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Haplogroup T (mtDNA)

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Haplogroup T
Possible time of origin	25,149 ± 4,668 Years Before Present
Possible place of origin	Mesopotamia / Fertile Crescent (modern Syria / Turkey)
Ancestor	J'T
Descendants	T1 and T2
Defining mutations	G709A, G1888A, A4917G, G8697A, T10463C, G13368A, G14905A, A15607G, G15928A, C16294T

In human population genetics, mitochondrial (mtDNA) haplogroups define the major lineages of direct maternal (female) lines back to a shared common ancestor in Africa. In human genetics, Haplogroup T is a predominately Eurasian lineage.

Origins

Mitochondrial (mtDNA) Haplogroup T derives from the haplogroup J'T that also gave rise to haplogroup J.

Distribution

Haplogroup T is found in approximately 10% of native Europeans.^[1]^[2]

Haplogroup T is currently found with high concentrations around the eastern Baltic Sea.

The geographic distribution within subclade T2 varies greatly with the ratio of subhaplogroup T2e to T2b reported to vary 40-fold across examined populations from a low in Britain and Ireland, to a high in Saudi Arabia (Bedford 2012). Within subhaplogroup T2e, a very rare motif is identified among Sephardic Jews of Turkey and Bulgaria and suspected conversos from the New World (Bedford 2012). Found in Svan population from Caucasus(Georgia) T* 10,4% and T1 4,2%

Africa

Haplogroup T is uncommon in Africa and is absent from most populations there. Its highest frequencies are in two Semitic speaking peoples: the Amhara and the Tigrai (Kivisild 2004).

Population	Location	Language Family	N	Frequency	Source
Amhara	Ethiopia	Afro-Asiatic > Semitic	5/120	4.17%	Kivisild 2004
Beta Israel	Ethiopia	Afro-Asiatic > Cushitic	0/29	0.00%	Behar 2008a
Dawro K.	Ethiopia	Afro-Asiatic > Omotic	2/137	1.46%	Castrì 2008 and Boattini 2013
Ethiopia	Ethiopia	Undetermined	2/77	2.60%	Soares 2011
Ethiopian Jew	Ethiopia	Afro-Asiatic > Cushitic	0/41	0.00%	Non 2011
Gurage	Ethiopia	Afro-Asiatic > Semitic	0/21	0.00%	Kivisild 2004
Hamer	Ethiopia	Afro-Asiatic > Omotic	0/11	0.00%	Castrì 2008 and Boattini 2013
Ongota	Ethiopia	Afro-Asiatic > Cushitic	0/19	0.00%	Castrì 2008 and Boattini 2013
Oromo	Ethiopia	Afro-Asiatic > Cushitic	0/33	0.00%	Kivisild 2004
Tigrai	Ethiopia	Afro-Asiatic > Semitic	3/44	6.82%	Kivisild 2004
Daasanach	Kenya	Afro-Asiatic > Cushitic	0/49	0.00%	Poloni 2009
Elmolo	Kenya	Afro-Asiatic > Cushitic	0/52	0.00%	Castrì 2008 and Boattini 2013
Kikuyu	Kenya	Niger-Congo	0/25	0.00%	Watson 1997
Luo	Kenya	Nilo-Saharan	0/49	0.00%	Castrì 2008 and Boattini 2013
Maasai	Kenya	Nilo-Saharan	0/81	0.00%	Castrì 2008 and Boattini 2013
Nairobi	Kenya	Niger-Congo	0/100	0.00%	Brandstatter 2004
Nyangatom	Kenya	Nilo-Saharan	0/112	0.00%	Poloni 2009
Rendille	Kenya	Afro-Asiatic > Cushitic	0/17	0.00%	Castrì 2008 and Boattini 2013
Samburu	Kenya	Nilo-Saharan	0/35	0.00%	Castrì 2008 and Boattini 2013
Turkana	Kenya	Nilo-Saharan	0/51	0.00%	Castrì 2008 and Boattini 2013
Turkana	Kenya	Nilo-Saharan	0/47	0.00%	Poloni 2009 and Watson 1997
Hutu	Rwanda	Niger-Congo	0/42	0.00%	Castrì 2009
Somali	Somalia	Afro-Asiatic > Cushitic	2/163	1.23%	Soares 2011 and Watson 1997
Dinka	Sudan	Nilo-Saharan	0/46	0.00%	Krings 1999
Sudan	Sudan	Undetermined	3/102	2.94%	Soares 2011
Burunge	Tanzania	Afro-Asiatic > Cushitic	0/38	0.00%	Tishkoff 2007
Datoga	Tanzania	Nilo-Saharan	1/57	1.75%	Tishkoff 2007 and Knight 2003
Iraqw	Tanzania	Afro-Asiatic > Cushitic	0/12	0.00%	Knight 2003
Sukuma	Tanzania	Niger-Congo	0/32	0.00%	Tishkoff 2007 and Knight 2003
Turu	Tanzania	Niger-Congo	0/29	0.00%	Tishkoff 2007
Yemeni	Yemen	Afro-Asiatic > Semitic	1/114	0.88%	Kivisild 2004

Asia

Europe

Subclades

Tree

This phylogenetic tree of haplogroup I subclades is based on the paper (van Oven 2008) and subsequent published research (Behar 2012b). For brevity, only the first three levels of subclades (branches) are shown.

T
- T1
  - T1a
    - T1a1
  - T1b
- T2
  - T2a
    - T2a1
  - T2b
    - T2b1
    - T2b2
    - T2b3
    - T2b4
    - T2b5
    - T2b6
  - T2c
    - T2c1
  - T2d
  - T2e
    - T2e2
  - T2f
    - T2f1
  - T2g

Health Issues

One study has shown Haplogroup T to be associated with increased risk for coronary artery disease (Sanger 2007). However, some studies have also shown that people of Haplogroup T are less prone to diabetes (Chinnery 2007 and González 2012).

A few tentative medical studies have demonstrated that Haplogroup T may offer some resistance to both Parkinson's disease and Alzheimer's disease.^{[Footnote 1]}

Certain medical studies had shown mitochondrial Haplogroup T to be associated with reduced sperm motility in males, although these results have been challenged (Mishmar 2002). According to the Departamento de Bioquimica y Biologica Molecular y Celular, Universidad de Zaragoza, Haplogroup T represents a weak genetic background that can predispose to asthenozoospermia (Ruiz-Pesini 2000). However, these findings have been disputed due to a small sample size in the study (Mishmar 2002).

Popular Culture

Popular Science

In his popular book The Seven Daughters of Eve, Bryan Sykes, who is in Haplogroup T, named the originator of this group "Tara," which means rocky hill in Gaelic. Sykes believes that: "Tara herself lived 17,000 years ago in the northwest of Italy among the hills of Tuscany and along the estuary of the river Arno" (Sykes 2002).

Famous Members

Nicholas II of Russia

The last Russian Tsar, Nicholas II, has been shown to be of Haplogroup T, specifically subclade T2 (Ivanov 1996). Assuming all relevant pedigrees are correct, this includes all female-line descendants of his female line ancestor Barbara of Celje (1390-1451), wife of Sigismund, Holy Roman Emperor. This includes a great number of European nobles, including George I of Great Britain and Frederick William I of Prussia (through the Electress Sophia of Hanover), Charles I of England, George III of the United Kingdom, George V of the United Kingdom, Charles X Gustav of Sweden, Gustavus Adolphus of Sweden, Maurice of Nassau, Prince of Orange, Olav V of Norway, and George I of Greece. Many European royals have been found to be of this mtDNA Haplogroup, in addition to Haplogroup H (mtDNA).^{[citation needed]}

Jesse James

The American outlaw Jesse James has been shown to be of subclade T2.

Eddie Izzard

The television program 'Meet the Izzards' features the British stand-up comedian, actor and writer Eddie Izzard as being of subclade T2f1a1.

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Molecular instability of the mitochondrial haplogroup T sequences at nucleotide positions 16292 and 16296.

Malyarchuk BA, Derenko MV.

Source

Institute of Biological Problems of the North, 685000 Magadan, Russia. rosa@online.magadan.su

Abstract

The mitochondrial haplogroup T, characterized by the nucleotide motif 16126C-16294T in the hypervariable segment I (HVS I), is one of the most frequent among Europeans. It has been shown that this haplogroup includes the only well-resolved subgroup, T1, but that other HVS I sequences cannot be differentiated into subgroups due to possible homoplasies at nucleotide positions 16292, 16296 and 16304, leading to the reticulations in the topology of phylogenetic networks. To study the problem of molecular instability at these positions, we have performed an analysis of 159 previously published West Eurasian HVS I sequences belonging to haplogroup T, together with 12 new HVS I sequences of Eastern Slavs. These 12 sequences represent 16.9% of a total of 71 samples analysed and identified as haplogroup T mtDNAs by RFLP analysis in this study.

A search for rare point mutations associated with different combinations of nucleotides 16292T, 16296T and 16304C within the haplogroup T sequences, and specific to certain populations or a group of closely related-by-descent populations, was performed. This analysis revealed 11 marker mutations, each of which was characteristic for a certain group of linguistically or geographically close individuals - the Adygei, Germans, Kazakhs and linguistic isolates of the Eastern Italian Alps. The occurrence of these rare population-specific polymorphisms in association with various combinations of mutations at positions 16292 and 16296 on the haplogroup T background provides evidence of molecular instability at these nucleotide positions.

Molecular instability in the haplogroup T HVS I sequences is also suggested by multiple independent losses of the haplogroup T diagnostic nucleotide variants in different populations. The results of the present study suggest that identical haplogroup T HVS I sequence types might have arisen independently in different human populations.

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Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study.

Kofler B, Mueller EE, Eder W, Stanger O, Maier R, Weger M, Haas A, Winker R, Schmut O, Paulweber B, Iglseder B, Renner W, Wiesbauer M, Aigner I, Santic D, Zimmermann FA, Mayr JA, Sperl W.

Source

Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. b.kofler@salk.at

Abstract

BACKGROUND:

There is strong and consistent evidence that oxidative stress is crucially involved in the development of atherosclerotic vascular disease. Overproduction of reactive oxygen species (ROS) in mitochondria is an unifying mechanism that underlies micro- and macrovascular atherosclerotic disease. Given the central role of mitochondria in energy and ROS production, mitochondrial DNA (mtDNA) is an obvious candidate for genetic susceptibility studies on atherosclerotic processes. We therefore examined the association between mtDNA haplogroups and coronary artery disease (CAD) as well as diabetic retinopathy.

METHODS:

This study of Middle European Caucasians included patients with angiographically documented CAD (n = 487), subjects with type 2 diabetes mellitus with (n = 149) or without (n = 78) diabetic retinopathy and control subjects without clinical manifestations of atherosclerotic disease (n = 1527). MtDNA haplotyping was performed using multiplex PCR and subsequent multiplex primer extension analysis for determination of the major European haplogroups. Haplogroup frequencies of patients were compared to those of control subjects without clinical manifestations of atherosclerotic disease.

RESULTS:

Haplogroup T was significantly more prevalent among patients with CAD than among control subjects (14.8% vs 8.3%; p = 0.002). In patients with type 2 diabetes, the presence of diabetic retinopathy was also significantly associated with a higher prevalence of haplogroup T (12.1% vs 5.1%; p = 0.046).

CONCLUSION:

Our data indicate that the mtDNA haplogroup T is associated with CAD and diabetic retinopathy in Middle European Caucasian populations.

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Anomalous Mitochondrial DNA Lineages in the Cherokee

Tuesday, October 13, 2009

ABSTRACT. A sample of 52 individuals who purchased mitochondrial DNA testing to determine their female lineage was assembled after the fact from the customer files of DNA Consultants. All claim matrilineal descent from a Native American woman, usually named as Cherokee. The main criterion for inclusion in the study is that test subjects must have obtained results not placing them in the standard Native American haplogroups A, B, C or D. Hence the use of the word "anomalous" in the title of a paper prepared by chief investigator Donald N. Yates, "Anomalous Mitochondrial DNA Lineages in the Cherokee."

Most subjects reveal haplotypes that are unmatched anywhere else except among other participants, and there proves to be a high degree of interrelatedness and common ancestral lines. Haplogroup T emerges as the largest lineage, followed by U, X, J and H. Similar proportions of these haplogroups are noted in the populations of Egypt, Israel and other parts of the East Mediterranean (see below).

The Cherokee and Admixture. According to a 2007 report from the U.S. Census Bureau, the Cherokee are the largest tribal group today, with a population of 331,000 or 15% of all American Indians. Despite their numbers, though, the Cherokee have had few DNA studies conducted on them. I know of only three reports on Cherokee mitochondrial DNA. A total of 60 subjects are involved, all from Oklahoma. Possibly the reason the Cherokee are not recruited for more studies, I would suggest, stems from their being perceived as admixed in comparison with other Indians. Accordingly, they are deemed less worthy of study.

In the past, whenever a geneticist or anthropologist conducting a study of Native Americans has encountered an anomalous haplogroup, that is, a lineage that does not belong to one of the five generally accepted American Indian mitochondrial DNA haplogroups A, B, C, D and X, it has been rejected as an example of admixture and not included in the survey results. This is true of the two examples of H and one of J reported by Cherokee descendants by Schurr (2000:253). Schurr takes these exceptions to prove the rule and regards them as instances of European admixture. The governing logic of population geneticists seems to go as follows:

Lineage A, B, C, D and X are American Indian.
Therefore, all American Indians are lineage A, B, C, D and X.

The fallacy in such reasoning is apparent. It could be restated as: "All men are two-legged creatures; therefore since the skeleton we dug up has two legs, it is human." It might be a kangaroo.

"The geneticists always seem to cry 'post-Columbian admixture,'" says Stephen C. Jett, a geographer at the University of California at Davis, "but fail to take into account that there are no plausible post-Columbian sources for the particular genetic mix encountered."

"Anomalous Mitochondrial DNA Lineages in the Cherokee" concentrates on the "kangaroos"- documented or self-identifying Cherokee descendants whose haplotypes do not fit the current orthodoxy in American Indian population genetics. Here are some highlights, organized by haplogroup.

Haplogroup H. Although this quintessentially European haplogroup would seem to be the most likely suspect if admixture were responsible for the anomalous haplogroups, there are but four cases of it.

Haplogroup X. Haplogroup X is a latecomer to the "pantheon" of Native American haplogroups. Its relative absence in Mongolia and Siberia and a recently proven center of diffusion in Lebanon and Israel (Brown et al. 1998, Malhi and Smith 2002; Smith et al. 1999; Reidla 2003; Shlush et al. 2009) pose problems for the standard account of the peopling of the Americas. DNA Consultants Cherokee-descended customers include seven instances of haplogroup X. David E. Lewis (whose Cherokee name is Wayauwetsi) traces his unmatched X haplotype back to Seyinus, a Cherokee woman of the Wolf Clan born on or near the Qualla Boundary in North Carolina in 1862. Two cases represent descendants (unknown to each other, incidentally) of the Cherokee woman called Polly who was the namesake for the Qualla reservation (the sound p lacking in the Cherokee language and being rendered with qu).

Haplogroup J. Two other cases, both J's, are related to Polly, tracing their lines back to Betsy Walker, a Cherokee woman born about 1720 in Soco (One-Town). A descendant was the wife or paramour of Col. Will Thomas, the first chief and founder of the Eastern Band of Cherokee Indians located today on the Qualla Boundary. Views about J are still evolving, but it seems to have originated in present-day Lebanon approximately 10,000 years before present. It is a major Jewish female lineage (Thomas 2002).

Haplogroup U has never been reported in American Indians to my knowledge. In our sample it covers 13 cases or 25% of the total, second in frequency only to haplogroup T. One of the U's is Mary M. Garrabrant-Brower. She belongs to U5a1a* (all U5a1a not matched or assigned) but has no close matches anywhere. Her great-grandmother was Clarissa Green of the Cherokee Wolf Clan, born 1846. Mary's mother Mary M. Lounsbury maintained the Cherokee language and rituals. One of the cases of U2e* is my own. This line evidently arose from a Jewish Indian trader and a Cherokee woman. My fifth-great-grandmother was born about 1790 on the northern Georgia and southwestern North Carolina frontier and had a relationship with a trader named Enoch Jordan. The trader's male line descendants from his white family in North Carolina possess Y chromosomal J, a common Jewish type. Some Jordans, in fact, bear the Cohen Modal Haplotype that has been suggested to be the genetic signature of Old Testament priests (Thomas et al. 1998). Enoch Jordan was born about 1768 in Scotland of forbears from Russia or the Ukraine. My mother, Bessie Cooper, was a double descendant of Cherokee chief Black Fox and was born on Sand Mountain in northeastern Alabama near Black Fox's former seat at Creek Path (and who was Paint Clan). All U2e* cases appear to have in common the fact that there are underlying Melungeon, Cherokee and Jewish connections.

Haplogroup T. "Tara," as she was named by Brian Sykes, is believed to have originated in Mesopotamia approximately 10,000 to 12,000 years ago and to have moved northwards through the Caucasus and westwards from Anatolia into Europe. The closer one goes to its origin in the Fertile Crescent the more likely T is to be found in higher frequencies. The haplogroup includes slightly fewer than 10% of modern Europeans, but accounts for 28% of people in the DNA Consultants study. The great-great-grandmother of Linda Burckhalter was Sully Firebush, the daughter of a Cherokee chief who married Solomon Sutton, the stowaway son of a London merchant, in what would seem to be another variation of the "Jewish trader marries chief's daughter" pattern. Three T1*'s are perfectly matching individuals completely unknown to one another before testing who are clearly descended from the same woman. Two of them claim Melungeon ancestry.

The many interrelationships noted above reinforce the conclusion that this is a faithful cross-section of a population. No such mix could have resulted from post-1492 European gene flow into the Cherokee Nation. So where do our non-European, non-Indian-appearing elements come from? The level of haplogroup T in the Cherokee (26.9%) approximates the percentage for Egypt (25%), one of the only lands where T attains a major position among the various mitochondrial lineages. In Egypt, T is three times what it is in Europe. Haplogroup U in our sample is about the same as the Middle East in general. Its frequency is similar to that of Turkey and Greece. J has a frequency not unlike Europe (a little less than 10%). The only other place on earth where X is found at an elevated level apart from other American Indian groups like the Ojibwe is among the Druze in the Hills of Galilee in northern Israel and Lebanon. The work of Shlush et al. (2009) demonstrates that this region was in fact the center of the worldwide diffusion of haplogroup X.

Phoenicians. On the Y chromosome side of Shlush et al.'s study, male haplogroup K was found to have a relatively high frequency of 11% in the Galilee region (2008:2). K (renamed T in the revised YCC nomenclature) has long been suspected to be the genetic signature of the Phoenicians. A TV show by National Geographic appeared about a year ago titled Who Were the Phoenicians?, in which Spencer Wells of the National Genographic Project, unveiled this theory. Without a doubt it was the Phoenicians, whose name among themselves was Cana'ni or KHNAI 'Canaanites', not Phoenikoi 'red paint people' (Aubet 2001:9-12; cf. Oxford Classical Dictionary s.v. "Phoenicians" ), who are referenced by James Adair when he observes that "several old American towns are called Kan?ai," and suggests that the Conoy Indians of Pennsylvania and Maryland were Canaanites and their tribal name a corruption of the word Canaan. The Conoy Indians are the same Indians William Penn around 1700 described as resembling Italians, Jews and Greeks. By about 1735 they had dwindled to a "remnant of a nation, or subdivided tribe, of Indians," according to Adair (1930:56, 67, 68). One of the oldest Cherokee clans is called Red Paint Clan (Ani-wodi).

So do the two subclades of X and other haplogroups represent Old World and New World branches diverging from each other as long ago as 30,000 years, or do the Native American "anomalous" haplotypes come more recently (but not as late as Columbus) from the same source in the East Mediterranean? The answer probably depends on how open one is to new evidence and revisionary thinking. According to Jett, "The splits may have taken place well before transfer, with one only or both being transferred to a new place and then one dying out in the home area (and the other in the new area, if both were transferred)." The distinction, at any rate, is irrelevant to the Cherokee who exhibit these not-so-rare haplogroups, although to those denied authenticity on the basis of anthropologists' hardened ideas about the genetic composition of American Indians it is welcome vindication either way.

References
1. Adair, James (1930). Adair's History of the American Indians, ed. by Samuel Cole Williams, originally published London, 1775. Johnson City: Watauga.
2. Richards, Martin et al. (2000). "Tracing European Founder Lineages in the Near Eastern mtDNA Pool." American Journal of Human Genetics 67:1251-76. Supplementary Data. URL: http://www.stats.gla.ac.uk/~vincent/founder2000/index.html.
3. Schurr, Theodore G. (2000). "Mitochondrial DNA and the Peopling of the New World," American Scientist 88:246-53.
4. Shlush, L. I. et al. (2009) "The Druze: A Population Genetic Refugium of the Near East." PLoS ONE 3(5): e2105. URL: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2324201

When Objects Become Subjects
(and Talk Back to Researchers)
Review
Paul Brodwin, "'Bioethics in Action' and Human Population Genetics Research"

Population genetics experts who lecture in the groves of academe or trudge through the jungles of the Amazon are not immune to racist bombshells and political dynamite. In 1991, Stanford geneticist Luigi Luca Cavalli-Sforza announced a project to study human genetic diversity. The ponderous monograph that issued forth in 1994 became as revered as it was unreadable. His History and Geography of Human Genes posited two main limbs in the human DNA tree, the African and non-African, with the latter branching off into Europeans (Caucasians) and Northeast Asians. Included in Northeast Asians were the so-called Amerindians. Amerinds were closest in genetic distance to Northern Turkic, Chukchi and other Arctic and Mongolian peoples.

Little did Cavalli-Sforza and his team expect to encounter any opposition to their benign project, much less withdrawal of funding by the U.S. government and United Nations, but this is exactly what happened. The genial professor was surprised one day by a letter from a Canadian human rights group called the Rural Advancement Foundation International. The group demanded he stop his work immediately. It accused the Human Genome Diversity Project of biopiracy, stealing DNA from unsuspecting indigenous people and mining it for valuable information pharmaceutical companies could use to make drugs Third World people could not afford.

Paul Brodwin's article published in 2005 in the journal Culture, Medicine and Psychiatry (29:145-78) reviewed this controversy, which had some positive repercussions in forcing researchers to rethink colonialist attitudes toward their subjects. But in the second case of "bioethics in action," Brodwin painted a much more ambiguous picture. It concerned the use of genetics by the ethnic group called Melungeons of Tennessee and Virginia to prove identity claims and press their ideas of special entitlements.

In the section of the article titled "The Reinvention of Melungeon Ethnicity," Brodwin chronicles the conflict between scientific genetics and the Melungeons' demand for collective recognition. Complicating this issue is that the academics were by no means certain among themselves about who or what Melungeons were from an anthropological perspective. A rancorous standoff between Virginia DeMarce and N. Brent Kennedy was matched by the tendentious nature of the Melungeons' own theories and assertions about themselves. Was there even such a thing as Melungeons or were they simply genealogical ghosts and lurid creations of popular journalism? Did they truly have some black and American Indian ancestry? Was the title only to apply to people in and around Newmans Ridge in Hancock County, Tennessee, or be extended to a wide range of persons of mixed ancestry like the Carolina Turks and Lumbee Indians? If the Melungeons went back before the arrival of Europeans, could they seek legal recognition as an indigenous American Indian tribe?

Questions abounded and it seemed all of them were murky, emotionally charged and political. Unlike the Human Genome Diversity battle, neither party seemed to gain any advantages in the free-for-all. There were apparently no lessons to be learned on either side. At the end of the day, everyone just gave up and went home, exhausted.

Brodwin obviously sympathizes with the forces of the Academy in all this. He throws his lot in with the geneticist Kevin Jones, who found "he did not control the goals of research or the interpretation of findings." The Melungeon fracas illustrated "the political and conceptual vulnerabilities of human population genetics." In my opinion, however, Brodwin missed the point. Whom do university professors and academic researchers serve, if not the public? They should rejoice that so many of the great unwashed (even in the hills and hollers of Tennessee) are engaged by and even interested in their research. And if they cannot achieve a satisfactory dialogue with their lay critics, whose fault is that? The debate should continue, not be swept under the rug of philosophical reflection. Whatever else they might be, Melungeons are people. As such, they should not be dismissed when they become intractable.

Introducing the DNA Fingerprint Plus

Since the disappearance of DNAPrint and AncestryByDNA from the market in February the demand for an autosomal test that would tell you whether you had Native American or other admixture and estimate what mix you had, has been unmet. While it is doubtful, for many reasons, there will ever be a test that can assign percentages to ethnicities, DNA Consultants has developed a panel of 18 markers potentially evident in a person's CODIS profile that have high probabilities for signaling different ethnic contributions. The Ethnic Panel has been added to the company's DNA Fingerprint Test in the DNA Fingerprint Plus.

As with all genetic markers, the fact that you do not have a marker does not mean that you lack that type of heredity, but its presence is a strong indicator of likelihood that you do possess certain genes. Because we receive one allele or unit of variation from one parent and one from another, and each parent possesses two themselves, one person can fail to inherit, say, a Native American marker but a sibling can have it.

DNA Consultants' chief investigator Dr. Donald Yates made the discoveries in July that laid the foundation for the new product, which was rolled out in early September. Like the CODIS test it is based on, the DNA Fingerprint Plus reflects your total ancestry, not just a male or female line. The 18 Marker Ethnic Panel costs $50.00 and there is no need to repeat any testing. It uses the results of your DNA Fingerprint Test.

The markers include checks for Native American, Ashkenazi Jewish, Northern European, Mediterranean, Sub-Saharan African, Asian and other types of probable contributions to your overall genetic legacy. They do not tell you how much of a given ancestry you may have or what line in your genealogy it might come from.

The way the Panel works is this: Depending on your ethnic mix, your score on a certain allele may fall near one end or the other on a probability scale. All these polarizations in the data correspond to major forks in the road of prehistoric human migrations.

They support the conclusions of Oxford geneticist Stephen Oppenheimer and others that early humans left Africa in one or two migrations that gave birth to all the ethnic types in the rest of the world, from Australian Aborigines to Europeans. Native Americans and Europeans are closer, genetically speaking, than Native Americans are to Asians. One of the markers apparently reflects a divide between Asian ancestry on the one hand and European/Native American on the other.

It is useful in distinguishing between Asian and Native American, two ethnicities that have a high degree of shared deep ancestry and are often otherwise mistaken for each other. Some ethnic markers can be shown by certain control measures to be a "false positive" and not indicative of that ancestry at all. They are also listed in the DNA Fingerprint Plus report.

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A Surprising Middle Eastern Component

Haplogroup T (named Tara by Bryan Sykes in The Seven Daughters of Eve) is usually not seen as a Native American lineage. But it is discussed as such in Donald Yates' Old World Roots of the Cherokee, where it takes its rightful place among other Middle Eastern haplogroups like U, J and X. Moreover, several geneticists have drawn attention to its prevalence in New World Jewish and Crypto-Jewish populations.

The following comes from Chapter 3, "DNA," pp. 55-57, and discusses some living examples of "Taras" who verified their Native American genealogies with a DNA test from DNA Consultants in 2007-2009, as reported in "Anomalous Mitochondrial DNA Lineages in the Cherokee."

Maternal lineage T arose in Mesopotamia approximately 10,000 to 12,000 years ago. It spread northward through the Caucasus and west from Anatolia into Europe. It shares a common source with haplogroup J in the parent haplogroup JT. Ancient people bearing haplogroup T and J are viewed by geneticists as some of the first farmers, introducing agriculture to Europe with the Neolithic Revolution. Europe’s previous substrate emphasized older haplogroups U and N. The T lineage includes about 10% of modern Europeans. The closer one goes to its origin in the Fertile Crescent the more prevalent it is.

All T’s in the Cherokee project are unmatched in Old World populations. They do, however, in some cases, match each other. Such kinship indicates we are looking at members of the same definite group, with the same set of clan mothers as their ancestors. So let us briefly introduce some of these descendants of Middle Eastern-originating Cherokee lines.

Jonlyn L. Roberts, had a puzzling, but typical genealogy that led her to embark on a lifelong quest for answers. Her mother, Zella, was adopted by the George and Mary Hand family of Hand County, South Dakota in 1901. Little information was passed down, but piecing together clues from her childhood, Roberts believes that her mother’s original family might have come from the Red Lake Ojibwe Indian Reservation or one of the North or South Dakota reservations. At any rate, her mtDNA haplotype is a unique form of T, one with certain distinctive variations in common with others in the study.

Another T in the study fully matched four people other people, all born in the United States. One of these noted their ancestor as being Birdie Burns, born 1889 in Arkansas, the daughter of Alice Cook, a Cherokee.

Gail Lynn Dean (T) is the wife of another participant, whose type belongs to anomalous U. Both she and her husband claim Cherokee ancestries.

T participant Linda Burckhalter is the great-great-granddaughter of Sully Firebush, the daughter of a Cherokee chief . Sully married Solomon Sutton, stowaway son of a London merchant, in what would seem to be another variation of “Jewish trader marries chief’s daughter.”

Two cases of T represent descent in separate lines from the historically documented Gentry sisters, Elizabeth and Nancy, daughters of Tyree Gentry, who moved to Arkansas in 1817. The tested descendants are aunts or cousins of Patrick Pynes, a non-registered Cherokee and professor of American Indian studies. Learning of the results of the study, Pynes commented, “The possible connections to Egyptian heritage among these Cherokee descendants are especially interesting. We have a photograph of one of the women in this T* line (a granddaughter of Nancy Gentry, I think), and she is wearing an Ankh necklace. We all thought that was kind of strange. As far as I know, the Gentrys were Methodist Episcopalians.”

Three participants with T previously unknown to each other, and living in different parts of the country, turn out to be very close cousins descended from the same Cherokee ancestress. Their mitochondrial mutations exactly and fully match. Two claim Melungeon ancestry—a Yates male-linked cousin of the author and a relative of Phyllis Starnes (U, matching the author’s). The third has adoption in the family, so the female ancestry is unknown.

A case of rare T5, Cheryl, took not only the mitochondrial test but also our CODIS-marker-based ethnic population test, DNA Fingerprint, to validate “Cherokee or Jewish ancestry” from her mother. The results of the DNA Fingerprint Test show Ashkenazi Jewish in the No. 1 position, followed by assorted American Indian matches. Cheryl says that she is exploring returning to Judaism, but that in the remote Texas town where her family lives there are few avenues or resources to pursue.

As tabulated in Appendix A, our small survey shows a great deal of diversity and relatedness. It includes more than a few participants who discovered they share the same Cherokee ancestry, maybe even the same clan. Unlike a random sample of the U.S. population, they exhibit a mix that turns the conventional numbers on their head. Haplogroup H, instead of an expected 50% dominant position, is one of the smallest, with only 7.7%. Haplogroup U, an older lineage representing the Stone Age colonization of Europe before the ascendency of H, contributes 25% of the total number. Haplogroup X, marked by an exiguous presence elsewhere, attains a frequency in the Cherokee more than tenfold that of Eurasia or rest of Native America.

Yet the most startling statistic concerns T haplotypes now verified in the Cherokee. At 27%, they constitute the leading anomalous haplogroup not corresponding to the types A, B, C, or D. Several of them evidently stem from the same Cherokee family or clan, although they have been scattered from their original home by historical circumstances. So much consistency in the findings reinforces the conclusion that this is an accurate cross-section of a population, not a random collection of DNA test subjects. No such mix could result from post-1492 European gene flow into the Cherokee Nation. To dismiss the evidence as admixture would mean that there was a large influx of Middle Eastern-born women selectively marrying Cherokee men in historical times, something not even suggested by historical records. Mitochondrial DNA can only come from mothers; it cannot be imported into a country by men.

If not from Siberia, Mongolia or Asia, where do our anomalous, non-Amerindian-appearing lineages come from? The level of haplogroup T in the Cherokee mirrors the percentage for Egypt, one of the only countries where T attains a major showing among the other types. In Egypt, T is three times what it is in Europe. Haplogroup U in our sample is about the same as the Middle East in general. Its frequency is similar to that of Turkey and Greece.

Above: Tistoe, or Tathtowe, one of the seven Cherokees who visited the British king George II with Sir Alexander Cumming in 1730. His name is a ceremonial title meaning "smoke maker" and may come from Greek typho. It was later applied to the figure of Santa Claus, because the holidays brought firecrackers and smoke (see p. 103). Winterthur Museum.

See Donald N. Panther-Yates,

“A Portrait of Cherokee Chief Attakullakulla from the 1730s? A Discussion of William Verelst’s ‘Trustees of Georgia’ Painting’,” Journal of Cherokee Studies 22 (2001) 4-20.

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Sephardic signature in haplogroup T mitochondrial DNA

Felice L Bedford¹

¹University of Arizona, Tucson, AZ, USA

Correspondence: Dr FL Bedford, University of Arizona, PO Box 210068, Tucson, AZ 85721, USA. Tel: +1 520 404 2669; Fax: +1 520 621 9306; E-mail: bedford@u.arizona.edu

Received 2 February 2011; Revised 19 September 2011; Accepted 29 September 2011
Advance online publication 23 November 2011

Top

Abstract

The incidence of subhaplogroup T2e decreased from the Western Arabian Peninsula to Italy to Spain and into Western Europe. The ratio of sister subhaplogroups T2e to T2b was found to vary 40-fold across populations from a low in the British Isles to a high in Saudi Arabia with the ratio in Sephardim more similar to Saudi Arabia, Egypt, and Italy than to hosts Spain and Portugal.

Coding region mutations of 2308G and 14499T may locate the Sephardic signature within T2e, but additional samples and reworking of current T2e phylogenetic branch structure is needed. The Sephardic Turkish community has a less pronounced founder effect than some Ashkenazi groups considered singly (eg, Polish), but other comparisons of interest await comparable averaging. Registries of signatures will benefit the study of populations with a large number of smaller-size founders.

Sephardic signature within mtDNA haplogroup T (?)

This paper proposes that "The haplotype of a suspected Sephardic origin has mutations 16114T-16126T-16153A-16192T-16294T-16519C in the first control region of mito-
chondrial DNA."

From the paper:

four avenues are pursued: (1) A search is conducted throughout multiple databases of the first control region of mitochondrial DNA for the T2e5 motif to ascertain the prevalence and geographic affiliation of the new haplotype. (2) One T2e5 sample is
sequenced for polymorphisms along the entire mitochondrial DNA and compared with T2e sequences to identify any potential coding region mutations that are important for the Sephardic sequence and its relation to other branches. (3) A phylogenetic tree is built from T2e control sequences to provide further information on the relation among lineages including the Sephardic cluster. Although full genomic sequences are usually preferable to avoid misclassifications based on control region information alone, T2e is an ideal subhaplogroup to exploit the more abundant control region data because it is defined by mutations in the control regions alone. Time to the most recent common ancestor is estimated to address questions of when the lineage emerged as well as where. (4) The frequencies of T sub-haplogroups are compared across growing published literature of various populations including from Europe, the Americas, and the Near East. Although the geographic distribution of haplogroup T has been investigated, less is known about the different subhaplogroups, especially T2e.

With respect to (1), the author writes:

The combined databases do not appear to have any biases for Iberia, Mexico, or Sephardim.

This is a rather weak claim, since the incidence of a haplotype in a given dataset depends on the relative number of samples of the different populations, and Sephardic Jews are indeed over-represented in the database searches relative to their actual population numbers. In any case, no explicit test of bias was performed

Stronger evidence for the Sephardic-ness of the haplotype in question could be arrived by dating it to a period consistent with the origins of that population. However:

Time estimates to the most recent common ancestor of the Sephardic signature T2e5 ranged all the way from after the expulsion – clearly impossible – to 415 000 years before present (YBP) (Fast: 338 YBP, 95% confidence interval (95% CI)=present to 763 YBP; Intermediate: 688 YBP, 95% CI=present-3820 YBP; slow: 6811 YBP, CI1=present to 15 245). Given mutations rates that vary by two orders of magnitude,22 as well as other issues with mutation rates and the rho statistic,23,41 at present coalescence analysis cannot be used to distinguish between different plausible timelines for the proposed Sephardic cluster.

The third piece of evidence in favor of the hypothesis of this paper is the relative frequency of the parent haplogroup T2e relative to T2b. This is, however, irrelevant, since mtDNA haplogroup T2e has been found in prehistoric European hunter-gatherers, so- its higher frequency in Saudi Arabia today does not indicate that its presence in Europe was effected in historical times, e.g., by Jews.

Moreover, higher frequency -in itself- does not indicate the direction of gene flow. Suppose that a particular haplogroup occurs at a frequency of 50% in a population A of 10 million that lives 2,000 miles away, and at a frequency of 10% in a population B of 500 million that lives 500 miles away. Clearly, population B is a much better source of the haplogroup than A, despite its lower frequency.

The final piece of evidence produced by the author:

The small T2e5 cluster satisfies criteria for being a signature. Although it is premature to set specific thresholds of a signature, a sample of 25% known Sephardic and 50% suspicion of Sephardic origin is overwhelmingly above what would be expected for a general European haplogroup.

On the contrary, T2e5 is found in Latin America (including Brazil), Iberia, and among Sephardic Jews who trace their ancestry to Iberia. Hence, if there is anything "in common" between the current T2e5 population, it is the geographical background of Iberia.

Strong evidence for the specific Jewish origin of T2e5 would be provided if it turned up in a different Jewish population. In that case, it could be well argued that this was indeed a lineage of Jewish origin that happened (for whatever reason) to become more frequent in the Sephardic population. On the contrary, the absence of T2e5 in non-Sephardic Jews suggests that this is not necessarily a Jewish-origin lineage.

In conclusion: this paper represents a valiant attempt to identify a Sephardic signature, but I remain unconvinced that a strong enough case for T2e5 being such a signature has been made. The evidence appears to be consistent with that hypothesis, but not sufficient to reject alternatives, namely that this is represents a European founder in the Sephardic population. Indeed, the author honestly admits that the origin of the "Sephardic signature" remains elusive:

These include Jewish settlers seeking asylum after destruction of temples in Jerusalem by Romans and Babylonians 2000–2500 years ago, slightly earlier Jewish settlers in Iberia,7,43 non-Jewish Muslims in the dispersal of Islam 1000+ years ago, non-Jewish Iberian peopling 2500+ years ago that predates all Jewish influx,44 and settlers in Iberia (or Italy) 45000 years ago that entirely predate the existence of Jewish groups. Thus, what is arguably the most contentious issue of whether there is genetic evidence of original Jewish DNA for the Sephardic line cannot be resolved.

Does it matter whether the line was originally Jewish or not? Not in the grand scheme of things, but it is certainly important for geneaologists: if it was originally Jewish then e.g., Latin Americans who belong to it must seek Sephardic Jewish ancestors; if it was pre-Jewish Iberian, then they may/may not have such ancestors.

PS: A minor mistake in the paper is the identification of a Sephardic sample as coming from "Salonica, Turkey". Salonica has, of course, never been part of Turkey: it was part of the Ottoman Empire and is now part of Greece. Fortunately Salonica is prominent enough to avoid confusion, but it's always a good idea to use appropriate terminology when referring to placenames.

European Journal of Human Genetics advance online publication 23 November 2011; doi: 10.1038/ejhg.2011.200

Sephardic signature in haplogroup T mitochondrial DNA

Felice L Bedford

Abstract
A rare combination of mutations within mitochondrial DNA subhaplogroup T2e is identified as affiliated with Sephardic Jews, a group that has received relatively little attention. Four investigations were pursued: Search of the motif in 250 000 control region records across 8 databases, comparison of frequencies of T subhaplogroups (T1, T2b, T2c, T2e, T4, T*) across 11 diverse populations, creation of a phylogenic median-joining network from public T2e control region entries, and analysis of one Sephardic mitochondrial full genomic sequence with the motif. It was found that the rare motif belonged only to Sephardic descendents (Turkey, Bulgaria), to inhabitants of North American regions known for secret Spanish–Jewish colonization, or were consistent with Sephardic ancestry. The incidence of subhaplogroup T2e decreased from the Western Arabian Peninsula to Italy to Spain and into Western Europe. The ratio of sister subhaplogroups T2e to T2b was found to vary 40-fold across populations from a low in the British Isles to a high in Saudi Arabia with the ratio in Sephardim more similar to Saudi Arabia, Egypt, and Italy than to hosts Spain and Portugal. Coding region mutations of 2308G and 14499T may locate the Sephardic signature within T2e, but additional samples and reworking of current T2e phylogenetic branch structure is needed. The Sephardic Turkish community has a less pronounced founder effect than some Ashkenazi groups considered singly (eg, Polish), but other comparisons of interest await comparable averaging. Registries of signatures will benefit the study of populations with a large number of smaller-size founders.

Mitochondrion. 2007 Jun 27;: 17660050 Cit:10

Mitochondrial haplogroup T is negatively associated with the status of elite endurance athlete.

Mónica G Castro, Nicolás Terrados, Julián R Reguero, Victoria Alvarez, Eliecer Coto

Mitochondrial function is absolutely necessary to supply the energy required for muscles, and germ line mutations in mitochondrial genes have been related with impaired cardiac function and exercise intolerance. In addition, alleles at several polymorphic sites in mtDNA define nine common haplogroups, and some of these haplogroups have been implicated in the risk of developing several diseases. In this study, we analysed the association between mtHaplogroups and the capacity to reach the status of elite endurance athlete. DNA was obtained from blood leukocytes of 95 Spanish elite endurance athletes and 250 healthy male population controls. We analysed eight mitochondrial polymorphisms and the frequencies were statistically compared between elite athletes and controls. Haplogroup T, specifically defined by 13368A, was significantly less frequent among elite endurance athletes (p =0.012, Fisher's exact test). Our study suggests that allele 13368A and mitochondrial haplogroup T might be a marker negatively associated with the status of elite endurance athlete. This mitochondrial variant could be related with a lower capacity to respond to endurance training, through unknown mechanisms involving a less efficient mitochondrial workload.

Keywords: haplogroup; athlete; elite endurance; elite; endurance; endurance athlete; mitochondrial; mitochondrial haplogroup; negatively associate; statu; negatively; mtdna; allele; elite athlete; endurance train;

[Show abstracts]

Latest citations:

Eur J Hum Genet. 2012 Apr ;20 (4):441-8 22108605

Sephardic signature in haplogroup T mitochondrial DNA.

Felice L Bedford

University of Arizona, Tucson, AZ 85721, USA. bedford@u.arizona.edu

A rare combination of mutations within mitochondrial DNA subhaplogroup T2e is identified as affiliated with Sephardic Jews, a group that has received relatively little attention. Four investigations were pursued: Search of the motif in 250 000 control region records across 8 databases, comparison of frequencies of T subhaplogroups (T1, T2b, T2c, T2e, T4, T(*)) across 11 diverse populations, creation of a phylogenic median-joining network from public T2e control region entries, and analysis of one Sephardic mitochondrial full genomic sequence with the motif. It was found that the rare motif belonged only to Sephardic descendents (Turkey, Bulgaria), to inhabitants of North American regions known for secret Spanish-Jewish colonization, or were consistent with Sephardic ancestry. The incidence of subhaplogroup T2e decreased from the Western Arabian Peninsula to Italy to Spain and into Western Europe. The ratio of sister subhaplogroups T2e to T2b was found to vary 40-fold across populations from a low in the British Isles to a high in Saudi Arabia with the ratio in Sephardim more similar to Saudi Arabia, Egypt, and Italy than to hosts Spain and Portugal. Coding region mutations of 2308G and 14499T may locate the Sephardic signature within T2e, but additional samples and reworking of current T2e phylogenetic branch structure is needed. The Sephardic Turkish community has a less pronounced founder effect than some Ashkenazi groups considered singly (eg, Polish), but other comparisons of interest await comparable averaging. Registries of signatures will benefit the study of populations with a large number of smaller-size founders.

Ann N Y Acad Sci. 2011 Jul ;1229 :103-14 21793845

Genomic biomarkers and clinical outcomes of physical activity.

Alberto Izzotti

Department of Health Sciences, Faculty of Medicine, University of Genoa, Genoa, Italy. izzotti@unige.it

Clinical and experimental studies in humans provide evidence that moderate physical activity significantly decreases artery oxidative damage to nuclear DNA, DNA-adducts related to age and dyslipedemia, and mitochondrial DNA damage. Maintenance of adequate mitochondrial function is crucial for preventing lipid accumulation and peroxidation occurring in atherosclerosis. Studies performed on human muscle biopsies analyzing gene expression in living humans reveal that physically active subjects improve the expression of genes involved in mitochondrial function and of related microRNAs. The attenuation of oxidative damage to nuclear and mitochondrial DNA by physical activity resulted in beneficial effects due to polymorphisms of glutathione S-transferases genes. Subjects bearing null GSTM1/T1 polymorphisms have poor life expectancy in the case of being sedentary, which was increased 2.6-fold in case they performed physical activity. These findings indicate that the preventive effect of physical activity undergoes interindividual variation affected by genetic polymorphisms.

Mol Neurodegener. 2011 ;6 (1):32 21595933

PGC-1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease.

Elahe Taherzadeh-Fard, Carsten Saft, Denis A Akkad, Stefan Wieczorek, Aiden Haghikia, Andrew Chan, Jörg T Epplen, Larissa Arning

Department of Human Genetics, Ruhr-University Bochum, Germany. larissa.arning@rub.de.

ABSTRACT: Huntington disease (HD) is an inherited neurodegenerative disease caused by an abnormal expansion of a CAG repeat in the huntingtin HTT (HD) gene. The primary genetic determinant of the age at onset (AO) is the length of the HTT CAG repeat; however, the remaining genetic contribution to the AO of HD has largely not been elucidated. Recent studies showed that impaired functioning of the peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1alpha) contributes to mitochondrial dysfunction and appears to play an important role in HD pathogenesis. Further genetic evidence for involvement of PGC-1alpha in HD pathogenesis was generated by the findings that sequence variations in the PPARGC1A gene encoding PGC-1alpha exert modifying effects on the AO in HD. In this study, we hypothesised that polymorphisms in PGC-1alpha downstream targets might also contribute to the variation in the AO. In over 400 German HD patients, polymorphisms in the nuclear respiratory factor 1 gene, NRF-1, and the mitochondrial transcription factor A, encoded by TFAM showed nominally significant association with AO of HD. When combining these results with the previously described modifiers rs7665116 in PPARGC1A and C7028T in the cytochrome c oxidase subunit I (CO1, mt haplogroup H) in a multivariable model, a substantial proportion of the variation in AO can be explained by the joint effect of significant modifiers and their interactions, respectively. These results underscore that impairment of mitochondrial function plays a critical role in the pathogenesis of HD and that upstream transcriptional activators of PGC-1alpha may be useful targets in the treatment of HD.

Int J Alzheimers Dis. 2011 ;2011 :709061 21423558

May "mitochondrial eve" and mitochondrial haplogroups play a role in neurodegeneration and Alzheimer's disease?

Elena Caldarazzo Ienco, Costanza Simoncini, Daniele Orsucci, Loredana Petrucci, Massimiliano Filosto, Michelangelo Mancuso, Gabriele Siciliano

Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126 Pisa, Italy.

Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Multiple evidences suggest that mitochondria may be crucial in ageing-related neurodegenerative diseases. Moreover, mitochondrial haplogroups have been linked to multiple area of medicine, from normal ageing to diseases, including neurodegeneration. Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to increased amount of reactive oxygen species, having either susceptibility or protective role in several diseases. Here, we highlight the role of the mitochondrial haplogroups in the pathogenetic cascade leading to diseases, with special attention to Alzheimer's disease.

Scand J Med Sci Sports. 2011 Mar 16;: 21410543

Importance of mitochondrial haplotypes and maternal lineage in sprint performance among individuals of West African ancestry.

M Deason, R Scott, L Irwin, V Macaulay, N Fuku, M Tanaka, R Irving, V Charlton, E Morrison, K Austin, Y P Pitsiladis

Institute of Cardiovascular and Medical Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK International Centre for East African Running Science (ICEARS), Glasgow, UK Department of Statistics, University of Glasgow, Glasgow, UK Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Department of Basic Medical Sciences, University of West Indies, Mona, Kingston, Jamaica University of Technology, Kingston, Jamaica.

Mitochondrial DNA (mtDNA) is inherited solely along the matriline, giving insight into both ancestry and prehistory. Individuals of sub-Saharan ancestry are overrepresented in sprint athletics, suggesting a genetic advantage. The purpose of this study was to compare the mtDNA haplogroup data of elite groups of Jamaican and African-American sprinters against respective controls to assess any differences in maternal lineage. The first hypervariable region of mtDNA was haplogrouped in elite Jamaican athletes (N=107) and Jamaican controls (N=293), and elite African-American athletes (N=119) and African-American controls (N=1148). Exact tests of total population differentiation were performed on total haplogroup frequencies. The frequency of non-sub-Saharan haplogroups in Jamaican athletes and Jamaican controls was similar (1.87% and 1.71%, respectively) and lower than that of African-American athletes and African-American controls (21.01% and 8.19%, respectively). There was no significant difference in total haplogroup frequencies between Jamaican athletes and Jamaican controls (P=0.551 ± 0.005); however, there was a highly significant difference between African-American athletes and African-American controls (P<0.001). The finding of statistically similar mtDNA haplogroup distributions in Jamaican athletes and Jamaican controls suggests that elite Jamaican sprinters are derived from the same source population and there is neither population stratification nor isolation for sprint performance. The significant difference between African-American sprinters and African-American controls suggests that the maternal admixture may play a role in sprint performance.

Br J Sports Med. 2010 Jun 15;: 20551160 Cit:1

Mitochondrial haplogroups associated with elite Japanese athlete status.

Eri Mikami, Noriyuki Fuku, Hideyuki Takahashi, Nao Ohiwa, Robert A Scott, Yannis P Pitsiladis, Mitsuru Higuchi, Takashi Kawahara, Masashi Tanaka

Graduate School of Sport Sciences, Waseda University, Saitama, Japan.

Purpose It has been hypothesised that certain mitochondrial haplogroups, which are defined by the presence of a characteristic cluster of tightly linked mitochondrial DNA polymorphisms, would be associated with elite Japanese athlete status. To examine this hypothesis, the frequencies of mitochondrial haplogroups found in elite Japanese athletes were compared with those in the general Japanese population. Methods Subjects comprised 139 Olympic athletes (79 endurance/middle-power athletes (EMA), 60 sprint/power athletes (SPA)) and 672 controls (CON). Two mitochondrial DNA fragments containing the hypervariable sequence I (m16024-m16383) of the major non-coding region and the polymorphic site at m.5178C>A within the NADH dehydrogenase subunit 2 gene were sequenced, and subjects were classified into 12 major mitochondrial haplogroups (ie, F, B, A, N9a, N9b, M7a, M7b, M*, G2, G1, D5 or D4). The mitochondrial haplogroup frequency differences among EMA, SPA and CON were then examined. Results EMA showed an excess of haplogroup G1 (OR 2.52, 95% CI 1.05 to 6.02, p=0.032), with 8.9% compared with 3.7% in CON, whereas SPA displayed a greater proportion of haplogroup F (OR 2.79, 95% CI 1.28 to 6.07, p=0.007), with 15.0% compared with 6.0% in CON. Conclusions The results suggest that mitochondrial haplogroups G1 and F are associated with elite EMA and SPA status in Japanese athletes, respectively.

Environ Mol Mutagen. 2010 Jun ;51 (5):440-50 20544884 Cit:13

Mitochondrial DNA mutations in disease and aging.

Douglas C Wallace

ORU for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA, USA. dwallace@uci.edu

The human mitochondrial genome involves over 1,000 genes, dispersed across the maternally inherited mitochondrial DNA (mtDNA) and the biparentally inherited nuclear DNA (nDNA). The mtDNA encodes 13 core proteins that determine the efficiency of the mitochondrial energy-generating system, oxidative phosphorylation (OXPHOS), plus the RNA genes for their translation within the mitochondrion. The mtDNA has a very high mutation rate, which results in three classes of clinically relevant mtDNA mutations: recently deleterious germline line mutations resulting in mitochondrial disease; ancient regional variants, a subset of which permitted humans to adapt to differences in their energetic environments; and somatic mutations that accumulate with age eroding mitochondrial energy production and providing the aging clock. Mutations in nDNA-encoded OXPHOS structural genes can also cause mitochondrial disease, and alterations in nDNA mitochondrial biogenesis genes can destabilize the mtDNA and lead to clinical phenotypes. Finally, when combined, nonpathogenic nDNA and mtDNA protein variants can be functionally incompatible and cause disease. The essential functions of the conserved mtDNA proteins and their high mutation rate raise the question as to why the cumulative mtDNA genetic load does not result in species extinction. Studies of mice harboring deleterious mtDNA mutations have shown that the mammalian ovary selectively eliminates the most deleterious mtDNA mutations. However, milder mtDNA mutations are transmitted through the ovary and the female germline and introduced into the general population. This unique genetic system provides a flexible method for generating genetic variation in cellular and organismal energetics that permits species to adapt to alterations in their regional energetic environment.

Med Sci Sports Exerc. 2010 May ;42 (5):835-46 20400881 Cit:3

Advances in exercise, fitness, and performance genomics.

Tuomo Rankinen, Stephen M Roth, Molly S Bray, Ruth Loos, Louis Pérusse, Bernd Wolfarth, James M Hagberg, Claude Bouchard

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808-4124, USA. rankint@pbrc.edu

An annual review publication of the most significant articles in exercise, fitness, and performance genomics begins with this article, which covers 2 yr, 2008 and 2009. The review emphasizes the strongest articles as defined by sample size, quality of phenotype measurements, quality of the exercise program or physical activity exposure, study design, adjustment for multiple testing, quality of genotyping, and other related study characteristics. With this avowed focus on the highest quality articles, only a small number of published articles are reviewed. Among the most significant findings reported here are a brief overview of the first genome-wide association study of the genetic differences between exercisers and nonexercisers. In addition, the latest results on the actinin alpha 3 (ACTN3) R577X nonsense polymorphism are reviewed, emphasizing that no definitive conclusion can be reached at this time. Recent studies that have dealt with mitochondrial DNA haplogroups and endurance performance are described. Published reports indicating that physical activity may attenuate the effect of the fat mass and obesity associated (FTO) gene risk allele on body mass index are reviewed. Articles that have tested the contributions of specific genes to the response of glucose and insulin metabolism traits to regular exercise or physical activity level are considered and found to be generally inconclusive at this stage. Studies examining ethnic differences in the response of blood lipids and lipoproteins to exercise training cannot unequivocally relate these to apolipoprotein E (APOE) genotypes. Hemodynamic changes with exercise training were reported to be associated to sequence variation in kinesin heavy chain (KIF5B), but no replication study is available as of yet. We conclude from this first installment that exercise scientists need to prioritize high-quality research designs and that replication studies with large sample sizes are urgently needed.

Annu Rev Genomics Hum Genet. 2009 ;10 :407-29 19630564 Cit:4

Genetics of athletic performance.

Elaine A Ostrander, Heather J Huson, Gary K Ostrander

Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. eostrand@mail.nih.gov

Performance enhancing polymorphisms (PEPs) are examples of natural genetic variation that affect the outcome of athletic challenges. Elite athletes, and what separates them from the average competitor, have been the subjects of discussion and debate for decades. While training, diet, and mental fitness are all clearly important contributors to achieving athletic success, the fact that individuals reaching the pinnacle of their chosen sports often share both physical and physiological attributes suggests a role for genetics. That multiple members of a family often participate in highly competitive events, such as the Olympics, further supports this argument. In this review, we discuss what is known regarding the genes and gene families, including the mitochondrial genome, that are believed to play a role in human athletic performance. Where possible, we describe the physiological impact of the critical gene variants and consider predictions about other potentially important genes. Finally, we discuss the implications of these findings on the future for competitive athletics.

Med Sci Sports Exerc. 2009 Jan ;41 (1):123-8 19092698 Cit:8

Mitochondrial haplogroups associated with elite Kenyan athlete status.

Robert A Scott, Noriyuki Fuku, Vincent O Onywera, Mike Boit, Richard H Wilson, Masashi Tanaka, William H Goodwin, Yannis P Pitsiladis

International Centre for East African Running Science, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UNITED KINGDOM.

UNLABELLED The maternal inheritance of mitochondrial DNA (mtDNA) has enabled construction of detailed phylogenies. Analysis of key polymorphisms from these phylogenies allows mtDNA to be assigned to haplogroups, which have been associated with elite endurance performance. PURPOSE To compare the frequencies of mtDNA haplogroups found in elite Kenyan athletes with those in the general Kenyan population. METHODS DNA samples were obtained from 221 national level Kenyan athletes (N), 70 international Kenyan athletes (I), and 85 members of the general Kenyan population (C). mtDNA haplogroups were classified by sequencing 340 bases of hypervariable section (HVS I) and by genotyping known restriction sites. Frequency differences between groups were assessed using exact tests of population differentiation. RESULTS The haplogroup distribution of national (P = 0.023) and international athletes (P < 0.001) differed significantly from controls, with international athletes showing a greater proportion of L0 haplogroups (C = 15%, N = 18%, I = 30%) and lower proportion of L3* haplogroups (C = 48%, N = 36%, I = 26%). Although a high number of international athletes originated from the Rift Valley province relative to controls (C = 20%, N = 65%, I = 81%), subjects from this province did not differ in haplogroup distribution from other regions (P = 0.23). Nor did Bantu subjects differ from Nilotic (P = 0.12) despite an overrepresentation of Nilotic languages among the athletes. CONCLUSIONS International athletes differed in their mtDNA haplogroup distribution relative to the general Kenyan population. They displayed an excess of L0 haplogroups and a dearth of L3* haplogroups. These findings suggest that mtDNA haplogroups are influential in elite Kenyan distance running, although population stratification cannot be ruled out.

Other papers by authors:

J Transl Med. 2010 ;8 :64 20594303 Cit:2

Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier.

Eliecer Coto, María Palacín, María Martín, Mónica G Castro, Julián R Reguero, Cristina García, José R Berrazueta, César Morís, Blanca Morales, Francisco Ortega, Ana I Corao, Marta Díaz, Beatriz Tavira, Victoria Alvarez

Genética Molecular, Red de Investigación Renal, and Fundación Renal, Hospital Universitario Central de Asturias, Oviedo, Spain. eliecer.coto@sespa.princast.es

HASH(0x14b98e90)

Am J Med Genet A. 2009 Jan 22;149A (2):286-289 19161138 Cit:1

Mutation analysis of the myocyte enhancer factor 2A gene (MEF2A) in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy.

Eliecer Coto, Mónica G Castro, Ana I Corao, Cristina Alonso-Montes, Julián R Reguero, César Morís, Victoria Alvarez

Genética Molecular and Cardiología-Fundación Asturcor, Hospital Universitario Central Asturias, Oviedo, Spain.

Dis Markers. 2008 ;25 (3):131-9 19096125 Cit:2

Mitochondrial transcription factors TFA, TFB1 and TFB2: A search for DNA variants/haplotypes and the risk of cardiac hypertrophy.

Cristina Alonso-Montes, Mónica G Castro, Julián R Reguero, Andreas Perrot, Cemil Ozcelik, Christian Geier, Maximilian G Posch, César Morís, Victoria Alvarez, Marta Ruiz-Ortega, Eliecer Coto

Genética Molecular, Hospital Central Asturias, Oviedo, Spain.

Mitochondrial transcription factors mtTFA, mtTFB1 and mtTFB2 are required for the replication of mitochondrial DNA (mtDNA), regulating the number of mtDNA copies. Mice with a mtTFA deletion showed a reduced number of mtDNA copies, a reduction in respiratory chain activity, and a characteristic dilated cardiomyopathy. DNA variants in these genes could be involved in the risk for cardiac hypertrophy (HCM). We determined the variation in the TFAM, TFB1M, and TFB2M genes (using SSCA, DHPLC, and direct sequencing) in a total of 200 HCM-patients from Spain and Germany, and in 250 healthy controls. We found several common polymorphisms that defined haplotype blocks in these genes, with frequencies that did not differ between patients and controls. We also found four novel variants in patients which were absent in the controls:-91 C > A (5'-UTR) and Ala105 > Thr in TFAM, and Thr211 > Ala and Arg256 > Lys in TFB1M. The three missense changes were in highly conserved amino acids, and could be involved in HCM-risk. In conclusion, common variants in the mitochondrial transcription factors were not associated with the risk for HCM. However, rare DNA variants (putative mutations) could be involved in the pathogenesis of HCM in a reduced number of cases.

Int J Cardiol. 2005 Nov 24;: 16313983 Cit:7

Mitochondrial DNA haplogroups in Spanish patients with hypertrophic cardiomyopathy.

Mónica G Castro, Cecilia Huerta, Julián R Reguero, María Isabel Soto, Enric Doménech, Victoria Alvarez, Montse Gómez-Zaera, Virginia Nunes, Pelayo González, Ana Corao, Eliecer Coto

Genética Molecular-Instituto de Estudios Nefrológicos, Hospital Central de Asturias-Maternidad 33006, Oviedo, Spain.

Mutations in mtDNA have been implicated in the development of hypertrophic cardiomyopathy (HCM), including cases from families with a maternal transmission. Alleles at several polymorphic sites in mtDNA define different haplogroups and some of these haplogroups have been involved in the risk of developing several diseases in which mitochondria should be involved. We analysed the association between the nine common European haplogroups and HCM. A total of 130 Spanish patients and 300 healthy controls were genotyped for eight mitochondrial single nucleotide polymorphisms (SNPs) through polymerase chain reaction followed by digestion with a restriction enzyme (PCR-RFLP). We compared the frequencies of these polymorphisms and mitochondrial haplogroups between patients and controls. Haplogroup T, specifically defined by 13368A, was significantly involved in the risk of developing HCM in our population (p=0.007; OR=2.42; 95% CI=1.25-4.67). Our data suggest that the genetic variation at the mitochondrial genome could significantly contribute to the risk for HCM.

J Mol Diagn. 2012 Jul 2;: 22765922

Resequencing the Whole MYH7 Gene (Including the Intronic, Promoter, and 3' UTR Sequences) in Hypertrophic Cardiomyopathy.

Eliecer Coto, Julián R Reguero, María Palacín, Juan Gómez, Belén Alonso, María Martín, Beatriz Tavira, Beatriz Díaz-Molina, Carlos Morales, César Morís, José L Rodríguez-Lambert, Ana I Corao, Marta Díaz, Victoria Alvarez

Genética Molecular-Laboratorio de Medicina-Fundación Renal (IRSIN-FRIAT), Hospital Universitario Central Asturias, Oviedo, Spain; Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain; Red de Investigación Renal (REDinREN), Oviedo, Spain.

MYH7 mutations are found in ∼20% of hypertrophic cardiomyopathy (HCM) patients. Currently, mutational analysis is based on the sequencing of the coding exons and a few exon-flanking intronic nucleotides, resulting in omission of single-exon deletions and mutations in internal intronic, promoter, and 3' UTR regions. We amplified and sequenced large MYH7 fragments in 60 HCM patients without previously identified sarcomere mutations. Lack of aberrant PCR fragments excluded single-exon deletions in the patients. Instead, we identified several new rare intronic variants. An intron 26 single nucleotide insertion (-5 insC) was predicted to affect pre-mRNA splicing, but allele frequencies did not differ between patients and controls (n = 150). We found several rare promoter variants in the patients compared to controls, some of which were in binding sites for transcription factors and could thus affect gene expression. Only one rare 3' UTR variant (c.*29T>C) found in the patients was absent among the controls. This nucleotide change would not affect the binding of known microRNAs. Therefore, MYH7 mutations outside the coding exon sequences would be rarely found among HCM patients. However, changes in the promoter region could be linked to the risk of developing HCM. Further research to define the functional effect of these variants on gene expression is necessary to confirm the role of the MYH7 promoter in cardiac hypertrophy.

Clin Chem. 2011 Nov ;57 (11):1614-6 21890708

Profile of microRNAs differentially produced in hearts from patients with hypertrophic cardiomyopathy and sarcomeric mutations.

María Palacín, Julián R Reguero, María Martín, Beatriz Díaz Molina, César Morís, Victoria Alvarez, Eliecer Coto

Rev Esp Cardiol. 2010 Jul ;63 (7):856-9 20609320

The spectrum of SCN5A gene mutations in Spanish Brugada syndrome patients.

Mónica García-Castro, Cristina García, Julián R Reguero, Ana Miar, José M Rubín, Victoria Alvarez, César Morís, Eliecer Coto

Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.

Brugada syndrome is characterized by right bundle branch block and ST-segment elevation in the right precordial ECG leads. Familial transmission is frequent and approximately 25% of cases exhibit mutations in the SCN5A gene. We analyzed the sequence of this gene in 25 Spanish patients with Brugada syndrome. In 4 (16%), we found mutations that had not previously been described: three were amino acid changes (i.e. Ala2>Thr, Ala735>Thr and Val1340>Ile) and one was an intron mutation that affected messenger RNA processing (i.e. IVS18-1G>A). These four patients had relatives who were also mutation carriers, several of whom had normal ECGs, even on flecainide challenge. Our study suggests that genetic analysis could be helpful in the presymptomatic diagnosis of Brugada syndrome, but may be less useful for stratifying the risk of adverse events.

Rev Esp Cardiol. 2009 Jan ;62 (1):48-56 19150014 Cit:2

Mutations in Sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in Patients With Hypertrophic cardiomyopathy.

Mónica García-Castro, Eliecer Coto, Julián R Reguero, José R Berrazueta, Victoria Alvarez, Belén Alonso, Rocío Sainz, María Martín, Cesar Morís

aGenética Molecular. Instituto de Investigación Nefrológica. Hospital Universitario Central de Asturias. Oviedo. Asturias. España.

INTRODUCTION AND OBJECTIVES: Mutation of a sarcomeric gene is the most frequent cause of hypertrophic cardiomyopathy. For each such gene, however, previous studies have reported a range of different mutation frequencies, and clinical manifestations have been highly heterogeneous, both of which limit the use of genetic information in clinical practice. Our aim was to determine the frequency of mutations in the sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in a cohort of Spanish patients with hypertrophic cardiomyopathy. METHODS: We used sequencing to analyze the coding regions of these five genes in 120 patients (29% with a family history) and investigated how the patient phenotype varied with the gene mutated. RESULTS: In total, 32 patients were found to have mutations: 10 in MYH7 (8%), 20 in MYBPC3 (16%), 2 in TNNT2, 1 in TPM1 and none in TNNI3. Overall, 61% of mutations had not been described before. Two patients had two mutations (i.e., double mutants). There was no difference in the mean age at diagnosis or the extent of the hypertrophy between those with MYH7 mutations and those with MYBPC3 mutations. CONCLUSIONS: Some 26% of patients had a mutation in one of the five sarcomeric genes investigated. More than half of the mutations had not been described before. The MYBPC3 gene was the most frequently mutated, followed by MYH7. No phenotypic differences were observed between carriers of the various mutations, which makes it difficult to use genetic information to stratify risk in these patients.

Int J Cardiol. 2006 Nov 11;: 17101185 Cit:3

Prevalence and spectrum of mutations in the sarcomeric troponin T and I genes in a cohort of Spanish cardiac hypertrophy patients.

Mónica García-Castro, Julián R Reguero, César Morís, Cristina Alonso-Montes, José R Berrazueta, Rocío Sainz, Victoria Alvarez, Eliecer Coto

Genética Molecular-Instituto de Investigación Nefrológica, Hospital Central de Asturias, Oviedo, Spain.

We sequenced the coding exons of the cardiac troponins T (TNNT2) and I (TNNI3) genes in 115 Spanish HCM-patients (32% with a family history of the disease). Only two (2%) had mutations in the TNNT2 (Arg278>Cys and Arg92>Lys). These mutations were associated with variable clinical outcomes. No patient had TNNI3-mutation. We also genotyped these patients and 320 healthy controls for a 5 bp insertion/deletion (I/D) polymorphism in intron 3 of TNNT2. DD-homozygotes for the 5 bp I/D polymorphism were significantly more frequent among the patients (OR=1.83, 95% CI=2.10-5.16).

Mov Disord. 2005 Dec ;20 (12):1626-9 16078201 Cit:4

Recessive hyperekplexia due to a new mutation (R100H) in the GLRA1 gene.

Eliecer Coto, Daniel Armenta, Raúl Espinosa, Joaquín Argente, Mónica G Castro, Victoria Alvarez

Genética Molecular, Hospital Central Asturias, Oviedo, Spain. eliecer.coto@sespa.princast.es

Hyperekplexia is commonly familial and with dominant transmission. The gene involved, GLRA1, encodes the alpha1 subunit of the glycine receptor. We describe 3 affected children homozygous for a new mutation, R100H. Both parents were heterozygous carriers; while the father was healthy, the mother has periodic limb movements during sleep. This suggests that Hys-100 could exhibit incomplete penetrance, but was linked to a severe classical form of hyperekplexia in homozygous.

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Scand J Med Sci Sports. 2012 Nov 19;: 23163620

Mitochondrial DNA variation is associated with elite athletic status in the Polish population.

A Maruszak, J G Adamczyk, M Siewierski, H Sozański, A Gajewski, C Zekanowski

Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland.

There is mounting evidence that genetic factors located in mitochondrial and nuclear genomes influence sport performance. Certain mitochondrial haplogroups and polymorphisms were associated with the status of elite athlete, especially in endurance performance. The aim of our study was to assess whether selected mitochondrial DNA (mtDNA) and nuclear DNA variants are associated with elite athlete performance in a group of 395 elite Polish athletes (213 endurance athletes and 182 power athletes) and 413 sedentary controls. Our major finding was that the mtDNA haplogroup H and HV cluster influence endurance performance at the Olympic/World Class level of performance (P = 0.018 and P = 0.0185, respectively). We showed that two polymorphisms located in the mtDNA control region were associated with achieving the elite performance level either in the total athlete's group as compared with controls (m.16362C, 3.8% vs 9.2%, respectively, P = 0.0025, odds ratio = 0.39, 95% confidence interval: 0.21-0.72), or in the endurance athletes as compared with controls (m.16080G, 2.35% vs 0%, respectively, P = 0.004). Our results indicate that mtDNA variability affects the endurance capacity rather than the power one. We also propose that mtDNA haplogroups and subhaplogroups, as well as individual mtDNA polymorphisms favoring endurance performance, could be population-specific, reflecting complex cross-talk between nuclear and mitochondrial genomes.

Scand J Med Sci Sports. 2012 Jan 31;: 22288660

Polymorphisms in the control region of mitochondrial DNA associated with elite Japanese athlete status.

E Mikami, N Fuku, H Takahashi, N Ohiwa, Y P Pitsiladis, M Higuchi, T Kawahara, M Tanaka

Graduate School of Sport Sciences, Waseda University, Saitama, Japan; Japan Society for the Promotion of Science, Tokyo, Japan; Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.

The control region of mitochondrial DNA (mtDNA) contains the main regulatory elements for mtDNA replication and transcription. Certain polymorphisms in this region would, therefore, contribute to elite athletic performance, because mitochondrial function is one of determinants of physical performance. The present study was undertaken to examine the effect of polymorphisms in this region on elite athlete status by sequencing the mtDNA control region. Subjects comprised 185 elite Japanese athletes who had represented Japan at international competitions (i.e., 100 endurance/middle-power athletes: EMA; 85 sprint/power athletes: SPA), and 672 Japanese controls (CON). The mtDNA control region was analyzed by direct sequencing. Frequency differences of polymorphisms (minor allele frequency ≥ 0.05) in the mtDNA control region between EMA, SPA, and CON were examined. EMA displayed excess of three polymorphisms [m.152T>C, m.514(CA)(n) repeat (n ≥ 5), and poly-C stretch at m.568-573 (C ≥ 7)] compared with CON. On the other hand, SPA showed greater frequency of the m.204T>C polymorphism compared with CON. In addition, none of the SPA had m.16278C>T polymorphism, whereas the frequencies of this polymorphism in CON and EMA were 8.3% and 10.0%, respectively. These findings imply that several polymorphisms detected in the control region of mtDNA may influence physical performance probably in a functional manner.

Int J Sports Med. 2012 Jan ;33 (1):76-80 22134884

MtDNA haplogroups and elite Korean athlete status.

K C Kim, H I Cho, W Kim

Biological Sciences, Dankook University, Cheonan, Republic of Korea.

Mitochondrial DNA (mtDNA) variation has recently been suggested to have an association with athletic performance or physical endurance. Since mtDNA is haploid and lacks recombination, specific mutations in the mtDNA genome associated with human exercise tolerance or intolerance arise and remain in particular genetic backgrounds referred to as haplogroups. To assess the possible contribution of mtDNA haplogroup-specific variants to differences in elite athletic performance, we performed a population-based study of 152 Korean elite athletes [77 sprint/power athletes (SPA) and 75 endurance/middle-power athletes (EMA)] and 265 non-athletic controls (CON). The overall haplogroup distribution of EMA differed significantly from CON (p<0.01), but that of SPA did not. The EMA have an excess of haplogroups M*(OR 4.38, 95% CI 1.63-11.79, p=0.003) and N9 (OR 2.32, 95% CI 0.92-5.81, p=0.042), but a dearth of haplogroup B (OR 0.26, 95% CI 0.09-0.75, p=0.003) compared with the CON. Thus, our data imply that specific mtDNA lineages may provide a significant effect on elite Korean endurance status, although functional studies with larger sample sizes are necessary to further substantiate these findings.

Mitochondrion. 2011 Nov ;11 (6):905-8 21856449

Are mitochondrial haplogroups associated with elite athletic status? A study on a Spanish cohort.

Gisela Nogales-Gadea, Tomàs Pinós, Jonatan R Ruiz, Pedro Femia Marzo, Carmen Fiuza-Luces, Ester López-Gallardo, Eduardo Ruiz-Pesini, Miguel Angel Martín, Joaquín Arenas, María Morán, Antoni L Andreu, Alejandro Lucia

Departament de Patología Mitocondrial i Neuromuscular, Institut de Recerca Hospital Universitari Vall d'Hebron, Barcelona, Spain.

There is increasing evidence regarding the association between mitochondrial DNA (mtDNA) and aerobic capacity; however, whether mtDNA haplogroups are associated with the status of being an elite endurance athlete is more controversial. We compared the frequency distribution of mtDNA haplogroups among the following groups of Spanish (Caucasian) men: 102 elite endurance athletes (professional road cyclists, endurance runners), 51 elite power athletes (jumpers, throwers and sprinters), and 478 non-athletic controls. We observed a significant difference between endurance athletes and controls (Fisher exact test=17.89, P=0.015; Bonferroni's significant threshold=0.017), yet not between power athletes and controls (Fisher exact test=47.99, P=0.381) or between endurance and power athletes (Fisher exact test=5.53, P=0.597). We observed that the V haplogroup was overrepresented in endurance athletes (15.7%) compared with controls (7.5%)(odds ratio: 2.284; 95% confidence interval: 1.237, 4.322). In conclusion, our findings overall support the idea that mtDNA variations could be among the numerous contributors to the status of being an elite endurance athlete, whereas no association was found with elite power athletic status.

Physiol Genomics. 2011 Jul 14;43 (13):789-98 21540298

The champions' mitochondria: is it genetically determined? A review on mitochondrial DNA and elite athletic performance.

Nir Eynon, María Morán, Ruth Birk, Alejandro Lucia

Faculty of Health Sciences, Department of Nutrition, Ariel University Center, Israel. eynon@wincol.ac.il

Aerobic ATP generation by the mitochondrial respiratory oxidative phosphorylation system (OXPHOS) is a vital metabolic process for endurance exercise. Notably, mitochondrial DNA (mtDNA) codifies 13 of the 83 polypeptides implied in the respiratory chain. As such, there is a strong rationale for identifying an association between mtDNA variants and "aerobic"(endurance) exercise phenotypes. The aim of this review is to summarize current knowledge on the association between mtDNA, nuclear genes involved in mitochondriogenesis, and elite endurance athletic status. Several studies in nonathletic people have demonstrated an association between certain mtDNA lineages and aerobic performance, characterized by maximal oxygen uptake (VO2max). Whether mtDNA haplogroups are also associated with the status of being an elite endurance athlete is more controversial, with differences between studies arising from the different ethnic backgrounds of the athletic cohorts (Caucasian of mixed geographic origin, Asiatic, or East African).

PLoS One. 2011 ;6 (3):e17558 21407828

Are 'endurance' alleles 'survival' alleles? Insights from the ACTN3 R577X polymorphism.

Carmen Fiuza-Luces, Jonatan R Ruiz, Gabriel Rodríguez-Romo, Catalina Santiago, Félix Gómez-Gallego, Thomas Yvert, Amalia Cano-Nieto, Nuria Garatachea, María Morán, Alejandro Lucia

Universidad Europea de Madrid, Madrid, Spain.

Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100 years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100-108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain 'survival' advantage brought about by α-actinin-3 deficiency and the 'endurance'/oxidative muscle phenotype that is commonly associated with this condition.

BMC Med Genet. 2010 Apr 1;11 (1):53 20356410 Cit:3

Maternal inheritance and mitochondrial DNA variants in familial Parkinson disease.

David K Simon, Nathan Pankratz, Diane K Kissell, Michael W Pauciulo, Cheryl A Halter, Alice Rudolph, Ronald F Pfeiffer, William C Nichols, Tatiana Foroud, The Parkinson Study Group Progeni Investigators

ABSTRACT: BACKGROUND: Mitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. METHOD: We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. RESULTS: The frequency of affected mothers of the proband with PD (83/167, 49.4%) was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4%)(Odds Ratio 1.22; 95%CI 0.83 - 1.81). After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. CONCLUSIONS: These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic mDNA mutations, contribute to the risk of familial PD.

Eur J Neurol. 2009 May 27;: 19486129 Cit:2

Short- and long-term effects of endurance training in patients with mitochondrial myopathy.

T D Jeppesen, M Dunø, M Schwartz, T Krag, J Rafiq, F Wibrand, J Vissing

Neuromuscular Research Unit, Department of Neurology, and the Copenhagen Muscle Research Centre, Rigshospitalet, Copenhagen, Denmark.

Background and purpose: It is unknown whether prolonged training is a safe treatment to alleviate exercise intolerance in patients with mitochondrial DNA (mtDNA) mutations. Methods: The effect of 3 and 12 months training and 3-12 months deconditioning was studied in four patients carrying different mtDNA mutations. Results: Three-month moderate-intensity training increased oxidative capacity by 23%, which was sustained after 6-12 months of low-intensity training. Training and deconditioning did not induce adverse effects on clinical symptoms, muscle morphology and mtDNA mutation load in muscle. Conclusion: Long-term training effectively improves exercise capacity in patients with mitochondrial myopathy, and appears to be safe.

Endocrine. 2009 Jun ;35 (3):347-55 19399650 Cit:3

Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas.

Jens Waldmann, Peter Langer, Nils Habbe, Volker Fendrich, Anette Ramaswamy, Matthias Rothmund, Detlef K Bartsch, Emily P Slater

Department of Surgery, University Hospital Giessen and Marburg, Baldingerstrasse, Marburg 35037, Germany. jwaldman@med.uni-marburg.de

The prevalence of germ line mutations within the RET-protooncogene and the tumor suppressor genes SDHB, SDHD, and VHL in pheochromocytomas (PC) varies in recent studies from 12 to 24%, if one look at them collectively. DNA was extracted from frozen tumor tissue as well as from blood leukocytes of 36 PC (26 sporadic/10 MEN2). Exons 1-8 of the SDHB-gene, 1-4 of the SDHD-gene, 1-3 of the VHL-gene, and exons 10, 11, 13, 14, 16 of the RET-gene were amplified by PCR and analyzed by DHPLC with the Transgenomic WAVE-System. Samples with aberrant wave profiles were subjected to direct sequencing. Genetic aberrations were correlated to clinical characteristics. Germ line mutations in sporadic PC were identified in four patients (11%) whereas somatic mutations were observed in two (5%) patients. Nine coding polymorphisms (PM) were identified in seven (19%) patients. Intronic variants were observed in six (17%) patients and were all located in the SHDB gene. Patients with wild type alleles in all assessed genes were older (53 vs. 37 years, P = 0.007) and presented with an increased tumor size (49 vs. 32 mm, P = 0.003) compared to patients with mutations. Malignant PC revealed multiple (>2) genetic alterations more frequently than benign PC (4/7 vs. 4/29, P = 0.03). Interestingly intronic variants of the SDHB gene occur more frequently in malignant than in benign PC (3/7 vs. 2/29, P = 0.04). The frequency of germ line mutations in sporadic pheochromocytomas was lower in our cohort than previously reported. Polymorphisms of the RET gene are common (17%) and occur in familial and sporadic PC. Multiple genetic alterations including mutations, polymorphisms and intronic variants are more frequently observed in malignant PC.

Leuk Lymphoma. 2009 Mar ;50 (3):341-8 19263296 Cit:2

Update on genetic and molecular markers associated with myelodysplastic syndromes.

Peter Valent, Rotraud Wieser

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria. peter.valent@meduniwien.ac.at

viernes, 26 de abril de 2013

BACKGROUND:

METHODS:

RESULTS:

CONCLUSION:

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