Ancient DNA mutations permitted humans to adapt to colder climates, UCI researchers find

01/12/04

Changes in cells' mitochondria may explain current predispositions to common diseases

Irvine, Calif., Jan. 12, 2004 -- How did early humans who migrated from Africa survive in the colder climates of Europe, Asia and the New World? According to a new UC Irvine study, it may be the same reason some people today are more prone to obesity, Alzheimer's disease and the effects of aging.

In the Jan. 9, 2004, issue of Science, a UCI research team reports that key mutations in the mitochondrial DNA (mtDNA) of human cells may have helped our migrating ancestors adapt to more northerly climates, and ultimately link people with this ancestral history to specific diseases.

Found outside the cell's nucleus, mitochondria are the power plants of cells that are responsible for burning the calories in our diet.

The cellular energy is used for two purposes: to generate heat to maintain our body temperature and to synthesize ATP (adenosine triphosphate), a chemical form of energy that permits us to do work such as exercise, think, write, and make and repair cells and tissues. The mtDNAs are the blue prints for our mitochondrial power plants and determine the proportion of the calories in our diet that are allocated to generate body heat versus work.

According to Douglas C. Wallace, the Donald Bren Professor of Biological Sciences and Molecular Medicine at UCI and one of the co-authors of the report, after early humans migrated to colder climates, their chances of survival increased when mutations in their mtDNA resulted in greater body heat production during the extreme cold of the northern winters.

"In the warm tropical and subtropical environments of Africa it was most optimal for more of the dietary calories to be allocated to ATP to do work and less to heat, thus permitting individuals to run longer, faster and to function better in hot climates," Wallace said. "In Eurasia and Siberia, however, such an allocation would have resulted in more people being killed by the cold of winter. The mtDNA mutations made it possible for individuals to survive the winter, reproduce and colonize the higher latitudes.

"This explains the striking correlation between mtDNA lineage and geographic location that we still see today in indigenous populations around the world."

It also explains why people with a certain ancestral history may be more susceptible to some diseases.

"When heat and cold are managed by technology, not metabolism, and people from warmer climates are eating the high fat and calorie diets of northern climates, there is a rise in obesity and the age-related degenerative diseases," Wallace said. "The caloric intake and local climate of many individuals are out of balance with their genetic history. Thus, our genetic history is linked to our current diseases, resulting in the new field of evolutionary medicine."

One link would be the production of oxygen radicals in cells. Created when mitochondria burn our dietary fuel, this by-product can be responsible for damaging and killing cells, leading to several age-related diseases. "When calories are unutilized for producing heat or ATP, they are redirected to generate oxygen radicals," Wallace said. "Since the mutated DNA of cold-adapted people allocates more calories to heat, there are fewer left over to generate oxygen radicals. Hence these people are less prone to aging and age-related degenerative diseases." (For more details on oxygen radicals, see below.)

In the study, Wallace and his UCI colleagues Eduardo Ruiz-Pesini, Dan Mishmar, Martin Brandon and Vincent Procaccio analyzed 1,125 human mtDNA sequences from around the world to reconstruct the mutational history of the human mtDNA back to the original mtDNA, known as the mitochondrial Eve.

Wallace is the director of the Center for Molecular and Mitochondrial Medicine and Genetics at UCI and is a faculty member in the Departments of Ecology and Evolutionary Biology, Biological Chemistry and Pediatrics. This study was funded by the National Institutes of Health and the Ellison Medical Foundation.

How mtDNA control the production of oxygen radicals

When mitochondria burn our dietary fuel, they generate a toxic by-product called oxygen radicals, the mitochondrial equivalent to the smoke generated by coal-burning power plants. Oxygen radicals damage the mitochondria, mtDNA and the surrounding cell. Eventually oxygen radicals can cause the cell to die when sufficient oxidative damage accumulates in the mitochondria and the cell.

Since many of the tissues of our bodies have a finite number of cells, when sufficient cells die organs malfunction, resulting in the symptoms of age-related degenerative diseases and aging. As a result, the chronic level of mitochondrial oxidative stress will determine an individual's aging rate and susceptibility to a variety of diseases such as diabetes, memory loss, forms of deafness and vision loss, cardiovascular disease, etc.

If all the calories that an individual consumes are used in generating carbon dioxide, water and energy, little fuel is left over to generate the oxygen radicals; however, if more calories are consumed than are needed to make energy, then these excess calories are stored as fat and drive a chronic increase in mitochondrial oxygen radical production.

Consider two individuals that eat the same number of calories and get the same amount of exercise. The individual with a mtDNA mutant that increases heat production will require more calories for energy production and thus will have fewer calories left over to produce oxygen radicals. This individual will be partially protected from age-related diseases and will live longer. By contrast, the individual with mitochondria that make more ATP per calorie burned will store fat and generate more oxygen radicals if he or she eats the same level of calories as the individual with the cold-adapted mitochondria.

About the University of California, Irvine: The University of California, Irvine is a top-ranked public university dedicated to research, scholarship and community. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 23,000 undergraduate and graduate students and about 1,300 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3 billion.

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