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The Archaeology And Genetics Of Malaria Resistance

Between 7,000 and 12,000 years ago, a dramatic climate change increased temperature and humidity in Africa, creating new lakes and pools of water.

At about the same time, in the Middle East and northeast Africa, the advent of agriculture resulted in forest clearing and an increase in sunlit pools of water.

These developments combined to create suitable conditions for malaria-carrying mosquitoes to breed and infect growing populations settling in one spot to raise crops instead of moving about in small groups as hunter-gatherers.

Studying these developments, with their ultimate effect on the human genome, combines genetics, archaeology and history to the betterment of each discipline -- and yields greater insight into infectious disease and human evolution.

Recent work by an international team of researchers shows how this works.

The gene mutation that gives humans natural resistance to malaria is a striking example of how infectious disease can shape the human genome. The discovery could lead to more effective treatments or vaccines to protect people against infectious diseases.

In a paper published in a recent issue of Science, Sarah Tishkoff and an international team of collaborators show that the history of mutations of the G6PD gene, which appears to provide resistance to malaria, the leading cause of death in humans, runs along the same time line as the history of the disease itself.

"This is a striking example of how infectious disease can shape the path of human evolution," says Tishkoff. "By studying how nature copes with a devastating infectious disease like malaria, we may be able to design more effective treatments or vaccines against these diseases. Similar types of analyses could be applied to the study of other infectious diseases, including tuberculosis and HIV."

The parallel time lines of malaria's development and genetic resistance to it are not coincidence, contends Tishkoff, a member of the university's biology faculty, but rather a result of genetic adaptation to a threat to the human species.

"In regions where malaria is prevalent, naturally occurring genetic defense mechanisms have evolved for resisting infection by malaria. We looked at variations of the mutation that have appeared independently in several areas of the world where the incidence of malaria is high," Tishkoff says. "In each region we studied, the mutations at G6PD that provide protection against malaria appear to have arisen at about the same time that history tells us malaria became prevalent.

"The genetic history tells us these malaria resistant mutations arose very recently. Those individuals who have these mutations are more likely to survive and to pass on their genes to their offspring, and therefore these mutations spread rapidly through populations."

All humans have the G6PD gene -- it's a general housecleaning agent, helping with glucose metabolism. Some people are born with a mutation of the G6PD gene, which, when reacting to certain triggers, such as infection (or some foods such as fava beans), can cause anemia, itself a serious and even deadly condition.

But those same people also seem more able to resist the worst effects of malaria, a mosquito-borne parasite that annually infects 500 million people and kills 2 million.

"In most cases, a genetic mutation is eventually eliminated by natural selection," says Tishkoff. "But by giving its carriers increased resistance to malaria, this G6PD mutation has been perpetuated."

Tishkoff's team studied the genetic histories of people with the mutated form of the G6PD in areas of Africa, the Middle East and the Mediterranean that have a high incidence of malaria.

Different variations of the gene appear in the different areas and seem to have evolved independently of each other, likely as a response to selection resulting from malarial infection.

"By studying the genetic footprint of selection, or signature of selection, at the G6PD gene resulting from malarial infection, we might be able to identify other genes that are targets of selection and may play an important role in human disease," says Tishkoff.

By looking at the number of variants that the G6PD gene has accumulated over time, Tishkoff and collaborator Andrew Clark, professor of biology at Pennsylvania State University, were able to determine the approximate age of the mutations at G6PD that provide protection against malaria.

"One mutation found throughout Africa arose within the past 3,840 to 11,760 years," says Tishkoff. "This estimate is consistent with archeological and historical documents that show malaria has had a significant impact on humans only within the past 10,000 years, since the origination of agriculture."

Another G6PD variant found in areas of the Mediterranean, the Middle East and India originated much more recently. According to Tishkoff's study, that variant developed within the past 1,600 to 6,640 years, a time frame that parallels historical Greek and Egyptian reports of the spread of a more severe form of malaria in those regions.

Tishkoff proposes that this mutation, which spread rapidly across a broad geographic region in a short time, may have been introduced by Greek migrations throughout the area. She speculates that it could have been spread by the army of Alexander the Great, which conquered regions throughout the Mediterranean, India, the Middle East and North Africa during the 4th century B.C.

"This is an excellent example of how we can combine genetics, archeology and history to study recent human evolution," says Tishkoff. "This study demonstrates how the environment, culture, genes and history interact to shape patterns of variation in the modern human genome."

The study was funded by an NSF Sloan fellowship, a Burroughs Wellcome Fund Career Award, an NSF grant to Sarah Tishkoff and another NSF grant awarded to Andrew Clark.

[Contact: Dr. Sarah Tishkoff, Ellen Ternes ]

26-Jun-2001

 

 

 

 

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