Surprising mtDNA diversity

Mitochondrial genomes are not uniform across cells of the body as previously believed, but vary between different tissue types, according to a study published online today (March 3) in Nature. Image: Wikimedia commons, NationalHuman Genome Research InstituteThe findings may affect forensics and the search for biomarkers, both of which utilize mitochondrial DNA. "I was surprised,"

By | March 3, 2010

Mitochondrial genomes are not uniform across cells of the body as previously believed, but vary between different tissue types, according to a study published online today (March 3) in Nature.
Image: Wikimedia commons, National
Human Genome Research Institute
The findings may affect forensics and the search for biomarkers, both of which utilize mitochondrial DNA. "I was surprised," said molecular cell biologist linkurl:Hans Spelbrink;http://www.uta.fi/imt/finmit/hanslab/ of the University of Tampere, Finland, who was not involved in the research. "Mostly the assumption is that from the start of life individuals are homoplasmic," meaning that within an individual, mitochondrial DNA (mtDNA) is the same. However, the results of this study demonstrate "that each individual is a mosaic of multiple [mt]DNA types in various frequencies in different tissues," he said. Previous studies have documented some degree of heteroplasmy -- variation in mtDNA in an individual -- but these findings were limited and mostly restricted to people with mitochondrial disorders, "where one would expect" to find such variation, Spelbrink said. "This is the first time [mitochondrial variation] was properly documented" in normal individuals. Using high throughput sequencing technology, molecular geneticist linkurl:Nickolas Papadopoulos;http://www.hopkinskimmelcancercenter.org/index.cfm/cID/1686/mpage/expertdata.cfm/expID/573 of the Ludwig Center for Cancer Genetic and Therapeutics and the Johns Hopkins Kimmel Cancer Center in Baltimore and his colleagues analyzed the mitochondrial genomes of a variety of tissues in 2 different people and the lining of the colon in 10 others. In every individual, the researchers found at least 1 allele that differed between tissues, and one individual had as many as 14 heteroplasmies. "That was a surprise when we saw the results," Papadopoulos said. "There's more than one mitochondrial genome present in each one of us. In addition to that, there were variations from tissue to tissue [in the levels of heteroplasmy observed], which may have implications in embryogenesis." The findings may also affect more practical applications in forensics science and the development of biomarkers for certain diseases, which often utilize mtDNA because it is abundant and easy to amplify, he added. "When you look for biomarkers, you want to establish what the normal tissue looks like" in order to have a reference with which to compare the disease state, Papadopoulos said. With the recognition that mitochondrial genomes are quite variable even in normal tissues, "now we have to keep in mind [that] some of the changes we see may not really be [disease-related] mutations." Thus, to use mitochondrial mutations as potential biomarkers, future studies "will have to investigate a lot of individuals...to carefully determine the normal control range," molecular biologist linkurl:Ian Holt;http://www.mrc-mbu.cam.ac.uk/people/holt of the Mitochondrial Biology Unit of the Medical Research Council in Cambridge, UK, wrote in an email to The Scientist. "Also, there is a big question mark about how early this increase in mtDNA variation appears in the blood. If it's only apparent once the cancer is well established then it isn't much use as a biomarker." With regard to forensics, the normal variation in mtDNA "complicates things a little bit," Papadopoulos said. Because the mtDNA in one tissue might vary from another tissue, caution must be used when comparing a hair sample, for example, to blood. "The positive side is that, in principle, you could even distinguish monozygous twins, if you can characterize their heteroplasmy pattern," added molecular evolutionary biologist Nicolas Galtier of the linkurl:Université Montpellier 2;http://www.univ-montp2.fr/ in an email. It's unclear why mtDNA is so variable. One reason may be that mitochondria have a higher mutation rate than nuclear DNA, said pediatrician and clinical geneticist linkurl:Richard Boles;http://www.usc.edu/schools/medicine/util/directories/faculty/profile.php?PersonIs_ID=117 of the Keck School of Medicine of University of Southern California. "It's really sitting in the heat of the furnace where it's likely to get damaged," Boles said, referring to the free radicals and other byproducts of energy metabolism that takes place in the mitochondria. Alternatively, it could be that the mitochondria have less effective DNA repair mechanisms. These findings are likely to spur future studies to further characterize the diversity in mitochondrial genomes and determine the mechanism underlying the variation, Boles said. "This is certainly going to raise a lot of eyebrows."
**__Related stories:__***linkurl:How mtDNA mutations cause aging;http://www.the-scientist.com/article/display/22731/
[15th July 2005]*linkurl:Mitochondrial DNA recombines;http://www.the-scientist.com/article/display/22173/
[14th May 2004]*linkurl:Mitochondrial DNA homoplasmy;http://www.the-scientist.com/article/display/20332/
[16th April 2002]

Comments

Avatar of: anonymous poster

anonymous poster

Posts: 10

March 3, 2010

Not really surprising given the recent data about the high mutation rates of mitochondrial DNA and the strong selection pressure.
Avatar of: Michael Shapira

Michael Shapira

Posts: 3

March 3, 2010

Since the mother's egg is where mitochondria in an individual come from, could the individual variability be attributed to initial variability in the egg, which is then distributed through cell divisions to the different tissues? (as an alternative to de novo generated mutations)\n\nRead more: The Scientist : Post a comment http://www.the-scientist.com/forum/addcomment/57199/#ixzz0h9ECIhFO
Avatar of: Jef Akst

Jef Akst

Posts: 28

March 3, 2010

It's a good point, and the authors of this study had the same question. To get at the answer, they analyzed the mtDNA from two families, each with a mother, father, and two children. The results confirmed that the mitochondrial genomes come from the mother only (not the father), and that some of the heteroplasmy was inherited. This was only a small fraction of the total heteroplasmy observed, however, and the rest was attributed to mutations that had occurred during development or later.
Avatar of: Jon Thaler

Jon Thaler

Posts: 1

March 3, 2010

What are the implications of this for the idea of a "mitochondrial eve"?
Avatar of: LISA VAWTER

LISA VAWTER

Posts: 4

March 3, 2010

Correction mechanisms were unknown for mtDNA. Is this still the case? If so, wouldn't it follow that heteroplasmy is expected?
Avatar of: anonymous poster

anonymous poster

Posts: 1

March 4, 2010

Mitochondrial DNA was used in the past to trace history and migration of human populations (maternal side). Although, if I remember well heteroplasmy was commented in this literature, I assume that these studies did not take into account a wide level of heteroplasmy, as this seems to be a very recent discovery. \nHow the outcome of these studies will be affected by these new data?
Avatar of: Jef Akst

Jef Akst

Posts: 28

March 4, 2010

This is a very good question -- one that I asked of Richard Boles, in fact. But the molecular clock scientists have generated from mtDNA to trace the history of populations is based on the germline mitochondria. Thus, "whatever changes occur in the somatic [cells]" -- as was studied here -- "are not going to affect the molecular clock," Boles said. No one has yet studied degree of heteroplasmy in the germline in this level of detail, but because those cells are segregated very early in the embryo, it is likely that there will be less heteroplasmy than was documented here in somatic tissues.
Avatar of: Hugh Fletcher

Hugh Fletcher

Posts: 44

March 4, 2010

The DNA polymerase (gamma, I believe) that replicates mitochondrial DNA is no better than it needs to be, and it is the high rate of mutation that makes mitochondria useful for following evolution over short recent timescales. Most of the mutations were somatic, and it doesn't matter what variants you have in your liver, they won't be passed to offspring. Mammalian female germline cells don't divide may times, and are mostly dormant, so there are fewer mitochondrial DNA replications to introduce mutations, and they need fewer mitochondria than energy intensive tissues. Hence female germ lines probably have a relatively low mutation rate compared to liver or mucosa or neurons.\nMany of the mutations were in coding sequences and are not seen as the sole type, so presumably are too deleterious to support an individual up to reproductive age, although they may not be significant at a frequency of a few percent in a few tissues.\nWhere heteroplasmy exists from the oocyte it can be transmitted through generations. One documented case is Holstein cows. More notable, Tsar Nicholas II, murdered/executed by Bolsheviks in 17th. July 1918, and his brother who died from disease, shared a heteroplasmy, now lost from their female relatives.\nEvolutionary studies make use of a small number of mutations that are fit for the purpose, meaning stable enough to be reliable and locally common or diagnostic. They have originated among, and spread with, particular human groups. \nLooking at the paper, the mother's mitochondrial type was reproduced in the offspring and was the most frequent type even in tissues with a high proportion of a new mutant type, so it would be identified. Because forensic and phylogenetic tests look for specific established mutations they would find them in any of these cells, so false negatives would be rare. False positives from new mutation are rare, but a known possibility, and examination of other diagnostic sequences would still allow maternity testing. There is a possibility that a small individual sample from historic material would give a deceptive result but again there would be other markers to check and anyway, outside the context of a family tree it would not matter. The transport of female slaves around Europe, Africa, Asia for millenia have ensured that any mitochondrial type could appear almost anywhere.
Avatar of: RON HANSING

RON HANSING

Posts: 20

March 4, 2010

What about different ages,say between 10 and 50, will the genomes within the specific tissue change also?\n\nAhhh,the thrill of discovery. Exciting, just when we think we have a handle on a topic, it radically changes. \n\nwhat affect will this knowledge have on past convictions?.... Problematic issue.\n\n
Avatar of: Ron Okimoto

Ron Okimoto

Posts: 1

March 16, 2010

Issues like the mitochondrial Eve story shouldn't be affected because those studies are based on substitution rates and mutation rates or rates of heteroplasmy are factors that affect the substitution rate, but are not what we have been studying with our current data sets.\n\nWhen I was a graduate student working on mitochondrial DNA back in the 1980's and 90's we talked about substitutions instead of mutations because we knew that we were working with populations of molecules in the cells. It was expected that the high substitution rate observed in mitochondria was due to high mutation rate, but we didn't know the mechanism for how a mutation took over the population.\n\nHeteroplasmy was expected. No one had a good way to study it when you could get a PhD thesis by sequencing one cDNA. The average cell has on the order of 100 MtDNA molecules. An egg cell has an order of magnitude more copies than that. There was a cow paper on a heteroplasmic individual, and the heteroplasmy could be transmitted to her offspring, but not to all of them. There seemed to be some mechanism where not all the MtDNA molecules were selected for replication, at least, during oogenesis. This is probably one mechanism to aid in selecting against detrimental mutations. Only a very few molecules might be amplified to get the thousands of copies that are in the egg. If the wrong ones are chosen the egg or the resulting individual isn't very viable. If good ones are chosen the individual is better off. If all molcules replicated you could have a lot of individuals that were intermediates, and you would accumulate a mitochondrial genetic load. With the high mutation rate, a mitochondrial genetic load would likely be something to worry about, but it doesn't seem to be a problem.

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