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Giunta S. Decoding human cancer with whole genome sequencing: a review of PCAWG Project studies published in February 2020. Cancer Metastasis Rev 2021; 40:909-924. [PMID: 34097189 PMCID: PMC8180541 DOI: 10.1007/s10555-021-09969-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/21/2021] [Indexed: 12/15/2022]
Abstract
Cancer is underlined by genetic changes. In an unprecedented international effort, the Pan-Cancer Analysis of Whole Genomes (PCAWG) of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) sequenced the tumors of over two thousand five hundred patients across 38 different cancer types, as well as the corresponding healthy tissue, with the aim of identifying genome-wide mutations exclusively found in cancer and uncovering new genetic changes that drive tumor formation. What set this project apart from earlier efforts is the use of whole genome sequencing (WGS) that enabled to explore alterations beyond the coding DNA, into cancer's non-coding genome. WGS of the entire cohort allowed to tease apart driving mutations that initiate and support carcinogenesis from passenger mutations that do not play an overt role in the disease. At least one causative mutation was found in 95% of all cancers, with many tumors showing an average of 5 driver mutations. The PCAWG Project also assessed the transcriptional output altered in cancer and rebuilt the evolutionary history of each tumor showing that initial driver mutations can occur years if not decades prior to a diagnosis. Here, I provide a concise review of the Pan-Cancer Project papers published on February 2020, along with key computational tools and the digital framework generated as part of the project. This represents an historic effort by hundreds of international collaborators, which provides a comprehensive understanding of cancer genetics, with publicly available data and resources representing a treasure trove of information to advance cancer research for years to come.
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Affiliation(s)
- Simona Giunta
- Laboratory of Genome Evolution, Department of Biology & Biotechnology "Charles Darwin", University of Rome Sapienza, Rome, Italy.
- The Rockefeller University, 1230 York Avenue, New York, NY, USA.
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Cisplatin selects short forms of the mitochondrial DNA OriB variant (16184-16193 poly-cytosine tract), which confer resistance to cisplatin. Sci Rep 2017; 7:46240. [PMID: 28393913 PMCID: PMC5385546 DOI: 10.1038/srep46240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/14/2017] [Indexed: 11/09/2022] Open
Abstract
A number of alternations in mitochondrial DNA (mtDNA) have been reported in different types of cancers, and the role of mtDNA in cancer has been attracting increasing interest. In order to investigate the relationship between mtDNA alternations and chemosensitivity, we constructed cybrid (trans-mitochondrial hybrid) cell lines carrying a HeLa nucleus and the mtDNA of healthy individuals because of the presence of somatic alternations in the mtDNA of many cancer cells. After a treatment with 1.0 μg/mL cisplatin for 10 days, we isolated 100 cisplatin-resistant clones, 70 of which carried the shorter mtDNA OriB variant (16184–16193 poly-cytosine tract), which was located in the control region of mtDNA. Whole mtDNA sequencing of 10 clones revealed no additional alternations. Re-construction of the HeLa nucleus and mtDNA from cisplatin-resistant cells showed that cisplatin resistance was only acquired by mtDNA alternations in the control region, and not by possible alternation(s) in the nuclear genome.
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Weng SW, Lin TK, Wang PW, Chen SD, Chuang YC, Liou CW. Single nucleotide polymorphisms in the mitochondrial control region are associated with metabolic phenotypes and oxidative stress. Gene 2013; 531:370-6. [DOI: 10.1016/j.gene.2013.08.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 08/02/2013] [Accepted: 08/05/2013] [Indexed: 12/22/2022]
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Ye Z, Gillson C, Sims M, Khaw KT, Plotka M, Poulton J, Langenberg C, Wareham NJ. The association of the mitochondrial DNA OriB variant (16184-16193 polycytosine tract) with type 2 diabetes in Europid populations. Diabetologia 2013; 56:1907-13. [PMID: 23702607 PMCID: PMC3737432 DOI: 10.1007/s00125-013-2945-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 05/03/2013] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS The association between the mitochondrial DNA 16181-16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case-Control Study and a meta-analysis to help quantify this association. METHODS We performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case-Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls. RESULTS Overall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case-Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03) CONCLUSIONS/INTERPRETATION: Results from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies.
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Affiliation(s)
- Zheng Ye
- Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, PO Box 285, Hills Road, Cambridge CB2 0QQ, UK.
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Palmieri VO, De Rasmo D, Signorile A, Sardanelli AM, Grattagliano I, Minerva F, Cardinale G, Portincasa P, Papa S, Palasciano G. T16189C mitochondrial DNA variant is associated with metabolic syndrome in Caucasian subjects. Nutrition 2010; 27:773-7. [PMID: 21146361 DOI: 10.1016/j.nut.2010.08.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Revised: 08/22/2010] [Accepted: 08/22/2010] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Different nuclear genes are thought to be involved in the regulation of the complex phenotype of metabolic syndrome (MS) and their number is increasing. A mutation in mitochondrial DNA (mtDNA), T4291C in transfer RNA isoleucine (tRNAile), has been associated with MS in a large American family. In addition, a mtDNA T16189C variant, already known to be associated with insulin resistance and type 2 diabetes mellitus in Caucasians, seems to underlie susceptibility to MS in the Chinese population. Our aim was to verify the T4291C and T16189C variants in subjects affected by different phenotypes of MS. METHODS Seventy patients with MS and 35 healthy individuals were investigated for the presence of the mtDNA variants by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS The T4291C variant was absent in patients and in controls. The T16189C variant was more frequent in patients with MS than in control subjects (21.4% versus 5.7%, P<0.04) and was associated with hypertension (P=0.01), waist circumference (P=0.02), body mass index (P=0.009), visceral fat thickness (P=0.04), homeostasis model assessment (P=0.03), and the number of MS diagnostic criteria (P=0.01). CONCLUSION The mtDNA T16189C variant is associated with MS and its different clinical expressions. Prospective studies are warranted to establish the clinical relevance of this association.
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Affiliation(s)
- Vincenzo Ostilio Palmieri
- Department of Internal Medicine and Public Medicine, Clinica Medica A. Murri, University of Bari, Bari, Italy.
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Abstract
Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders.
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Kang BY, Choi H, Kwon J, Lee JK. The 5178C/A and 16189T/C polymorphisms of mitochondrial DNA in Korean men and their associations with blood iron metabolism. Mol Biol Rep 2010; 37:4051-7. [DOI: 10.1007/s11033-010-0064-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2009] [Accepted: 03/05/2010] [Indexed: 01/17/2023]
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Wang PW, Lin TK, Weng SW, Liou CW. Mitochondrial DNA variants in the pathogenesis of type 2 diabetes - relevance of asian population studies. Rev Diabet Stud 2009; 6:237-46. [PMID: 20043036 DOI: 10.1900/rds.2009.6.237] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Mitochondrial dysfunction involves defective insulin secretion by pancreatic beta-cells, and insulin resistance in insulin-sensitive tissues such as muscle and adipose tissue. Mitochondria are recognized as the most important cellular source of energy, and the major generator of intracellular reactive oxygen species (ROS). Intracellular antioxidative systems have been developed to cope with increased oxidative damage. In case of minor oxidative stress, the cells may increase the number of mitochondria to produce more energy. A mechanism called mitochondrial biogenesis, involving several transcription factors and regulators, controls the quantity of mitochondria. When oxidative damage is advanced beyond the repair capacity of antioxidative systems, then oxidative stress can lead to cell death. Therefore, this organelle is central to cell life or death. Available evidence increasingly shows genetic linkage between mitochondrial DNA (mtDNA) alterations and type 2 diabetes (T2D). Based on previous studies, the mtDNA 16189 variant is associated with metabolic syndrome, higher fasting insulin concentration, insulin resistance index and lacunar cerebral infarction. These data support the involvement of mitochondrial genetic variation in the pathogenesis of T2D. Importantly, phylogeographic studies of the human mtDNAs have revealed that the human mtDNA tree is rooted in Africa and radiates into different geographic regions and can be grouped as haplogroups. The Asian populations carry very different mtDNA haplogroups as compared to European populations. Therefore, it is critically important to determine the role of mtDNA polymorphisms in T2D.
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Affiliation(s)
- Pei-Wen Wang
- Department of Internal Medicine, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 83305
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Pierron D, Rocher C, Amati-Bonneau P, Reynier P, Martin-Négrier ML, Allouche S, Batandier C, Mousson de Camaret B, Godinot C, Rotig A, Feldmann D, Bellanne-Chantelot C, Arveiler B, Pennarun E, Rossignol R, Crouzet M, Murail P, Thoraval D, Letellier T. New evidence of a mitochondrial genetic background paradox: impact of the J haplogroup on the A3243G mutation. BMC MEDICAL GENETICS 2008; 9:41. [PMID: 18462486 PMCID: PMC2409300 DOI: 10.1186/1471-2350-9-41] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Accepted: 05/07/2008] [Indexed: 11/10/2022]
Abstract
BACKGROUND The A3243G mutation in the tRNALeu gene (UUR), is one of the most common pathogenic mitochondrial DNA (mtDNA) mutations in France, and is associated with highly variable and heterogeneous disease phenotypes. To define the relationships between the A3243G mutation and mtDNA backgrounds, we determined the haplogroup affiliation of 142 unrelated French patients - diagnosed as carriers of the A3243G mutation - by control-region sequencing and RFLP survey of their mtDNAs. RESULTS The analysis revealed 111 different haplotypes encompassing all European haplogroups, indicating that the 3243 site might be a mutational hot spot. However, contrary to previous findings, we observed a statistically significant underepresentation of the A3243G mutation on haplogroup J in patients (p = 0.01, OR = 0.26, C.I. 95%: 0.08-0.83), suggesting that might be due to a strong negative selection at the embryo or germ line stages. CONCLUSION Thus, our study supports the existence of mutational hotspot on mtDNA and a "haplogroup J paradox," a haplogroup that may increase the expression of mtDNA pathogenic mutations, but also be beneficial in certain environmental contexts.
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Affiliation(s)
- Denis Pierron
- 1Université Bordeaux 1, Laboratoire d'Anthropologie des Populations du Passé, UMR 5199 PACEA, 33400 Talence, France.
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Wani AA, Ahanger SH, Bapat SA, Rangrez AY, Hingankar N, Suresh CG, Barnabas S, Patole MS, Shouche YS. Analysis of mitochondrial DNA sequences in childhood encephalomyopathies reveals new disease-associated variants. PLoS One 2007; 2:e942. [PMID: 17895983 PMCID: PMC1976591 DOI: 10.1371/journal.pone.0000942] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2007] [Accepted: 08/30/2007] [Indexed: 12/01/2022] Open
Abstract
Background Mitochondrial encephalomyopathies are a heterogeneous group of clinical disorders generally caused due to mutations in either mitochondrial DNA (mtDNA) or nuclear genes encoding oxidative phosphorylation (OXPHOS). We analyzed the mtDNA sequences from a group of 23 pediatric patients with clinical and morphological features of mitochondrial encephalopathies and tried to establish a relationship of identified variants with the disease. Methodology/Principle Findings Complete mitochondrial genomes were amplified by PCR and sequenced by automated DNA sequencing. Sequencing data was analyzed by SeqScape software and also confirmed by BLASTn program. Nucleotide sequences were compared with the revised Cambridge reference sequence (CRS) and sequences present in mitochondrial databases. The data obtained shows that a number of known and novel mtDNA variants were associated with the disease. Most of the non-synonymous variants were heteroplasmic (A4136G, A9194G and T11916A) suggesting their possibility of being pathogenic in nature. Some of the missense variants although homoplasmic were showing changes in highly conserved amino acids (T3394C, T3866C, and G9804A) and were previously identified with diseased conditions. Similarly, two other variants found in tRNA genes (G5783A and C8309T) could alter the secondary structure of Cys-tRNA and Lys-tRNA. Most of the variants occurred in single cases; however, a few occurred in more than one case (e.g. G5783A and A10149T). Conclusions and Significance The mtDNA variants identified in this study could be the possible cause of mitochondrial encephalomyopathies with childhood onset in the patient group. Our study further strengthens the pathogenic score of known variants previously reported as provisionally pathogenic in mitochondrial diseases. The novel variants found in the present study can be potential candidates for further investigations to establish the relationship between their incidence and role in expressing the disease phenotype. This study will be useful in genetic diagnosis and counseling of mitochondrial diseases in India as well as worldwide.
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Affiliation(s)
| | | | | | | | - Nitin Hingankar
- Division of Biochemical Sciences, National Chemical Laboratory, Pune, India
| | - C. G. Suresh
- Division of Biochemical Sciences, National Chemical Laboratory, Pune, India
| | - Shama Barnabas
- Division of Biochemical Sciences, National Chemical Laboratory, Pune, India
| | | | - Yogesh S. Shouche
- National Centre for Cell Science, Pune, India
- * To whom correspondence should be addressed. E-mail:
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Salvador M, Villegas A, Llorente L, Ropero P, González FA, Bustamante L. 16189 Mitochondrial variant and iron overload. Ann Hematol 2007; 86:463-4. [PMID: 17340136 DOI: 10.1007/s00277-007-0270-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2007] [Accepted: 01/25/2007] [Indexed: 11/26/2022]
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Szibor R, Plate I, Heinrich M, Michael M, Schöning R, Wittig H, Lutz-Bonengel S. Mitochondrial D-loop (CA)n repeat length heteroplasmy: frequency in a German population sample and inheritance studies in two pedigrees. Int J Legal Med 2006; 121:207-13. [PMID: 16645851 DOI: 10.1007/s00414-006-0096-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2005] [Accepted: 03/29/2006] [Indexed: 11/26/2022]
Abstract
Sequence analysis of the human mitochondrial genome (mtDNA) has proven to be a valuable tool in forensic identity testing and the analysis of crime scene stains. In contrast to the very expensive sequencing technique, typing of different length variants can greatly facilitate screening of a large number of traces for their relevance during casework. Within the mitochondrial control region, a dinucleotide (CA)( n ) repeat locus is present. To assess the discrimination power of this marker, we have determined (CA)( n ) allele distribution and the frequency of heteroplasmy in a population sample of 2,458 Germans. The inclination to develop heteroplasmic mixtures (CA)( n )/(CA)( n-1) was positively correlated with the number of CA repeats in the mtDNA. In addition, we have studied the inheritance patterns of (CA)( n ) repeat sequence heteroplasmy in two pedigrees. In one pedigree, we also found a length heteroplasmy in the homopolymeric C-tract (nt 303-309). Our data show stable inheritance of heteroplasmy within the homopolymeric C-stretch, but rather unstable inheritance regarding the (CA)( n ) repeat locus.
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Affiliation(s)
- Reinhard Szibor
- Institut für Rechtsmedizin, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany.
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Cardaioli E, Da Pozzo P, Cerase A, Sicurelli F, Malandrini A, De Stefano N, Stromillo ML, Battisti C, Dotti MT, Federico A. Rapidly progressive neurodegeneration in a case with the 7472insC mutation and the A7472C polymorphism in the mtDNA tRNA ser(UCN) gene. Neuromuscul Disord 2005; 16:26-31. [PMID: 16368237 DOI: 10.1016/j.nmd.2005.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2005] [Revised: 09/28/2005] [Accepted: 11/02/2005] [Indexed: 10/25/2022]
Abstract
The authors report the clinical, neuroimaging, muscle biopsy and mtDNA findings in a patient affected by bilateral hearing loss and mental retardation since infancy, presenting at age 31 years with a rapid deterioration of mental status and ataxia leading to vegetative condition and death at the age of 32 years. Clinical and genetic studies have been also performed in the mother, affected by neurosensorial hearing loss. Muscle biopsy showed severe mitochondrial alterations in the propositus and evidence of mitochondrial alterations in his mother. Direct mtDNA sequencing in all family members revealed the known 7472insC mutation and the recently described A7472C sequence variation in the tRNA(Ser(UCN))gene. RFLP-PCR confirmed the heteroplasmic nature of the two mutations and failed to find the second transversion in 200 controls. The percentage of mutant genomes harbouring 7472insC ranged from 3 to 7% in asymptomatic family members to 70% in the proband and his mother, whereas the percentage of A7472C mutant genomes was about 90% in all maternal relatives except the proband (56%) and his sister (5%). In conclusion, this is the first report of a rapidly progressive encephalopathy in association with the 7472insC mutation in mtDNA, combined with an A>C variation at the same nucleotide with a possible suppression effect on the pathogenic mutation.
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Affiliation(s)
- Elena Cardaioli
- Department of Neurological and Behavioural Sciences, Medical School, University of Siena, Viale Bracci 2, 53100 Siena, Italy
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Mohlke KL, Jackson AU, Scott LJ, Peck EC, Suh YD, Chines PS, Watanabe RM, Buchanan TA, Conneely KN, Erdos MR, Narisu N, Enloe S, Valle TT, Tuomilehto J, Bergman RN, Boehnke M, Collins FS. Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns. Hum Genet 2005; 118:245-54. [PMID: 16142453 DOI: 10.1007/s00439-005-0046-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2004] [Accepted: 07/12/2005] [Indexed: 12/29/2022]
Abstract
Mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, suggesting that variants in the mitochondrial genome may contribute to diabetes susceptibility. In a study of Finnish families ascertained for type 2 diabetes mellitus (T2DM), we genotyped single nucleotide polymorphisms (SNPs) based on phylogenetic networks. These SNPs defined eight major haplogroups and subdivided groups H and U, which are common in Finns. We evaluated association with both diabetes disease status and up to 14 diabetes-related traits for 762 cases, 402 non-diabetic controls, and 465 offspring of genotyped females. Haplogroup J showed a trend toward association with T2DM affected status (OR 1.69, P=0.056) that became slightly more significant after excluding cases with affected fathers (OR 1.77, P=0.045). We also genotyped non-haplogroup-tagging SNPs previously reported to show evidence for association with diabetes or related traits. Our data support previous evidence for association of T16189C with reduced ponderal index at birth and also show evidence for association with reduced birthweight but not with diabetes status. Given the multiple tests performed and the significance levels obtained, this study suggests that mitochondrial genome variants may play at most a modest role in glucose metabolism in the Finnish population. Furthermore, our data do not support a reported maternal inheritance pattern of T2DM but instead show a strong effect of recall bias.
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Affiliation(s)
- Karen L Mohlke
- Department of Genetics, University of North Carolina, 4109-F Neurosciences Research Building, 103 Mason Farm Road, CB#7264, 27599-7264, Chapel Hill, NC, USA.
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Weng SW, Liou CW, Lin TK, Wei YH, Lee CF, Eng HL, Chen SD, Liu RT, Chen JF, Chen IY, Chen MH, Wang PW. Association of mitochondrial deoxyribonucleic acid 16189 variant (T->C transition) with metabolic syndrome in Chinese adults. J Clin Endocrinol Metab 2005; 90:5037-40. [PMID: 15972579 DOI: 10.1210/jc.2005-0227] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
OBJECTIVE A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T-->C transition) has been associated with small birth size, adulthood hyperglycemia, and insulin resistance in Caucasians. In this study, we investigated whether mtDNA 16189 variant is associated with metabolic syndrome in Chinese subjects. METHODS Six hundred fifteen Chinese adults, aged 40 yr or older, were recruited in this study. The 16189 variant of mtDNA was detected using PCR and restriction enzyme digestion. Metabolic syndrome was diagnosed on modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using body mass index (BMI) instead of waist circumference. An association study was performed with chi2 test and logistic regression analysis. RESULTS The prevalence of the 16189 variant was higher in patients with metabolic syndrome than in those without: 44% (125 of 284) vs. 33.2% (110 of 331) (P = 0.006). The association between this 16189 variant of mtDNA and metabolic syndrome (P = 0.021) remained significant even after correcting for age and BMI. As to the individual traits, the prevalence of fasting plasma glucose of at least 110 mg/dl (> or =6.1 mmol/liter) [(51.5% (121 of 235) vs. 42.1% (160 of 380); P = 0.023], type 2 diabetes mellitus [48.1% (113 of 235) vs. 39.2% (149 of 380); P = 0.031], and hypertriglyceridemia [44.3% (104 of 235) vs. 35.8% (136 of 380); P = 0.037] were significantly higher in subjects harboring the 16189 variant of mtDNA than those with the wild type. However, the prevalence of hypertension [53.2% (125 of 235) vs. 47.6% (181 of 380); P = 0.180], BMI greater than 25 kg/m2 [48.5% (114 of 235) vs. 43.9% (167 of 380); P = 0.270], and low high-density lipoprotein cholesterol [61.3% (144 of 235) vs. 54.7% (208 of 380); P = 0.111] did not reach a significant difference between the two groups. Furthermore, there was a trend of increasing frequency of occurrence of the 16189 variant in individuals having an increasing number of components of metabolic syndrome (Ptrend < 0.005). CONCLUSION Our data strongly suggest that mtDNA 16189 variant underlies susceptibility to metabolic syndrome in the Chinese population.
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Affiliation(s)
- Shao-Wen Weng
- Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-sung Hsiang, Kaohsiung Hsien, Taiwan 833
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Bini C, Pappalardo G. mtDNA HVI length heteroplasmic profile in different tissues of maternally related members. Forensic Sci Int 2005; 152:35-8. [PMID: 15939174 DOI: 10.1016/j.forsciint.2005.03.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2004] [Revised: 03/04/2005] [Accepted: 03/05/2005] [Indexed: 11/18/2022]
Abstract
Sequencing of the homopolymeric tract of cytosines (C-stretch) in human mitochondrial HVI region usually results in a blurred pattern beyond it when a T/C transition at nt 16189 occurs: it depends on a length heteroplasmy probably arising through a replication slippage. This study aims to investigate the distribution of heteroplasmic length variants within three related individuals along maternal lineage by cloning approach. Sequencing of multiple independent clones (12--14) is sufficient to yield heteroplasmic profiles. In addition, we illustrate a direct correlation between expansion of heteroplasmy modal length and reduction of the number of adenines preceding the homopolymeric tract; this association may be useful in pedigree analysis and in forensic field for tissues comparison, single hair sample included.
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Affiliation(s)
- C Bini
- Department of Medicine and Public Health, Section of Legal Medicine, University of Bologna, via Irnerio 49, 40126 Bologna, Italy
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Dai JG, Lei X, Min JX, Zhang GQ, Wei H. Mitochondrial DNA sequence analysis of two mouse hepatocarcinoma cell lines. World J Gastroenterol 2005; 11:264-7. [PMID: 15633228 PMCID: PMC4205414 DOI: 10.3748/wjg.v11.i2.264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study genetic difference of mitochondrial DNA (mtDNA) between two hepatocarcinoma cell lines (Hca-F and Hca-P) with diverse metastatic characteristics and the relationship between mtDNA changes in cancer cells and their oncogenic phenotype.
METHODS: Mitochondrial DNA D-loop, tRNAMet+Glu+Ile and ND3 gene fragments from the hepatocarcinoma cell lines with 1100, 1126 and 534 bp in length respectively were analysed by PCR amplification and restriction fragment length polymorphism techniques. The D-loop 3’ end sequence of the hepatocarcinoma cell lines was determined by sequencing.
RESULTS: No amplification fragment length polymorphism and restriction fragment length polymorphism were observed in tRNAMet+Glu+Ile, ND3 and D-loop of mitochondrial DNA of the hepatocarcinoma cells. Sequence differences between Hca-F and Hca-P were found in mtDNA D-loop.
CONCLUSION: Deletion mutations of mitochondrial DNA restriction fragment may not play a significant role in carcinogenesis. Genetic difference of mtDNA D-loop between Hca-F and Hca-P, which may reflect the environmental and genetic influences during tumor progression, could be linked to their tumorigenic phenotypes.
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MESH Headings
- Animals
- Base Sequence
- Carcinoma, Hepatocellular/genetics
- Cell Line, Tumor
- DNA Primers
- DNA, Mitochondrial/genetics
- Liver Neoplasms/genetics
- Mice
- Mutation
- Polymerase Chain Reaction
- Polymorphism, Restriction Fragment Length
- RNA, Transfer, Glu/genetics
- RNA, Transfer, Ile/genetics
- RNA, Transfer, Met/genetics
- Restriction Mapping
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Affiliation(s)
- Ji-Gang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
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18
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Da Pozzo P, Cardaioli E, Radi E, Federico A. Sequence analysis of the complete mitochondrial genome in patients with mitochondrial encephaloneuromyopathies lacking the common pathogenic DNA mutations. Biochem Biophys Res Commun 2004; 324:360-4. [PMID: 15465027 DOI: 10.1016/j.bbrc.2004.09.058] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2004] [Indexed: 11/29/2022]
Abstract
The purpose of this study was to identify novel mitochondrial deoxyribonucleic acid (mtDNA) mutations in a series of patients with clinical and/or morphological features of mitochondrial dysfunction, but still no genetic diagnosis. A heterogeneous group of clinical disorders is caused by mutations in mtDNA that damage respiratory chain function of cell energy production. We developed a method to systematically screen the entire mitochondrial genome. The sequence-data were obtained with a rapid automated system. In the six mitochondrial genomes analysed we found 20 variants of the revised Cambridge reference sequence [Nat. Genet. 23 (1999) 147]. In skeletal muscle nineteen novel mtDNA variants were homoplasmic, suggesting secondary pathogenicity or co-responsibility in determination of the disease. In one patient we identified a novel heteroplasmic mtDNA mutation which presumably has a pathogenic role. This screening is therefore useful to extend the mtDNA polymorphism database and should facilitate definition of disease-related mutations in human mtDNA.
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Affiliation(s)
- Paola Da Pozzo
- Unit of Neurology and Neurometabolic Diseases, Department of Neurological and Behavioural Sciences and Centre for Research, Therapy and Prevention of Neurohandicap, University of Siena, Italy
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19
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LIOU CHIAWEI, LIN TSUKUNG, HUANG FENGMEI, CHEN TZULING, LEE CHENGFENG, CHUANG YAOCHUNG, TAN TENGYEOW, CHANG KUCHOU, WEI YAUHUEI. Association of the Mitochondrial DNA 16189 T to C Variant with Lacunar Cerebral Infarction: Evidence from a Hospital-Based Case-Control Study. Ann N Y Acad Sci 2004. [DOI: 10.1196/annals.1293.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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20
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Liou CW, Lin TK, Huang FM, Chen TL, Lee CF, Chuang YC, Tan TY, Chang KC, Wei YH. Association of the mitochondrial DNA 16189 T to C variant with lacunar cerebral infarction: evidence from a hospital-based case-control study. Ann N Y Acad Sci 2004; 1011:317-24. [PMID: 15126308 DOI: 10.1007/978-3-662-41088-2_31] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A transition of T to C at nucleotide position 16189 in the hypervariable D-loop region of mitochondrial DNA (mtDNA) has attracted research interest for its probable correlation with increasing insulin resistance and development of diabetes mellitus (DM) in adult life. In this article, we present our observations of the positive relationship between this variant and cerebral infarction. Six hundred and one subjects in two groups-one with cerebral infarction (307 cases), the other with no cerebral infarction (294 cases)-were recruited. Their clinical features, fasting blood sugar and insulin levels, and insulin resistance index, were recorded. Patients with cerebral infarction were further categorized into four different subgroups according to the TOAST criteria for stroke classification. The results showed the occurrence of the mtDNA 16189 variant in 34.2% of patients with cerebral infarction and in 26.5% of normal controls. The difference in the occurrence rates between the two groups was statistically significant (P = 0.041). Further studies of the occurrence rate in each stroke subgroup revealed that the variant occurred at the highest frequency in the small vessel subgroup (41.5%). The difference in occurrence rate between this subgroup and the normal controls is highly significant (P = 0.006). These results correlated well with the findings of significantly increased levels of average fasting blood insulin and a higher index of average insulin resistance in the small vessel subgroup of patients harboring this mtDNA variant. Taken together, we suggest that the mtDNA 16189 variant is a predisposing genetic factor for the development of insulin resistance and may be related to various phenotypic expressions in adult life such as development of DM and vascular pathologies involved in stroke and cardiovascular diseases.
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Affiliation(s)
- Chia-Wei Liou
- Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
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21
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Momiyama Y, Furutani M, Suzuki Y, Ohmori R, Imamura SI, Mokubo A, Asahina T, Murata C, Kato K, Anazawa S, Hosokawa K, Atsumi Y, Matsuoka K, Kimura M, Kasanuki H, Ohsuzu F, Matsuoka R. A mitochondrial DNA variant associated with left ventricular hypertrophy in diabetes. Biochem Biophys Res Commun 2004; 312:858-64. [PMID: 14680844 DOI: 10.1016/j.bbrc.2003.10.195] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2003] [Indexed: 11/28/2022]
Abstract
Diabetes was reported to be associated with a mitochondrial (mt) DNA mutation at 3243 and variants at 1310, 1438, 3290, 3316, 3394, 12,026, 15,927, and 16,189. Among these mtDNA abnormalities, those at 3243, 3316, 15,927, and 16,189 were also suggested to cause cardiomyopathies. We investigated the prevalence of such mtDNA abnormalities in 68 diabetic patients with LV hypertrophy (LVH), 100 without LVH, and 100 controls. Among the 9 mtDNA abnormalities, those at 3243, 3316, and 15,927 tended to be more prevalent in diabetic patients with LVH than in those without LVH (1%, 1%, and 4% vs. 0%, 0%, and 0%). Notably, the variant at 16,189 was more prevalent in diabetic patients with LVH than without LVH (46% vs. 24%, [Formula: see text] ). The odds ratio for LVH was 3.0 (95% CI, 1.5-6.1) for the 16,189 variant. A common mtDNA variant at 16,189 was found to be associated with LVH in diabetic patients.
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Affiliation(s)
- Yukihiko Momiyama
- The Heart Institute of Japan, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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22
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Livesey KJ, Wimhurst VLC, Carter K, Worwood M, Cadet E, Rochette J, Roberts AG, Pointon JJ, Merryweather-Clarke AT, Bassett ML, Jouanolle AM, Mosser A, David V, Poulton J, Robson KJH. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J Med Genet 2004; 41:6-10. [PMID: 14729817 PMCID: PMC1757237 DOI: 10.1136/jmg.2003.008805] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. METHODS Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. RESULTS The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). CONCLUSIONS Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.
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Affiliation(s)
- K J Livesey
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, UK
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23
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Sudoyo H, Suryadi H, Sitorus N, Soegondo S, Pranoto A, Marzuki S. Mitochondrial genome and susceptibility to diabetes mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 531:19-36. [PMID: 12916778 DOI: 10.1007/978-1-4615-0059-9_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Herawati Sudoyo
- Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta, Indonesia.
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24
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Bayona-Bafaluy MP, Fernández-Silva P, Enríquez JA. The thankless task of playing genetics with mammalian mitochondrial DNA: a 30-year review. Mitochondrion 2002; 2:3-25. [PMID: 16120305 DOI: 10.1016/s1567-7249(02)00044-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2002] [Revised: 05/22/2002] [Accepted: 06/05/2002] [Indexed: 10/27/2022]
Abstract
The advances obtained through the genetic tools available in yeast for studying the oxidative phosphorylation (OXPHOS) biogenesis and in particular the role of the mtDNA encoded genes, strongly contrast with the very limited benefits that similar approaches have generated for the study of mammalian mtDNA. Here we review the use of the genetic manipulation in mammalian mtDNA, its difficulty and the main types of mutants accumulated in the past 30 years and the information derived from them. We also point out the need for a substantial improvement in this field in order to obtain new tools for functional genetic studies and for the generation of animal models of mtDNA-linked diseases.
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Affiliation(s)
- M Pilar Bayona-Bafaluy
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Miguel Servet 177, Zaragoza 50013, Spain
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25
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Kim JH, Park KS, Cho YM, Kang BS, Kim SK, Jeon HJ, Kim SY, Lee HK. The prevalence of the mitochondrial DNA 16189 variant in non-diabetic Korean adults and its association with higher fasting glucose and body mass index. Diabet Med 2002; 19:681-4. [PMID: 12147150 DOI: 10.1046/j.1464-5491.2002.00747.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS To evaluate the prevalence of the 16189 variant of mitochondrial DNA in Korean adults and its association with insulin resistance. METHODS We investigated 160 non-diabetic subjects from a community-based diabetes survey conducted in Yonchon County, Korea in 1993. We extracted the DNA from peripheral blood and examined the 16189 variant by polymerase chain reaction and restrictive enzyme digestion. We compared body mass index (BMI), blood pressure, fasting plasma glucose, 2-h plasma glucose after 75 g glucose load, fasting insulin, cholesterol, and homeostasis model assessment of insulin resistance and beta-cell function between the subjects with 16189 variant and wild type. RESULTS The prevalence of the 16189 variant in Korean adults was 28.8% (46 of 160). Subjects with the 16189 variant had higher fasting glucose and BMI than those with wild type, but fasting insulin, homeostasis model assessment of insulin resistance and beta-cell function, cholesterol, and blood pressure were not different between two groups. CONCLUSION Our results provide evidence for an association of a frequent mitochondrial polymorphism with higher fasting glucose and the risk factors of diabetes mellitus.
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Affiliation(s)
- J H Kim
- Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea
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26
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Imaizumi K, Parsons TJ, Yoshino M, Holland MM. A new database of mitochondrial DNA hypervariable regions I and II sequences from 162 Japanese individuals. Int J Legal Med 2002; 116:68-73. [PMID: 12056523 DOI: 10.1007/s004140100211] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A database of mitochondrial DNA (mtDNA) hypervariable region 1 (HV1) and region 2 (HV2) sequences of the mtDNA control region was established from 162 unrelated Japanese individuals. The random match probability and the genetic diversity for this database were 0.96% and 0.997, respectively. Length heteroplasmy in the C-stretch regions located around position 16189 in HVI and 310 in HV2 was observed in 37% and 38% of the samples, respectively. A strategy using internal sequencing primers was devised to obtain confirmed sequences in these length heteroplasmic individuals. This database, combined with other mtDNA sequence databases from the Japanese population, will permit the significance of mtDNA match results to be properly reported in mtDNA typing casework in Japan.
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Affiliation(s)
- K Imaizumi
- National Research Institute of Police Science, Kashiwa, Chiba, Japan.
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27
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Farge G, Touraille S, Le Goff S, Petit N, Renoux M, Morel F, Alziari S. The nuclear genome is involved in heteroplasmy control in a mitochondrial mutant strain of Drosophila subobscura. EUROPEAN JOURNAL OF BIOCHEMISTRY 2002; 269:998-1005. [PMID: 11846802 DOI: 10.1046/j.0014-2956.2001.02737.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Most (78%) mitochondrial genomes in the studied mutant strain of Drosophila subobscura have undergone a large-scale deletion (5 kb) in the coding region. This mutation is stable, and is transmitted intact to the offspring. This animal model of major rearrangements of mitochondrial genomes can be used to analyse the involvement of the nuclear genome in the production and maintenance of these rearrangements. Successive backcrosses between mutant strain females and wild-type males yield a biphasic change in heteroplasmy level: (a) a 5% decrease in mutated genomes per generation (from 78 to 55%), until the nuclear genome is virtually replaced by the wild-type genome (seven to eight crosses); and (b) a continuous decrease of 0.5% per generation when the nuclear context is completely wild-type. In parallel with these changes, NADH dehydrogenase activity, which is halved in the mutant strain (five subunits of this complex are affected by the mutation), gradually increases and stabilizes near the wild-type activity. A return to a nuclear context is accompanied by the opposite phenomena: progressive increase in heteroplasmy level and stabilization at the value seen in the wild-type strain and a decrease in the activity of complex I. These results indicate that the nuclear genome plays an important role in the control of heteroplasmy level and probably in the production of rearranged genomes.
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Affiliation(s)
- Géraldine Farge
- Equipe Génome Mitochondrial, UMR CNRS 6547, Université Blaise Pascal-Clermont II, Aubière, France
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28
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Abstract
Low birthweight is linked to increased risk of adulthood type 2 diabetes and this risk may be secondary to adaptive metabolic/endocrine mechanisms in the fetus which ensure survival during undernutrition. Thrifty genotypes, which enhance these adaptations to undernutrition may further protect survival from fetal life to reproductive age, but at the expense of longer-term disease risk. Potential fetal thrifty genotypes include the insulin gene variable number of tandem repeats class III/III genotype which is associated with larger size at birth and type 2 diabetes in adults and these effects may relate to paternally inherited genotypes. In contrast, mechanisms, which restrain fetal growth and protect maternal survival may be inherited on mitochondrial DNA or maternally expressed imprinted genes such as IGF2R. Finally, larger early postnatal size is also important for survival and some genotypes may promote infancy growth, but in affluent societies may predispose to obesity and increased risks for adulthood type 2 diabetes.
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Affiliation(s)
- K K Ong
- Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Box 116, Cambridge CB2 2QQ, UK
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29
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Affiliation(s)
- L A Tully
- Biotechnology Division, National Institute of Standards and Technology, 100 Bureau Drive, Stop 8311, Gaithersburg, MD 20899-8311, USA
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30
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Gill-Randall R, Sherratt EJ, Thomas AW, Gagg JW, Lee A, Alcolado JC. Analysis of a polycytosine tract and heteroplasmic length variation in the mitochondrial DNA D-loop of patients with diabetes, MELAS syndrome and race-matched controls. Diabet Med 2001; 18:413-6. [PMID: 11472454 DOI: 10.1046/j.1464-5491.2001.00477.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM The T to C substitution at position 16189 nt of the human mitochondrial genome has been associated with the development of heteroplasmic length variation in the control region of mtDNA. Previous reports have suggested that this defect may be associated with the development of other pathogenic mtDNA mutations, including the diabetogenic A to G mutation in the tRNALEU(UUR). Recently the 16189 nt variant has also been associated with insulin resistance in British adult men. In order to investigate these associations further we studied 23 patients with the 3243 nt mutation, 150 patients with Type 2 diabetes and 149 non-diabetic controls. METHODS The region around 16189 nt was investigated by polymerase chain reaction-restriction fragment length polymorphism analysis and automated sequencing. RESULTS We find that the T to C substitution at 16189 nt is associated with heteroplasmic length variation only when the resultant polycytosine tract is not interrupted by a second mutation. There are no significant differences in the prevalence of the 16189 nt variant or heteroplasmic length variation between patients with the 3243 nt mutation, patients with Type 2 diabetes or race-matched normal controls. CONCLUSIONS We conclude that these variants are likely to represent normal polymorphisms and that previously reported associations should be treated with caution unless they can be replicated in other populations.
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Affiliation(s)
- R Gill-Randall
- Department of Medicine, University of Wales College of Medicine and School of Applied Sciences, University of Wales Institute of Cardiff, Cardiff, UK
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31
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Calloway CD, Reynolds RL, Herrin GL, Anderson WW. The frequency of heteroplasmy in the HVII region of mtDNA differs across tissue types and increases with age. Am J Hum Genet 2000; 66:1384-97. [PMID: 10739761 PMCID: PMC1288202 DOI: 10.1086/302844] [Citation(s) in RCA: 120] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/1999] [Accepted: 01/25/2000] [Indexed: 11/03/2022] Open
Abstract
An immobilized sequence-specific oligonucleotide (SSO) probe system consisting of 16 SSO probes that detect sequence polymorphisms within five regions of the mtDNA control region was used to investigate the frequency of heteroplasmy in human mtDNA. Five regions of hypervariable region II (HVII) of the control region were studied in blood-, muscle-, heart-, and brain-tissue samples collected from 43 individuals during autopsy. An initial search for heteroplasmy was conducted by use of the SSO probe system. Samples in which multiple probe signals were detected within a region were sequenced for the HVII region, to verify the typing-strip results. The frequency of heteroplasmy was 5 of 43 individuals, or 11.6%. The frequency of heteroplasmy differed across tissue types, being higher in muscle tissue. The difference in the frequency of heteroplasmy across different age groups was statistically significant, which suggests that heteroplasmy increases with age. As a test for contamination and to confirm heteroplasmy, the samples were sequenced for the HVI region and were typed by use of a panel of five polymorphic nuclear markers. Portions of the tissues that appeared to be heteroplasmic were extracted at least one additional time; all gave identical results. The results from these tests indicate that the multiple sequences present in individual samples result from heteroplasmy and not from contamination.
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Affiliation(s)
- C D Calloway
- Roche Molecular Systems, Alameda, CA, 94501, USA. Sandy.
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32
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Nishimaki Y, Sato K, Fang L, Ma M, Hasekura H, Boettcher B. Sequence polymorphism in the mtDNA HV1 region in Japanese and Chinese. Leg Med (Tokyo) 1999; 1:238-49. [PMID: 12935475 DOI: 10.1016/s1344-6223(99)80044-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
We investigated the nucleotide substitution and insertion/deletion polymorphism of the HV1 region in mtDNA by sequencing blood samples from 150 unrelated Japanese and 120 unrelated Chinese and revealed 108 sequence types from the Japanese group and 87 sequence types from the Chinese. Some substitutions were characteristic of East Asian populations as compared with data reported on Caucasian populations, and some were area-specific among East Asians. The level of genetic diversity and genetic identity revealed by this system was superior to that obtained by VNTR systems for nuclear DNA. These results show the usefulness of mtDNA sequencing in forensic examination for individual identification. We also found some sequence variations in the homopolymeric tract of cytosine (np16180-16194 in the Anderson's reference sequence) that might suggest some hints regarding the mechanisms for and the development of heteroplasmic length variations in this tract.
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Affiliation(s)
- Y Nishimaki
- Department of Legal Medicine, Tokyo Medical and Dental University School of Medicine, Tokyo 113-8519, Japan
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33
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Comparative Identity and Homogeneity Testing of the mtDNA HV1 Region Using Denaturing Gradient Gel Electrophoresis. J Forensic Sci 1999. [DOI: 10.1520/jfs14586j] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Tamura G, Nishizuka S, Maesawa C, Suzuki Y, Iwaya T, Sakata K, Endoh Y, Motoyama T. Mutations in mitochondrial control region DNA in gastric tumours of Japanese patients. Eur J Cancer 1999; 35:316-9. [PMID: 10448277 DOI: 10.1016/s0959-8049(98)00360-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The non-coding control region of mitochondrial DNA (mtDNA), containing the hypervariable regions HV1 and HV2 and the D-loop region, was screened for mutations in 45 gastric tumours (15 tumours each of adenoma, differentiated adenocarcinoma and undifferentiated carcinoma). We found mutations in two of the 45 tumours (4%); a 1 bp A deletion at nucleotide position 248 in a differentiated adenocarcinoma and a G to A transition at nucleotide position 16,129 in an adenoma. We also observed 10 polymorphisms, four of which were not previously recorded. Both mtDNA mutations were present in replication error negative (RER-) tumours. Short mono- or dinucleotide repeats in the control region, such as (C)7, (A)5 or (CA)5, were not altered regardless of nuclear genetic instability. In summary, mtDNA is mutated in a subset of benign and malignant gastric tumours, but, disruption of the mtDNA repair system appears not to be significantly involved in gastric tumours of Japanese patients.
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Affiliation(s)
- G Tamura
- Department of Pathology, Yamagata University School of Medicine, Japan.
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35
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Abstract
Rapid progress has been made in the identification of mitochondrial DNA mutations which are typically associated with diseases of the nervous system and muscle. The well established mitochondrial disorders are maternally inherited and males and females are equally affected. An exception is Leber's hereditary optic atrophy (LHON) which is observed much more frequently in males than in females. There are three common point mutations in LHON which can be homoplasmic or heteroplasmic. In mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) most mutations are single base changes and lie within the tRNA-Leu gene. Point mutations in myoclonic epilepsy with ragged red fibres (MERRF) usually occur within the tRNA-Lys gene but mutations of the tRNA-Leu gene are also observed. MELAS and MERRF mutations are heteroplasmic and there is considerable clinical overlap between these diseases. Point mutations within the ATPase6 gene result in either neuropathy, ataxia and retinitis pigmentosa (NARP) or in Leigh's syndrome. The latter occurs if the mutation is present in the majority of mitochondria (extreme heteroplasmy). Finally, mitochondrial DNA deletions are the cause underlying Kearns-Sayre syndrome (KSS). Apart from the well-established mitochondrial diseases, there is increasing evidence that mitochondrial mutations may also play a role in the neurodegenerative disorders Parkinson, Alzheimer and Huntington disease. The complex I defect found in Parkinson disease is especially interesting in this respect. However, no causative mitochondrial mutation has as yet been established in any of these three common disorders.
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Affiliation(s)
- M B Graeber
- Department of Neuromorphology, Max-Planck-Institute of Psychiatry, Martinsried, Germany.
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36
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Hofmann S, Jaksch M, Bezold R, Mertens S, Aholt S, Paprotta A, Gerbitz KD. Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease. Hum Mol Genet 1997; 6:1835-46. [PMID: 9302261 DOI: 10.1093/hmg/6.11.1835] [Citation(s) in RCA: 126] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
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.
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Affiliation(s)
- S Hofmann
- Institute of Clinical Chemistry, Academic Hospital Schwabing, Munich, Germany
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Alonso A, Martin P, Albarran C, Aquilera B, Garcia O, Guzman A, Oliva H, Sancho M. Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis. Electrophoresis 1997; 18:682-5. [PMID: 9194590 DOI: 10.1002/elps.1150180504] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Each entire hypervariable region of the mitochondrial DNA control region was screened for mutations from paired normal and tumor DNA corresponding to a group of 21 patients (13 colorectal and 8 gastric adenocarcinomas) using both heteroduplex analysis and single-strand conformation analysis. These two mutation scanning strategies allowed the identification of sequence alterations in 3/13 (23%) colorectal tumors and in 3/8 (37%) gastric tumors. Heteroduplex analysis showed the heteroplasmic state of the majority of these tumor mutations. Sequence analysis revealed two A:T/G:C transitions (nucleotide positions: 16241 and 16166) in hypervariable region 1 (HV1) and two C:G/T:A transitions (nucleotide positions: 76 and 312), one A:T/G:C transition (nucleotide position: 93), a 1-basepair C:G deletion (nucleotide position: 309), and a 2-base-pair CC:GG insertion (nucleotide position: 309) in the HV 2 region. A considerable proportion of these mutations was found in homopolymeric regions which are highly polymorphic among humans. Different mechanisms (clonal expansion, increased oxidative damage, and nuclear mutator mutations) were suggested to explain the increased mitochondrial DNA mutation rate observed in cancer.
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Affiliation(s)
- A Alonso
- Biology Section, Institute of Toxicology, Madrid, Spain
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Affiliation(s)
- G K Brown
- Department of Biochemistry, University of Oxford, UK
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