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The Other Human Genome
Mitochondria are the focus of new research on Alzheimerís, Parkinsonís and diabetes
Edward R. Winstead

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Two decades before the human genome was sequenced, a human mitochondrial genome was sequenced. Mitochondria are the indispensable energy producers of human cells who live outside the nucleus and have their own DNA, genes and proteins. The mitochondrion sequenced in 1981 became known as the Cambridge reference sequence and has been used extensively in research. A few years ago, scientists re-sequenced the DNA to eliminate minor errors.

Cell and mitochondrion

New research has just been published that may be a reference point for the next generation of studies. Scientists have sequenced 560 human mitochondrial genomes from individuals of Asian, European, and African descent. This is probably the largest collection of mitochondrial DNA sequences from a diverse human population, and it is available to researchers on the Web site of MitoKor, a biotechnology company in San Diego, California.

A team led by MitoKor scientists built the database to discover mutations in mitochondrial DNA associated with human diseases and develop novel therapies. The loss of energy production can be disastrous for cells and has been blamed for a range of disorders. The MitoKor team aims to discover risk factors for Alzheimer's, Parkinson's and adult-onset diabetes, among other diseases, by comparing mitochondrial DNA from patients and healthy individuals.

"We will use the database to look as definitively as one can at the role of mitochondrial DNA in several of the major diseases," says Neil Howell of MitoKor, who led the study. Making the connection between mitochondrial DNA and neurological disorders that occur late in life will not be easy, Howell adds.

In the case of Parkinson's, for instance, the researchers are confident that no single mutations in mitochondrial DNA cause the disease. But they suspect that some Parkinson's patients may have multiple mutations in certain mitochondrial genes. Or, some patients may have mutations in several genes involved in the same biological pathway.

Mitochondrial DNA

"The bottom line is that there are no simple answers, and we will need to go to larger population sizes to find the answers," says Howell. The database is a way to gain a rough picture of mitochondrial genomes in the general population. As the company's internal database grows, researchers will analyze the DNA and health histories of patient populations and matched controls.

If the researchers find risk factors for disease, one potential avenue of treatment could be to replace the defective mitochondrial DNA through some form of gene therapy. But this option is unlikely in the near future. Drugs may be able to eliminate energy deficits, however. Selecting the right potential drugs, says Howell, will require sufficient knowledge of the biological pathways involved in energy production.

"You need very well characterized patient populations as well as normal controls in order to undertake population studies," says Corinna Herrnstadt, who heads the project at MitoKor. The company's internal database has now grown to nearly a thousand genomes. "It is essential that we keep building the database in order to do the disease studies," she adds.

An analysis of the sequenced 560 genomes appears in The American Journal of Human Genetics, and the researchers say they found more variation among the sequences than they expected. The challenge now is to determine which variants, or polymorphisms, are harmless and which may be pathogenic mutations. As a first step in the process, every sequence is being compared to every other sequence and to the revised Cambridge reference sequence.

Relative to the human genome with its three billion letters of DNA, the human mitochondrial genome is tiny—about 16,500 base pairs long. All of the 560 sequences were classified according to DNA patterns described in previous studies of mitochondrial genomes. These patterns—sets of polymorphisms—have been used to track the movements of early humans.

The origin and dispersal of modern humans, Homo sapiens. The time of origin of modern humans is not well known but may have been about 200,000 (130,000-465,000) years ago. New evidence from mitochondrial genomes bolsters the hypothesis that the place of origin was sub-Saharan Africa and that the dispersal from Africa occurred within the past 100,000 years. The earliest known fossil and archaeological evidence on each continent, shown on the map, is consistent with this view.

Mitochondrial DNA has been used to generate theories about the origins of Homo sapiens because it is inherited from the mother and does not to undergo 'recombination'—the crossing-over of parental genomes that occurs during reproduction. One theory says that modern humans originated in Africa while another says that humans arose simultaneously in different regions of the world.

The theory that humans originated in Africa and subsequently migrated to Europe, Asia, and the Americas was bolstered by a study of mitochondrial genomes two years ago. Ulf Gyllensten, of the University of Uppsala in Sweden, and colleagues sequenced the mitochondrial genomes of 53 persons of diverse geographical, racial, and linguistic backgrounds.

Based on analyses of patterns of mitochondrial DNA, the researchers estimated that an exodus from Africa occurred within the past 100,000 years. The founding population in Africa probably carried with it a subset of the mitochondrial gene variants found in today's population, the scientists reported in Nature.

A far greater number of mitochondrial sequences are needed to clarify questions about our evolutionary history. In a commentary accompanying the Nature study, S. Blair Hedges of Pennsylvania State University called the work "a start for population genomics." The new MitoKor database builds on that start.

Nine European, five Asian (including Native American), and three African mitochondrial DNA patterns, also known as haplogroups, were represented in the 560 genomes. The MitoKor analysis revealed "a richer, finer grain structure" in the mitochondrial DNA patterns, says Howell. Many new mitochondrial DNA markers were found that could now be used to track the inheritance of disease in families and populations.

The 560 human mitochondrial genome sequences are available at the MitoKor Web site.

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Herrnstadt, C. et al. Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70, 1152-1171 (May 2002).
Ingman, M. et al. Mitochondrial genome variation and the origin of modern humans. Nature 408, 708-713 (December 7, 2000).
Hedges, S.B. Human evolution: A start for population genomics. Nature 408, 652-653 (December 7, 2000).
Andrews, R.M. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23, 147 (October 1999).

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