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WASHINGTON — A gene mutation that arose thousands of years ago now protects hundreds of millions of people from severe malaria, the mosquito-borne disease that is the world’s deadliest infection. 

Researchers report Friday in the journal Science that they have traced the natural evolution in Africa, Asia and the Mediterranean area of the mutation that gives some protection from malaria’s most serious effects. 

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

“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, said Sarah A. Tishkoff of the University of Maryland. 

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

The researchers 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 response to widespread infection from the mosquito-borne parasite that causes malaria. In its mutated form, it helps block the reproduction of the malaria parasite. 

“Malaria may have been present in a mild form throughout human evolution,” said Tishkoff. Primitive hunters and gatherers wandered the land, not staying in one place long enough for malaria to take a significant toll. 

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

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

“We think a more deadly strain became prevalent and began having a major impact on humans,” said Tishkoff. 

Evidence of this is indirect. Specimens from Egyptian mummies contain swollen spleens and 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. 

The mutation of G6PD provides a more direct indication of how malaria affected humans. 

Since humans developed a genetic defense, said Tishkoff, it suggests that the disease was prevalent enough to exert “a strong selective force.” 

She said mutations occur randomly. 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. 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 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 resistance evolve may help scientists develop therapies, he said. 

On the Net: 

Malaria: http://www.diseaseworld.com/malaria.htm 

Science: http://www.eurekalert.org