RESEARCHERS trace history of genetic resistance to malaria

Thursday, June 21st 2001, 12:00 am

By: News On 6

WASHINGTON (AP) _ Malaria, still the most lethal infection in humans, would be even more devastating except for a dramatic millennia-old genetic change that protects many people against the worst of the disease.

A study appearing Friday in the journal Science traces the natural evolution of a human gene mutation that gives millions of people some protection from the most serious ravages of malaria in Africa, Asia and around the Mediterranean.

Malaria annually infects about 500 million people and kills about 2 million, making it globally a more deadly disease than HIV/AIDS or tuberculosis. But without the mutation, it could be even worse.

The gene mutation ``is really evolution in action,'' says Sarah A. Tishkoff of the University of Maryland. ``This is a striking example of how infectious disease can shape the path of human evolution'' and how organisms battle for survival on a molecular level.

Tishkoff is first author of the study with 17 co-authors from eight countries.

The researchers, using the known patterns of genetic changes, traced the development of a malaria resistant gene that they believe first appeared in humans thousands of years ago in Africa and later among people in the lands of the Mediterranean and parts of Asia.

Tishkoff said the mutation of an X chromosome gene called G6PD evolved as a natural genetic response to the mosquito-borne parasite that causes malaria. A normal G6PD produces an enzyme that helps metabolize glucose and combats oxygen radicals. In its mutated form, it also helps block the reproduction of the malaria parasite.

Malaria, Tishkoff said, may have first appeared millions of years ago, but for most of that time it was only a minor disease. Primitive people lived as hunters and gatherers, wandering the land and not staying in one place long enough for malaria to take a significant toll.

That all changed, Tishkoff said, with the invention of agriculture about 10,000 years ago. Forests were cleared and sunlit still waters became mosquito breeding sites. People concentrated, living near their crops, and the first cities were born.

There also was a change in African weather, becoming wetter and hotter about 12,000 years ago.

Under those conditions, she said, malaria became a killer.

``We think it was probably devastating,'' said Tishkoff.

Evidence of this is indirect. Specimens from Egyptian mummies contain antigens to malaria. Homer, an 8th century B.C. Greek poet, described a disease thought to have been malaria. Later, rich Romans left their city in the summer to escape a disease Tishkoff said was probably malaria.

It's even possible, said Tishkoff, that the army of Alexander the Great spread malaria throughout the Middle East, North Africa and India in the 4th century B.C.

A more direct indication of how malaria affected humans is the mutation of G6PD.

Tishkoff said mutations occur randomly and in virtually every generation. If some such mutation protects against a disease that is killing others, then people with that gene change have a greater chance to survive and to reproduce. Over many generations, this advantage becomes more common and widespread.

By analyzing how and where the mutations accumulated over time, Tishkoff and her colleagues determined that a G6PD mutation arose in Africa 3,800 to 11,700 years ago. The gene variant developed independently at 1,600 to 6,640 years ago around the Mediterranean, in the Middle East and in India.

The G6PD gene variant differs slightly from region to region, but Tishkoff said about 400 million people now carry the mutation.

In Africa, studies have shown the mutation lowers the risk of severe malaria by up to 58 percent.

Such protection, however, is not without risks, she said. Some people with the mutation develop a severe anemia from infection, drugs or from eating fava beans.

A mutation that causes sickle cell anemia also is thought to have originated as a defense against malaria, but double mutations of the gene can cause a deadly disorder.

Jonathan Friedlaender, a biological anthropologist at Temple University in Philadelphia, said the study by Tishkoff and her colleagues is an ``elegant'' look at how disease and disease resistance can develop over time.

``It's like an arms race, but nobody wins because everything is constantly changing,'' he said.

Understanding how disease and disease resistance evolve may help scientists develop therapies, he said.