Sunday, 2 August 2009
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.
Ina's clan -Haplogroup B
Mitochondrial DNA (or mtDNA for short) is present in every cell in the body, and it remains virtually unchanged (aside from random mutations which may occur every 10,000 years or so) as it passes from mother to daughter. By quantifying and analyzing the mutations of this relatively stable circle of DNA, Bryan Sykes, professor of human genetics at the University of Oxford and founder of Oxford Ancestors, was able to determine that nearly all modern Europeans descend from one of seven "clan mothers" who lived at different times during the Ice Age. He named these women Xenia, Ursula, Helena, Velda, Tara, Katrina, and Jasmine; and his findings were made popular in his book, "The Seven Daughters of Eve".
In addition to those seven women, Sykes also discovered 29 others from whom the rest of the world's population descend. Of those 29, just four are the ancestresses of the earliest colonizers of North and South America. Their names are Aiyana/Ai, Ina, Chochmingwu/Chie, and Djigonasee/Sachi. The haplogroups used to identify each "clan mother" are based upon the grouping of genetic sequences (known as "polymorphisms") into distinct families. Ina's clan are identified by Haplogroup B (the B clade of the human family tree).
Unlike the other three, Ina's clan is known to have populated not only North and South America, but the Pacific Islands and possibly Madagascar as well. Her name comes form the Polynesian mythological figure "Ina", who appears on the banknotes of Rarotonga in the Cook Islands riding on the back of a shark to the island Mangaia. She is representative of the "first woman" and is also often personified in the moon
All of these women are daughters of the 'Mitochondrial Eve', a single East African woman who lived approximately 150,000 years ago and from whom all of humanity descend. Obviously, she was not the only woman alive during her time, but only her maternal lineage has survived unbroken to the present day.
After coming out of Africa, modern humans first spread to Asia following two main routes - a Southern one and a Northern one. The Southern one is represented by macro-haplogroup M which radiated some 30,000–57,600 yrs BP (before present) and is overwhelmingly present in India  and Eastern Asia where it possibly originated and expanded as haplogroups C, D, G, and others .
The other major branch that left Africa, the Northern one, is represented by macro-haplogroup N. It has a lower bound of 43,000–53,000 yrs BP, and spread into at least three main clusters. The first cluster comprises haplogroups X and A, with only a shared mutation between them and different geographic distributions (A is widespread in Asia, X is mainly restricted to Europe). The second cluster groups minor haplogroups W, I, and N1b (each of which is present in low frequencies in Europe, the Near East, and the Caucasus).
The last cluster radiated around 39,000–52,000 yrs BP and gave rise to four major ancestral clusters: Two of them, B and F, derive from N through a common ancestor with most Europeans - phylogenetic node R . The others originated haplogroups J, T, H, V, K, and U, which expanded from the Near East-Caucasus area. 
Haplogroup B expanded from Central Asia to Eastern Asia, reaching Japan and the Southeastern Pacific Archipelagos. And, unlike previously believed, it is also found in some Siberian populations. [3, 5, 6]. From there, a substantial number of Ina's descendants then reached North America, either with the other colonists around 13,000 yrs BP via the Bering land bridge, or in a sea-borne colonization along the coast (or both).
HVR-1 Mutation Table
My mtDNA HVR-1 region differs from the Cambridge Reference Sequence (CRS) at the following sequence locations in HVR-1 (For all other locations, refer to the DNA sequence above): Location Mutation Type Nucleotide Change 16183 Substitution A > c 16189 Substitution T > c 16217 Substitution T > c 16519 Substitution T > c
Results HVR-2 DNA Sequence
HVR-2 Mutation Table
My MtDNA HVR-2 region differs from the Cambridge Reference Sequence (CRS) at the following sequence locations in HVR-2 (For all other locations, refer to the DNA sequence above):
Location Mutation Type Nucleotide Change 73 Substitution A > g 263 Substitution A > g 309 Insertion C 315 Insertion C
mtDNA Backbone SNP Results SNP Markers
SNP Location Mutations SNP Identity Result
2352 T > C T Negative 3594 C > T C Negative 3693 G > A G Negative 4312 C > T C Negative 4580 G > A G Negative 4833 A > G A Negative 5178 C > A C > T C Negative 7028 C > T T Positive 7055 A > C A > G A Negative 7598 G > A G Negative 8618 T > C T Negative 10086 A > G A Negative 10310 G > A G Negative 10400 C > T C Negative 10873 T > C T Negative 11251 A > G A Negative 11719 G > A A Positive 12308 A > G A Negative 12705 C > T C Negative 14766 C > T T Positive
Article first published online: 12 JAN 2006
Annals of the New York Academy of Sciences
Volume 1011, Mitochondrial Pathogenesis: From Genes and Apoptosis to Aging and Disease pages 317–324, April 2004
Association of the Mitochondrial DNA 16189 T to C Variant with Lacunar Cerebral Infarction: Evidence from a Hospital-Based Case-Control Study
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.
From Wikipedia, the free encyclopedia
|Classification and external resources|
CT scan slice of the brain showing a right-hemispheric cerebral infarct (left side of image).
A cerebral infarction is the ischemic kind of stroke due to a disturbance in the blood vessels supplying blood to the brain. It can be atherothrombotic or embolic. From stroke caused by cerebral infarction two other kinds of stroke should be distinguished: cerebral hemorrhage and subarachnoid hemorrhage.
There are various classification systems for a cerebral infarction. The Oxford Community Stroke Project classification (OCSP, also known as the Bamford or Oxford classification) relies primarily on the initial symptoms; based on the extent of the symptoms, the stroke episode is classified as total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) or posterior circulation infarct (POCI).
These four entities predict the extent of the stroke, the area of the brain affected, the underlying cause, and the prognosis. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification is based on clinical symptoms as well as results of further investigations; on this basis, a stroke is classified as being due to (1) thrombosis or embolism due to atherosclerosis of a large artery, (2) embolism of cardiac origin, (3) occlusion of a small blood vessel, (4) other determined cause, (5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).
Symptoms of cerebral infarction are determined by topographical localisation of cerebral lesion. If it is located in primary motor cortex- contralateral hemiparesis occurs, for brainstem localisation typical are brainstem syndromes: Wallenberg's syndrome, Weber's syndrome, Millard-Gubler syndrome, Benedikt syndrome or others.
In last decade, similar to myocadial infarction treatment, thrombolytic drugs were introduced in the therapy of cerebral infarction. The use of intravenous rtPA therapy can be advocated in patients who arrive to stroke unit and can be fully evaluated within 3 h of the onset.
Haplogroup b and diabetis in Filippinos
Mitochondrial DNA (T/C) 16189 Polymorphism, Variants and Heteroplasmy among Filipinos with Type 2 Diabetes Mellitus (Abstract)
Mitochondrial DNA polymorphisms have been implicated in the development of type 2 diabetes mellitus. Data on these polymorphisms are scarce among Asia-Pacific populations.
DNA extracted from peripheral blood of 30 Filipino adults with type 2 diabetes mellitus and 28 normal controls were analyzed using polymerase chain reaction, restriction enzyme digestion, and gel electrophoresis techniques.
The wild type allele was present in 46.7% (14/30) of diabetics compared to 28.6% (8/28) of controls. Four of the 30 diabetics (13.3%) and 2 of the 28 controls (7.1%) had the (T/C) 16189 polymorphism. Different restriction enzyme digestion patterns with regions of
heteroplasmy were found in 51.7% (30/58). Diabetics with the 16189 polymorphism had lower body weights, body mass indices, and
abdominal circumferences, but had higher mean arterial pressures than diabetics with the wild type allele.
Further molecular studies need to be performed among the latter group of subjects to elucidate on these observed variations.
Haplogroup B and diabetis
Mitochondrial DNA variation at position 16189 and diabetes: frequency amongst South Eastern Kenyan populationsApril 12, 2010
Arroyo JP, Batai K, Williams SR. Mitochondrial DNA variation at position 16189 and diabetes: frequency amongst South Eastern Kenyan populations. Abstract submitted for the 79th annual meeting of the American Association of Physical Anthropologists in Albuquerque, NM, April 14 to April 17, 2010
My friend is presenting a paper on our project on mtDNA variation in Kenya at the American Association of Physical Anthropologists (AAPA) meeting this week. Here is the abstract.
Certain mitochondrial mutations have been suggested as risk factors for maternally inherited diabetes and metabolic syndrome. A substitution of thymidine for cytosine (T→C) at nucleotide position 16189 of the mitochondrial DNA (mtDNA) may be associated with insulin resistance and type 2 Diabetes Mellitus. An analysis of five Asian countries indicated an association, but a meta-analysis of European samples showed no association.
However, ethnic differences may underlie risk association in diabetes because genetic/environmental interactions influence many aspects of the phenotype. Consequently, two southeast African populations were surveyed for the mutation to examine prevalence in African populations.
The mutation was found at low frequencies in the Kenyan populations, 8.61% in the Taita and 9.62% in the Mijikenda. In contrast, previous studies indicated frequencies of 31.0% in Asian and 9.2% in European samples.
Thus, if this mutation at position 16189 does prove to be a risk factor for diabetes in some populations, the Kenyan groups will be relatively unaffected because of the mutation’s low frequency in these populations.
Before this mutation can be conclusively shown to elevate risk of diabetes, more detailed studies of its specific metabolic effects are required. If the 16189C variant does prove to be associated with diabetes risk though, its high prevalence in Asian samples and much lower frequencies in European and African groups suggest that its effects will be largely confined to Asian populations.
We have a lot more that we have to do with this project.
Mtdna haplogroup B
Analysis of the mitochondrial DNA from patients with Wolfram (DIDMOAD) syndrome.
Institute of Clinical Chemistry, Academic Hospital Schwabing, Munich, Germany.
Wolfram or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, which has long been known as an autosomal-recessive disorder, has recently been proposed to be a mitochondrial-mediated disease with either a nuclear or a mitochondrial genetic background.
The phenotypic characteristics of the syndrome resemble those found in other mitochondrial (mt)DNA mediated disorders such as Leber's hereditary optic neuropathy (LHON) or maternally inherited diabetes and deafness (MIDD).
Therefore, we looked for respective mtDNA alterations in blood samples from 7 patients with DIDMOAD syndrome using SSCP-analysis of PCR-amplified fragments, encompassing all mitochondrial ND and tRNA genes, followed by direct sequencing.
Subsequently, we compared mtDNA variants identified in this disease group with those detected in a group of LHON patients (n = 17) and in a group of 69 healthy controls. We found that 4/7 (57%) DIDMOAD patients harbored a specific set of point mutations in tRNA and ND genes including the so-called class II or secondary LHON mutations at nucleotide positions (nps) 4216 and 4917 (haplogroup B).
In contrast, LHON-patients were frequently (10/17, 59%) found in association with another cluster of mtDNA variants including the secondary LHON mutations at nps 4216 and 13708 and further mtDNA polymorphisms in ND genes (haplogroup A), overlapping with haplogroup B only by variants at nps 4216 and 11251.
The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. We propose that haplogroup B represents a susceptibility factor for DIDMOAD which, by interaction with further exogeneous or genetic factors, might increase the risk for disease.
Mtdna haplogroup B story
|Updated 3/13/2008 11:18 AM | Comments 30 | Recommend 10|
Those women left a particular DNA legacy that persists to today in about about 95% of Native Americans, researchers said.
The finding does not mean that only these six women gave rise to the migrants who crossed into North America from Asia in the initial populating of the continent, said study co-author Ugo Perego.
The women lived between 18,000 and 21,000 years ago, though not necessarily at exactly the same time, he said.
The work was published this week by the journal PLoS One. Perego is from the Sorenson Molecular Genealogy Foundation in Salt Lake City and the University of Pavia in Italy.
The work confirms previous indications of the six maternal lineages, he said. But an expert unconnected with the study said the findings left some questions unanswered.
Perego and his colleagues traced the history of a particular kind of DNA that represents just a tiny fraction of the human genetic material, and reflects only a piece of a person's ancestry.
This DNA is found in the mitochondria, the power plants of cells. Unlike the DNA found in the nucleus, mitochondrial DNA is passed along only by the mother. So it follows a lineage that connects a person to his or her mother, then the mother's mother, and so on.
The researchers created a "family tree" that traces the different mitochondrial DNA lineages found in today's Native Americans. By noting mutations in each branch and applying a formula for how often such mutations arise, they calculated how old each branch was. That indicated when each branch arose in a single woman.
The six "founding mothers" apparently did not live in Asia because the DNA signatures they left behind aren't found there, Perego said. They probably lived in Beringia, the now-submerged land bridge that stretched to North America, he said.
Connie Mulligan of the University of Florida, an anthropolgist who studies the colonization of the Americas but didn't participate in the new work, said it's not surprising to trace the mitochondrial DNA to six women. "It's an OK number to start with right now," but further work may change it slightly, she said.
That finding doesn't answer the bigger questions of where those women lived, or of how many people left Beringia to colonize the Americas, she said Thursday.
The estimate for when the women lived is open to question because it's not clear whether the researchers properly accounted for differing mutation rates in mitochondrial DNA, she said. Further work could change the estimate, "possibly dramatically," she said.
Haplogroup B is highest among Polynesians (95%). It is present in Tibetans, Koreans, Japanese, and Mongolians  at moderate levels, and is widely spread throughout Southern Siberian populations, although at lower levels .
Researchers have published several studies detailing the population frequency of this Haplogroup in Asian populations.
These include the following:
Hurles ME, Irven C, Nicholson J, Taylor PG, Santos FR, Loughlin J, Jobling MA, Sykes BC.
European Y-chromosomal lineages in Polynesians: a contrast to the population structure revealed by mtDNA.
Am J Hum Genet. 1998 Dec;63(6):1793-806. [Full Publication]
Kivisild T, Kaldma K, Metspalu M, Parik J, Papiha S, Villems R.
The Place of the Indian mtDNA Variants in the Global Network of Maternal Lineages and the Peopling of the Old World. Genomic Diversity. 1999; 135-152. [Full Publication]
Quintana-Murci L, Chaix R, Wells RS, Behar DM, Sayar H, Scozzari R, Rengo C, Al-Zahery N, Semino O, Santachiara-Benerecetti AS, Coppa A, Ayub Q, Mohyuddin A, Tyler-Smith C, Mehdi SQ, Torroni A, and McElreavey K. Where West Meets East: The Complex mtDNA Landscape of the Southwest and Central Asian Corridor. [Full Study]
Schurr TG. Molecular Genetic Diversity of Indigenous Siberians: Implications for Ancient DNA Studies of Cis-Baikal Archeological Populations.(2004). [Full Paper]
In Chile, Haplogroup B is most frequent in the North, among the Aymaras (57%).  In the Quechua-speaking Andean population from Peru, it reaches 54%.
But, it is lowest in the North Amazon and it is absent from some Southern populations . The dominance of Haplogroup B is also manifested in numerous North American populations, mostly in the Southwest, such as the Kiliwa (100%) and Jemez Pueblo (89%), as indicated in the following studies:
Bolnick DA, Smith DG.
Unexpected Patterns of Mitochondrial DNA Variation Among Native Americans From the Southeastern United States. AAmer. J. Phys. Antrhop. 122:336–354 (2003). [Complete Study]
Carlyle SW, Parr RL, Hayes MG, and O'Rourke DH.
Context of Maternal Lineages in the Greater Southwest. Amer. J. Phys. Antrhop. 113:85-101 (2000). [Pubmed]
Carlyle SW, O'Rourke DH.
MtDNA variation among the Western Anasazi. Amer. J. Phys. Antrhop. Suppl. 32:47 (2001).
Malhi RS, Mortensen HM, Eshleman JA, Kemp BM, Lorenz JG, Kaestle FA, Johnson JR, Gorodezky C, Smith DG.
Native American mtDNA Prehistory in the American Southwest. Am J Phys Anthropol. 2003 Feb;120(2):108-24. [Pubmed]
Rubicz, R, TG Schurr, PL Babb, MH Crawford.
Mitochondrial DNA Variation and the origins of the Aleuts. Human Biology 75(6):809-835 (2003).
Ruiz E, Villena M, Rochet D, Godino C.
Mitochondrial DNA Haplogroup B Predominance in the Aymara Population Living in the Andes.
High Altitude Medicine & Biology, 3(1): 99-137 (2002).
Schmitt R, Bonatto SL, Freitas LB, Muschner VC, Hill K, Hurtado AM, Salzano FM..
Extremely limited mitochondrial DNA variability among the Ache Natives of Paraguay. Ann Hum Biol. 2004 Jan-Feb;31(1):87-94.
Tuross N, Kolman CJ. Report to DOJ & DOI: Potential for
DNA Testing of the Human Remains from Columbia Park, Kennewick, Washington. (2004). [Table 2]
To see a graphic representation of various mtDNA distribution patterns provided by the McDonald Group of the University of Illinois at Urbana-Champaign's School of Chemical Sciences, click here.
Beringian Standstill and Spread of Native American FoundersNative Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear.
To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia.
This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported.
The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades.
This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic.
Haplogroup B is believed to have arisen in Asia some 50,000 years before present. Its ancestral haplogroup was Haplogroup R.
Since the migration to the Americas by the ancestors of Native Americans is generally believed to have been from Siberia, it is especially surprising that Haplogroup B is the only haplogroup found in Native Americans which is not found in modern North Siberian populations. However, Haplogroup B has been found among Southern Siberians, such as Tuvans, Altays, and Buryats. This haplogroup is also found in Mongolians, Tibetans, Koreans, and among populations of Japan, China, Vietnam, Malaysia, Taiwan, Indonesia, Madagascar, the Philippines, Melanesia, Micronesia, and Polynesia.
This phylogenetic tree of haplogroup B subclades is based on the paper by Mannis van Oven and Manfred Kayser Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation and subsequent published research.
Haplogroup B ..
Multifactorial diseases: The OriB Variant
MtDNA variants in common multi-factorial diseases
Important diseases associated with aging, such as diabetes, are linked to OriB variants both in mtDNA and in nuclear genes involved in mtDNA maintenance.
MtDNA contributes to common diseases such as type 2 diabetes and dilated cardiomyopathy (the commonest cause for heart transplants in young people).
We have studied a common polymorphic mtDNA variant ( the so-called OriB variant, see below), which is present in 8% of UK Caucasians, 50% of Pima Indians and >95% of Polynesians.
We have shown that the 16189 variant is associated with i) type 2 diabetes, ii) thinness up to middle life, iii) high placental weight, iv) iron loading in haemochromatosis , v) dilated cardiomyopathy and deafness.
Investigators in other centres have confirmed the association with diabetes and with thinness, and have also shown that it is a risk factor for endometrial cancer and other multifactorial disorders.
Unlike many other polymorphisms that have been implicated in type 2 diabetes, the variant is likely to have bona fide functional consequences because it has arisen many times independently in the various populations studied, excluding a founder effect.
Furthermore we have preliminary evidence that the variant has functional effects on glucose uptake and mtDNA segregation in cultured cells.
Understanding the contribution of mtDNA to common diseases may lead to new therapies. Even a modest reduction would have profound implications on health expenditure, as diabetes and its complications are the sixth largest cost on the British National Health Service budget.
Technical Definition of the OriB Variant
ccccctcccc Wild type sequence
cccccccccc 16189 variant (9 to 14C in length)
ccccccctcc T16189C plus C16191T (EXCLUDED)
We defined the 16189 variant as the DNA sequence associated with an uninterrupted polydC tract of length 9-13, resulting from a T16189C transition. This may generate heteroplasmic length variation.
Heteroplasmic length variation does not occur when the polymeric tract is interrupted by a c to t transition at several different sites but commonly at bp 16186 or 16192.
Individuals with these additional polymorphisms are excluded from the definition of the 16189 variant that we use, because they no longer have a long homopolymeric c tract.
The variant does not alter any coding sequences yet lies near to mtDNA control sequences which can explain its effects on mitochondrial function.
In studies of disease associations with variants in this region we chose to investigate the 16189 variant rather than any other sequence change, because of the likely functional effects of the homopolymeric C tract and heteroplasmic length variation.
Mtdna B and thinness at birth
A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring
1Nuffield Department of Obstetrics and Gynaecology, The Women’s Centre, John Radcliffe Hospital, Oxford; 2Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton, United Kingdom; 3Department of Child and Adolescent Development and Rehabilitation, Women’s and Children’s Hospital, Adelaide, South Australia; and 4Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, United Kingdom
Submitted 21 December 2004 ; accepted in final form 27 June 2005
A common mitochondrial (mt)DNA variant that is maternally inherited, the 16189 variant, is associated with type 2 diabetes and thinness at birth.
To elucidate the association of the variant with thinness, we studied the 16189 variant in a well-characterized Australian cohort (n = 161) who were followed up from birth to age 20 yr. PCR analysis and mtDNA haplotyping was carried out on DNA from 161 offspring from consecutive, normal, singleton pregnancies followed from birth to age 20 yr.
The 16189 mtDNA variant was present in 14 of the 161 20 yr olds (8.7%). Both the mothers with the 16189 variant and their 20-yr-old offspring were thinner than those without. Median (interquartile range) BMI was 21.9 kg/m2 (20.4 to 22.9) in mothers with the variant compared with 23.5 (21.4 to 26.6) in those without (P = 0.013) and 22.2 (21.1 to 23.8) in 20 yr olds with the variant compared with 22.7 (20.8 to 25.6) in those without (P = 0.019).
The 16189 variant was also associated with a high placental weight and high placental-to-birth weight ratio (P = 0.051 and P = 0.0024, respectively). Insulin sensitivity was normal in 20 yr olds with the 16189 variant.
This contrasts with 20 yr olds who did not have the variant but who had been thin or small at birth and who had normal BMI and normal placental-to-birth weight ratio, but were insulin resistant.
This study suggests that the 16189 mtDNA variant is associated with maternally inherited thinness in young adults. This may be mediated by effects on mtDNA replication and, thence, placental function. Further research is required to confirm these hypotheses.
mitochondrial deoxyribonucleic acid; placenta; birth weight; 16189 variant; OriB variant; 16189-16193 Poly-C tract
A Common Mitochondrial DNA Variant and Increased Body Mass Index as Associated Factors for Development of Type 2 Diabetes: Additive Effects of Genetic and Environmental FactorsChia-Wei Liou, Tsu-Kung Lin, Hsu Huei Weng, Cheng-Feng Lee, Tzu-Ling Chen, Yau-Huei Wei, Shang-Der Chen, Yao-Chung Chuang, Shao-Wen Weng and Pei-Wen Wang
Departments of Neurology (C.-W.L., T.-K.L., S.-D.C., Y.-C.C.), Radiology (H.H.W.), and Internal Medicine (S.-W.W., P.-W.W.), Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan 83305; Department of Biochemistry and Center for Cellular and Molecular Biology (C.-F.L., T.-L.C., Y.-H.W.), National Yang-Ming University, Taipei, Taiwan 112
Address all correspondence and requests for reprints to: Pei-Wen Wang, M.D., Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, 123, Ta-Pei Road, Niao Sung Hsiang, Kaohsiung, Taiwan 83305. E-mail: email@example.com.
Objective: The suggested correlation between a T-to-C transition at the nucleotide 16189 in mitochondrial DNA (mtDNA) with increasing insulin resistance and adult-onset diabetes mellitus (DM) is debatable.
Methods: Our study examined mtDNA from 462 subjects with type 2 diabetes (T2DM) and 592 normoglycemic controls (non-DM). Each participant’s body mass index (BMI), fasting plasma glucose, fasting insulin concentration, insulin resistance index, and ß-cell function were measured.
Sequencing for mtDNA, focusing on exploration of the hypervariable polycytosine tract within the control region, was also conducted in all subjects.
Results: Prevalence of the mtDNA 16189 variant was significantly different between DM and non-DM subjects (39.2% vs. 30.7% respectively; P = 0.004).
Increased incidence of DM was noted in those harboring the 16189 variant compared with those lacking the variant (multivariate odds ratio, 1.38; 95% confidence interval, 1.07–1.80). Moreover, increased BMI was identified as an aggravating factor for development of DM in subjects harboring the variant.
Odds ratio determinations yielded 2.14 in overweight and 4.63 in obese subjects harboring the variant in comparison with subjects without (1.83 in overweight and 2.16 in obese subjects).
This is consistent with a progressively increased prevalence of the mtDNA 16189 variant in the non-DM groups with higher fasting insulin concentration, insulin resistance index, and ß-cell function (all Ptrend <>
Conclusion: The mtDNA 16189 variant can influence development of T2DM. The demonstrated dynamic between the 16189 variant and increased BMI exemplify an additive effect of genetic and environmental factors on the pathogenesis of T2DM.
Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells
- C-W Liou1,
- T-K Lin1,
- J-B Chen2,
- M-M Tiao3,
- S-W Weng4,
- S-D Chen1,
- Y-C Chuang1,
- J-H Chuang5,
- P-W Wang4
+ Author Affiliations
- 1Department of Neurology, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- 2Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- 3Departments of Pediatrics, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- 4Division of Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- 5Departments of Pediatrics Surgery, Chang Gung Memorial Hospital–Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Correspondence to Dr Pei-Wen Wang, Division of Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, 123, Ta-Pei Rd, Niao Sung Hsiang, Kaohsiung, Taiwan; firstname.lastname@example.org
- Received 26 January 2010
- Revised 7 April 2010
- Accepted 21 April 2010
- Published Online First 12 September 2010
Background A T-to-C transition at mitochondrial DNA (mtDNA) nucleotide position 16189 can generate a variable length polycytosine tract (poly-C). This tract variance has been associated with disease. A suggested pathogenesis is that it interferes with the replication process of mtDNA, which in turn decreases the mtDNA copy number and generates disease.
Methods In this study, 837 healthy adults' blood samples were collected and determined for their mtDNA D-loop sequence. The mtDNA copy number in the leucocytes and serum levels of oxidative thiobarbituric acid reactive substance (TBARS) and antioxidative thiols were measured. All subjects were then categorised into three groups: wild type or variant mtDNA with presence of an interrupted/uninterrupted poly-C at 16180–16195 segment.
Results A step-wise multiple linear regression analysis identified factors affecting expression of mtDNA copy number including TBARS, thiols, age, body mass index and the mtDNA poly-C variant. Subjects harbouring a variant uninterrupted poly-C showed lowest mean (SD) mtDNA copy number (330 (178)), whereas an increased copy number was noted in subjects harbouring variant, interrupted poly-C (420 (273)) in comparison with wild type (358 (215)).
The difference between the three groups and between the uninterrupted poly-C and the composite data from the interrupted poly-C and wild type remained consistent after adjustment for TBARS, thiols, age and body mass index (p=0.001 and p=0.011, respectively). A trend for decreased mtDNA copy number in association with increased number of continuous cytosine within the 16180–16195 segment was noted (ptrend
Conclusions Our results substantiate a previous suggestion that the mtDNA 16189 variant can cause alteration of mtDNA copy number in human blood cells.
Haplogroup B in Chinese populations
Association of Mitochondrial Deoxyribonucleic Acid 16189 Variant (T" border="0">C Transition) with Metabolic Syndrome in Chinese AdultsShao-Wen Weng, Chia-Wei Liou, Tsu-Kung Lin, Yau-Huei Wei, Cheng-Feng Lee, Hock-Liew Eng, Shang-Der Chen, Rue-Tsuan Liu, Jung-Fu Chen, I-Ya Chen, Ming-Hong Chen and Pei-Wen Wang
Departments of Internal Medicine (S.-W.W., R.-T.L., J.-F.C., I.-Y.C., M.-H.C., P.-W.W.), Neurology (C.-W.L., T.-K.L., S.-D.C.), and Pathology (H.-L.E.), Chang Gung Memorial Hospital, Kaohsiung, Taiwan 833; and Department of Biochemistry and Center for Cellular and Molecular Biology (Y.-H.W., C.-F.L.), National Yang-Ming University, Taipei, Taiwan 112
Address all correspondence and requests for reprints to: Pei-Wen Wang, M.D., Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-sung Hsiang, Kaohsiung Hsien, Taiwan 833. E-mail: email@example.com.
Objective: A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T" border="0">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 2 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 (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 <>Conclusion: Our data strongly suggest that mtDNA 16189 variant underlies susceptibility to metabolic syndrome in the Chinese population.
As shown by various studies, deletion mtDNAs from haplogroup B are broadly distributed in Asian populations. Recent population expansions associated with the spread of Austronesian languages appear to have brought these haplotypes from Southeast Asia into Polynesia around 5000-1000 YBP.
Many Polynesian haplogroup B mtDNAs also possess a set of polymorphisms that distinguishes them from similar types in other Asian populations (Hagelberg and Clegg 1993; Hagelberg et al. 1994; Lum et al. 1994; Melton et al. 1995, 1998; Redd et al. 1995; Sykes et al. 1995; Lum and Cann 1998; Richards et al. 1998). This set of mutations, which includes the 16217 T->C, 16247 A->G, and 16261 C->T transitions (or "CGT"), has been called the "Polynesian Motif" because of its uniqueness to Polynesian and related populations (Hagelberg and Clegg 1993; Hagelberg et al. 1994; Lum et al. 1994).
The Polynesian Motif evolved from mtDNAs bearing the ancestral 16189C and 16217C sequence motif through a series of mutational steps (CAC->CAT->CGT) that probably began in Taiwan and continued as populations spread south into the Philippines, Indonesia, and Melanesia (Melton et al. 1995, 1998; Redd et al. 1995), although some favor an Indonesian source for this lineage (Richards et al. 1998).
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Haplogroup B mtDNAs are also found in Vietnamese, Malaysian, and Bornean populations (Ballinger et al. 1992). However, none of the HVS-I sequences identified in these deletion haplotypes show the Polynesian Motif (CGT), and only one (Sabah Aborigine, SA26; Ballinger et al. 1992) has the hypothesized intermediate state, CAT.
These findings are generally concordant with those of Melton et al. (1995, 1998), who observed the Polynesian Motif at the highest frequency in Polynesians and coastal Papua New Guineans, and at modest frequencies in East Indonesians and Malays, with the intermediate form (CAT) occurring at the highest frequencies in Taiwanese aborigines and moderate frequencies in Filipinos and east Indonesians.
Ballinger et al. (1992) also suggested that two deletion haplogroups were present in Asian populations, with these being called C* and D*. Haplogroup D* has since been renamed haplogroup B (Torroni et al. 1992), but C* has received little attention since its first description. So as not to confuse it with haplogroup C, which is not closely related to either deletion lineage, haplogroup C* will henceforth be called haplogroup B*, since this letter designation will associate it with the other major deletion haplogroup.
With respect to their mutational composition, haplogroup B is characterized by the Region V 9-bp deletion and the HaeIII 16517 mutation, while, in addition to these polymorphisms, haplogroup B* also has the -DdeI 3534, -AluI 3537, DdeI 10394, -HinfI 15234; and MboI 15235 mutations (Ballinger et al. 1992; Passarino et al. 1993) (Table 4).
When subjected to phylogenetic analysis, the haplotypes from both of these haplogroups clustered together but formed separate branches (Figure 2 in Ballinger et al. 1992).
However, this association occurred in part because of the inclusion of the 9-bp deletion as an RFLP character in the haplotype data matrix. If this marker is eliminated from the data set, then the two branches are positioned in separate portions of the Asian mtDNA tree because of the presence of the DdeI 10394 site in B* mtDNAs (data not shown).
Regardless of their positions, however, haplogroup B* had long branches connecting mutationally diverse haplotypes, whereas haplogroup B had shorter and shallower branches of haplotypes. These data suggested that B* could be an older deletion lineage, or else a highly divergent subbranch of haplogroup B.
By contrast, the shallower branches of shorter lengths for haplogroup B suggested that it could be a younger deletion lineage that had rapidly diversified and been spread in East Asia in relatively recent prehistory.
However, both of these putative deletion lineages are approximately the same age. Based on the maximum likelihood estimates of haplogroup diversity presented in Ballinger et al. (1992), haplogroup B arose between 33,500-16,750 YBP, while haplogroup B* emerged between 44,500-22,250 YBP (Table 5).
These age estimates are supported by a recent median network analysis of RFLP and HVS-I sequence data from haplogroup B in which its expansion in Asia was calculated to be 29,100 /- 7100 YBP (Forster et al. 2001). Such findings suggested that haplogroup B could possibly have evolved from haplogroup B*, or, alternatively, that both haplogroups represented independent occurrences of the Region V 9-bp deletion in different mtDNA lineages that were subsequently distributed in Asia at similar times.
To discriminate between these possibilities, it will be necessary to determine whether the DdeI 10394 site present in B* haplotypes is the same phylogenetically ancient site that is present in African mtDNAs, or, instead, a secondary occurrence of this polymorphism in mtDNAs that originally lacked the DdeI/ AluI sites.
Mitochondrial DNA Variants in the Pathogenesis of Type 2 Diabetes - Relevance of Asian Population Studies
Pei-Wen Wang1, Tsu-Kung Lin2, Shao-Wen Weng1, Chia-Wei Liou21Department of Internal Medicine, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 83305
2Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 83305
Address correspondence to: Chia-Wei Liou, e-mail: firstname.lastname@example.org
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.
Kearns: DNA study: Colombia;s founding mothers recognized
By Rick Kearns / Indian Country Today
Story Published: Nov 9, 2006
Story Updated: Sep 10, 2008
According to a recently released DNA survey, 85.5 percent of all Colombian women have indigenous mitochondria, a component of DNA that is passed down unaltered through the maternal line.
Dr. Emilio Yunis Turbay, a distinguished scientist who founded the Genetics Institute at the National University at Bogota, was the principle author of the study. Yunis Turbay assembled a team of specialists, including his son, Dr. Juan Jose Yunis, who analyzed 1,522 samples of mitochondrial (mt) DNA from across Colombia.
The final analysis yielded a startling conclusion: Almost 90 percent of all Colombian women have a Native grandmother in their ancestry. This finding echoes the results gathered in Puerto Rico three years ago, where it was discovered that 61 percent of all Puerto Ricans had indigenous mitochondrial DNA.
According to Dr. Juan Martinez Cruzado, author of the Puerto Rico study, this signals a trend.
;'This seems to be a common thread in all Latin America,'' he asserted. ''I spoke with a Mexican researcher who tested some Mexicans in the north of their country as well as Mexicans living in the southwestern United States, and over 80 percent of them had the indigenous mitochondrial DNA.''
Martinez Cruzado added that he had examined 16 indigenous mtDNA samples from Aruba recently and 86 percent of those samples showed the indigenous mtDNA. He has been in contact with Venezuelan scientists who informed him that a majority of the residents of Caracas, the capital city, also contained indigenous mtDNA.
''And in Argentina, which is so white, so European and which is most identified with Italy and Spain, most of the Argentineans also have indigenous mtDNA, according to the research of the well-known scientist Claudio Bravi,'' asserted Martinez Cruzado.
The presence of these grandmothers in the histories of Colombia and probably all of Latin America will force a re-evaluation of each country's story. And while the role of fathers and grandfathers is very important in any culture, it is the mother who teaches the children directly. It is the mother and grandmother who transmit the cultural values and beliefs.
For anyone who comes from Latin America, a great many of us are ''part-Indian.'' The ramifications of this historical fact will produce some similar results as well as some that are unique to each country.
Yunis Turbay put forward a similar argument in other media statements. He noted that upon analyzing the genetic structure of the Colombian population, one re-invents the history of the country as one reaches the conclusion that Colombia (like many Latin American countries) is genetically
fragmented. But for Colombians specifically, there is another aspect of their genetic fragmentation that bears examination, according to the famous scientist.
There are ''the mulattoes on one side, the blacks on another, the indigenous in another, the white mestizos [mixes] in another,'' he pointed out. ''One begins to make a picture that shows a country made up of genetic patches. Looking at it this way explains the utilization of the tools of power to exclude populations,'' he asserted.
''The unity of Colombia is made by 'superstructures,' not by a structural development based on means of communication that integrate the market, allowing for the exchange of products, of cultures and unions of different origins,'' he continued. ''We have made Colombia a very unequal country, and what is worse, with citizens of different categories. We have regionalized race.''
Yunis Turbay and others in Colombia there are trying desperately to unify the country, an extremely difficult task for now. However, there is a good chance that Yunis Turbay's research and calls for action will be taken seriously. He is possibly the most well-respected scientist in his country, who has also contributed to national Colombian discussion on identity. He conducted a larger genetic study of the country in 1992 and authored a book, ''Why Are We This Way? What Happened in Colombia? An Analysis of the Mixing (Mestizaje).'' This work contains a series of essays in which he connected genetics, history, geography and politics to advance his argument of how to unify the country through markets and geography.