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, 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."
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[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]