were compared, the used frequency of nucleotide was calculated and the molecular phylogenetic tree constructed by Neighbor-Joining method using T. japonica as outgroup. The confidence of nodes in the trees was evaluated by bootstrap (1000 replicates). These sequences were the middle part of Cyt b gene, and in the obtained sequences, A% + T% was about 70.4% and G% + C% only 29.6%. The sequence data revealed considerable variation in 177 nucleotide sites (about 41.0%) among the analyzed individuals from 8 different families. From every amino acid codon, A% + T% in the third site was higher (86.6%) than the other two sites and lower than other insects in the corresponding region. The NJ tree suggested that 11 individuals from the 8 families clustered in 4 groups, among which Gomphoceridae and Pamphagidae firstly clustered and then together with Arcypteridae and Acrididae to form group I; Cluster II was made of three species from Catantopidae, O. japonica, O. chinensis and O. intricata; Pyrgmorphidae and Oedipodidae formed group III and Chrotogonidae single as cluster IV, respectively. The phylogenetic relationships of the 8 families was: Chrotogonidae-->Pyrgomorphidae and Oedipodidae-->Catantopidae-->Acrididae-->Arcypteridae-->Gomphoceridae and Pamphagidae, which is little different from the morphological results.
Mitochondrial DNA (mtDNA) analysis of forensic samples typically is performed when the quantity and quality of DNA are insufficient for nuclear DNA analysis or when maternal relatives may be the only reference source. Many of the steps required in the analytical process are both lengthy and labor intensive. Therefore, improvements in the process that reduce labor without compromising the quality of the data are desirable. The current procedure requires purification of the amplicons by centrifugal filtration after PCR and prior to cycle sequencing. Because this method requires several manipulations to perform, alternate cleanup procedures were investigated. These include the use of 1) Qiagen QlAquick PCR Purification columns, 2) Concert Rapid PCR Purification columns, and 3) ExoSAP-IT reagent. When the yield of purified amplicons, quality of the sequence profile, and ease of assay were evaluated, the use of ExoSAP-IT reagent for post-amplification purification was chosen to replace the filtration method.
The operation of the structural and functional units of the myocardial contractile apparatus relies on mutual myofilament movement, totally ATP dependent. As a consequence, cardiac action is integrally connected with the production of high energy ATP molecules, which are mainly synthesised in cellular mitochondrial structures. Mitochondrial dysfunction can lead to a reduced level of ATP, which is necessary to generate movement in the actino-myosin system. ATP insufficiencies may be a result of the genetic mitochondrial material (mtDNA) mutation, poorer expression of mitochondrial genes (at the transcription and/or translation stage), distorted import of proteins from the cytoplasm to the mitochondria or erroneous composition of mitochondrial breathing complexes. It has been proved that the efficacy of oxidative phosphorylation (mitochondrial ATP synthesis) is reduced with accumulated mutation of mitochondrial and/or nuclear DNA. The paper is a review of findings on the mutation of mitochondrial DNA discovered in patients with hypertrophy of the cardiac muscle. In many cases these changes accompany the mutations of the nuclear genes, but they may also be the only change discovered in the patient's genetic material.
PCR-RFLP technique was employed to amplify about 827bp of mtDNA D-loop hypervariable region of Leuciscus baicalensis, L.merzbacheri and L.idus in Xinjiang. The PCR products of 56 samples with four restriction enzymes were digested: ScaI,HinfI,AluI,DdeI,and RFLP analysis was done then. The study indicates that all of L. species and populations have six haplotypes, L.merzbacheri has two haplotypes: BDAA,BDBA; L.baicalensis has three:AAAA,ABAA,ACAA; L.idus has one:CAAA. It is primarily considered that L.merzbacheri and L.baicalensis have more intra-population mutations. The UPGMA trees with 6 haplotypes and net genetics distance pointed out that L.merzbacheri might be original species, L.baicalensis and L.idus are evolved from L.merzbacheri.
Molecular genetic data were used to investigate population genetic structure and differentiation of Pelophylax nigromaculata (Anura: Ranidae). Frogs were collected from 12 localities across Chinese mainland. Sample sizes of up to 10 frogs per population were assayed for mitochondrial control region sequence variation. The aligned 685 bp of the 5'CR include 111 variable sites. Sixty-seven haplotypes were defined. Most of the haplotypes are unique to local populations, only 7 of the 67 are shared among a few local populations. The overall species haplotype diversity is quite high (h = 0.98 +/- 0.005), and the nucleotide diversity is also high (pi = 0.0303 +/- 0.0029). This is corresponding to huge population size and extensive distribution of Pelophylax nigromaculata throughout Palaearctic and Oriental Regions. Phylogenetic tree of mtDNA control region haplotypes based on maximum parsimony algorithm and reconstructed phylogenetic relationships among the local populations based on neighbor joining algorithm all suggest that the haplotypes of Jiling and Liaoning populations in northeastern China have a sister relationship with 10 local populations in northern, central, southern and southwestern China. The analysis of molecular variance (AMOVA), the pairwise FST values and nucleotide divergence all support significant population subdivision between the Jilin-Liaoning group and multi-population group. The most possible cause of the significant genetic subdivision between the two groups might be referred to the effect of Quaternary glaciation. The possible reasons for the lack of obvious geographic structure on the whole in the multi-population group and the genetic differentiation in some local populations of the multi-population group were also discussed.
This article summarizes the structure and heredity characteristics of sex chromosomes and mtDNA, presents the advantages and disadvantages of genetic markers' on them in the practice of forensic medicine which aims at promoting more widely using of the non-euchromosome DNA genetic markers in the forensic science.