AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participant...AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G】A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G】A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G】A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G】A heteroplasmy correlated both with age (r = 0.331, P 【 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G】A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G】A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G】A heteroplasmy level were found to have significantly higher age (P 【 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G】A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G】A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G】A mutation heteroplasmy with essential hypertension.展开更多
We report for the first time the occurrence of heteroplasmy in Grey Partridge(Perdix perdix)revealed by means of two mitochondrial fragments.The possible serious biological and management implications of this exceptio...We report for the first time the occurrence of heteroplasmy in Grey Partridge(Perdix perdix)revealed by means of two mitochondrial fragments.The possible serious biological and management implications of this exception to unilateral inheritance of mtDNA were underlined.展开更多
In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of gene...In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of genetic predisposition. The sequencing of the human genome, which has led to the discovery of millions of sequence variations, makes it possible to study variations within sequences. These variations are limited to Single Nucleotide Polymorphisms (SNPs) and this common form of polymorphism occurs approximately every 1000 bases in the human genome and 1.8 million SNPs are currently listed according to [1]. The aim of this study is to gain a better understanding of the impact of mutations in the D-loop region of mtDNA on ovarian cancer in Senegalese women. This study involved searching for mutations in our study population after DNA extraction and sequencing. Mutations were found after a comparison of our sequences with the Cambridge reference sequence (NC_012920). The mutations found in the DNA studied extend from position 7 to position 16568 and most of these mutations are located in the hypervariate zones (HV1 and HV2). Heteroplasmy with three mutant alleles was also found in certain variants. Common mutations were found in both healthy and cancerous tissues, with almost identical frequencies in both types of tissue. This enabled us to understand the spread of tumor cells throughout the ovary.展开更多
Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteropl...Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, cor- resnondin to abottleneck of about 200 mtDNA.展开更多
Few studies have explored the differences between Sanger and HTS methods in the results of mitogenome sequencing. We used a single individual of insect to study the differences between the sequences given by Sanger an...Few studies have explored the differences between Sanger and HTS methods in the results of mitogenome sequencing. We used a single individual of insect to study the differences between the sequences given by Sanger and PCR-free HTS methods. Here we provided evidence for biased results of sequencing due to different methods in the mitochondrial genes of atp6, atp8, cox1, cox2, cox3, Cytb, nad2, nad3, nad4, nad5, rrn S, rrnL, trnH, trn I, and control region at various degrees. Especially, in cox1, the differently sequenced nucleotides account for 2.6% of the complete length. Furthermore, the highest value of the intraspecific genetic distance based on K2 P accounts for 2.5% using a barcode fragment size of cox1（651 bp, Sanger）, while the maximum distance of the corresponding cox1 fragment obtained by the two sequencing methods was 5.0%. We revealed that the methods of Sanger and HTS may give different sequencing results of mitochondrial genes, which may reflect the heteroplasmy of mitogenomes within an insect individual. Therefore, researchers should be very cautious in using the mixed data of a gene given by different methods of sequencing.展开更多
Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the co...Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.展开更多
In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would ...In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would particularly profit from providing more data about multisystem disease,from providing the current medication,the cerebro-spinal fluid findings,the detailed phenotypic presentation,and the genotype of first-degree relatives.Since the index patient had experienced recurrent seizures it is crucial to know the current and previous anti-seizure medication as it may strongly determine the outcome.Some of them are mitochondrion-toxic and particularly valproic acid may exhibit fatal side effects.The outcome may also depend on the degree of multisystem involvement why it is crucial to prospectively investigate the patient for subclinical involvement of organs not obviously affected.Additionally,the outcome of the stroke-like lesions on imaging would be interesting to see.Strokelike lesions may completely disappear or may end up as white matter lesion,laminar cortical necrosis,focal atrophy,cyst,or as the so-called toenail sign.There is also a need of discussing more profoundly the imaging findings and their diagnostic significance and to investigate first degree relatives of the index patient clinically and genetically.Though highly interesting,the presentation of this case of a mitochondrial disorder lacks clinical and genetic data of the patient and his relatives.Outcome parameters,such as severity of disease,degree of progression,drugs,pathogenicity of the mutation,and multisystem involvement require a profound discussion.展开更多
Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spec...Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A〉G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease. Methods： Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A〉G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A〉G mutation ratio was performed by polymerase chain reaction （PCR）-restriction fragment length polymorphism. Correlation between m.3243A〉G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test. Results： Sixty-six patients （66%） had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures （76%）, short stature （73%）, elevated plasma lactate （70%）, abnormal magnetic resonance imaging/computed tomography （MRI/CT） changes （68%）, vomiting （55%）, decreased vision （52%）, headache （50%）, and muscle weakness （48%）. The mutation ratio was correlated negatively with onset age （r = -0.470, P 〈 0.001）. Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A〉G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio. Conclusions： Our study showed that half of Chinese pediatric patients with m.3243A〉G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A〉G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.展开更多
The purpose of this study was to investigate mitochondrial DNA (mtDNA) hypervariable segment-I (HVS-I) C-stretch variations and explore the significance of these variations in forensic and population genetics studies....The purpose of this study was to investigate mitochondrial DNA (mtDNA) hypervariable segment-I (HVS-I) C-stretch variations and explore the significance of these variations in forensic and population genetics studies. The C-stretch sequence variation was studied in 919 unrelated individuals from 8 Chinese ethnic groups using both direct and clone sequencing ap-proaches. Thirty eight C-stretch haplotypes were identified, and some novel and population specific haplotypes were also detected. The C-stretch genetic diversity (GD) values were relatively high, and probability (P) values were low. Additionally, C-stretch length heteroplasmy was observed in approximately 9% of individuals studied. There was a significant correlation (r=-0.961, P<0.01) between the expansion of the cytosine sequence length in the C-stretch of HVS-I and a reduction in the number of up-stream adenines. These results indicate that the C-stretch could be a useful genetic maker in forensic identification of Chinese populations. The results from the Fst and dA genetic distance matrix, neighbor-joining tree, and principal component map also suggest that C-stretch could be used as a reliable genetic marker in population genetics.展开更多
基金Supported by The Russian Ministry of Science and Education
文摘AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G】A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G】A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G】A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G】A heteroplasmy correlated both with age (r = 0.331, P 【 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G】A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G】A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G】A heteroplasmy level were found to have significantly higher age (P 【 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G】A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G】A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G】A mutation heteroplasmy with essential hypertension.
文摘We report for the first time the occurrence of heteroplasmy in Grey Partridge(Perdix perdix)revealed by means of two mitochondrial fragments.The possible serious biological and management implications of this exception to unilateral inheritance of mtDNA were underlined.
文摘In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of genetic predisposition. The sequencing of the human genome, which has led to the discovery of millions of sequence variations, makes it possible to study variations within sequences. These variations are limited to Single Nucleotide Polymorphisms (SNPs) and this common form of polymorphism occurs approximately every 1000 bases in the human genome and 1.8 million SNPs are currently listed according to [1]. The aim of this study is to gain a better understanding of the impact of mutations in the D-loop region of mtDNA on ovarian cancer in Senegalese women. This study involved searching for mutations in our study population after DNA extraction and sequencing. Mutations were found after a comparison of our sequences with the Cambridge reference sequence (NC_012920). The mutations found in the DNA studied extend from position 7 to position 16568 and most of these mutations are located in the hypervariate zones (HV1 and HV2). Heteroplasmy with three mutant alleles was also found in certain variants. Common mutations were found in both healthy and cancerous tissues, with almost identical frequencies in both types of tissue. This enabled us to understand the spread of tumor cells throughout the ovary.
基金supported by the grant from the National Cancer Institute(RO1 CA104666)supported in part by the Vanderbilt-Ingram Cancer Center(P30 CA68485)
文摘Little is known about the inheritance of very low heteroplasmy mitochondria DNA （mtDNA） variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, cor- resnondin to abottleneck of about 200 mtDNA.
基金supported by the National Natural Science Foundation of China(31222051)
文摘Few studies have explored the differences between Sanger and HTS methods in the results of mitogenome sequencing. We used a single individual of insect to study the differences between the sequences given by Sanger and PCR-free HTS methods. Here we provided evidence for biased results of sequencing due to different methods in the mitochondrial genes of atp6, atp8, cox1, cox2, cox3, Cytb, nad2, nad3, nad4, nad5, rrn S, rrnL, trnH, trn I, and control region at various degrees. Especially, in cox1, the differently sequenced nucleotides account for 2.6% of the complete length. Furthermore, the highest value of the intraspecific genetic distance based on K2 P accounts for 2.5% using a barcode fragment size of cox1（651 bp, Sanger）, while the maximum distance of the corresponding cox1 fragment obtained by the two sequencing methods was 5.0%. We revealed that the methods of Sanger and HTS may give different sequencing results of mitochondrial genes, which may reflect the heteroplasmy of mitogenomes within an insect individual. Therefore, researchers should be very cautious in using the mixed data of a gene given by different methods of sequencing.
基金Supported by The Russian Ministry of Science and Education
文摘Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.
文摘In a recent article Fu et al reported about a 52 years old female with a mitochondrial disorder due to the variant m.10158T>C in the mtDNA located gene MT-ND3.The study has a number of shortcomings.The study would particularly profit from providing more data about multisystem disease,from providing the current medication,the cerebro-spinal fluid findings,the detailed phenotypic presentation,and the genotype of first-degree relatives.Since the index patient had experienced recurrent seizures it is crucial to know the current and previous anti-seizure medication as it may strongly determine the outcome.Some of them are mitochondrion-toxic and particularly valproic acid may exhibit fatal side effects.The outcome may also depend on the degree of multisystem involvement why it is crucial to prospectively investigate the patient for subclinical involvement of organs not obviously affected.Additionally,the outcome of the stroke-like lesions on imaging would be interesting to see.Strokelike lesions may completely disappear or may end up as white matter lesion,laminar cortical necrosis,focal atrophy,cyst,or as the so-called toenail sign.There is also a need of discussing more profoundly the imaging findings and their diagnostic significance and to investigate first degree relatives of the index patient clinically and genetically.Though highly interesting,the presentation of this case of a mitochondrial disorder lacks clinical and genetic data of the patient and his relatives.Outcome parameters,such as severity of disease,degree of progression,drugs,pathogenicity of the mutation,and multisystem involvement require a profound discussion.
基金This study was supported by grants from National Natural Science Foundation of China （No. 81271256 and No. 81471153） and the Capital Characteristic Clinical Application Research Projects （No. Z 1311070022 13062）.
文摘Background： Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A〉G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease. Methods： Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A〉G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A〉G mutation ratio was performed by polymerase chain reaction （PCR）-restriction fragment length polymorphism. Correlation between m.3243A〉G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test. Results： Sixty-six patients （66%） had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures （76%）, short stature （73%）, elevated plasma lactate （70%）, abnormal magnetic resonance imaging/computed tomography （MRI/CT） changes （68%）, vomiting （55%）, decreased vision （52%）, headache （50%）, and muscle weakness （48%）. The mutation ratio was correlated negatively with onset age （r = -0.470, P 〈 0.001）. Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A〉G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio. Conclusions： Our study showed that half of Chinese pediatric patients with m.3243A〉G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A〉G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation.
基金supported by the Sciences and Technological Fundamental Resources Data of the Ministry of Education, China (No. 505015)the Key Project for Science and Technology of Shaanxi Province, China (No. 2004K09-G12)
文摘The purpose of this study was to investigate mitochondrial DNA (mtDNA) hypervariable segment-I (HVS-I) C-stretch variations and explore the significance of these variations in forensic and population genetics studies. The C-stretch sequence variation was studied in 919 unrelated individuals from 8 Chinese ethnic groups using both direct and clone sequencing ap-proaches. Thirty eight C-stretch haplotypes were identified, and some novel and population specific haplotypes were also detected. The C-stretch genetic diversity (GD) values were relatively high, and probability (P) values were low. Additionally, C-stretch length heteroplasmy was observed in approximately 9% of individuals studied. There was a significant correlation (r=-0.961, P<0.01) between the expansion of the cytosine sequence length in the C-stretch of HVS-I and a reduction in the number of up-stream adenines. These results indicate that the C-stretch could be a useful genetic maker in forensic identification of Chinese populations. The results from the Fst and dA genetic distance matrix, neighbor-joining tree, and principal component map also suggest that C-stretch could be used as a reliable genetic marker in population genetics.
