For Pygmies, Size May Not Matter

From the outside, evolution sometimes seems fairly obvious: Finch beaks got bigger to crack harder nuts, dolphins and sharks developed shapes that let them move smoothly through the water. A peek under the skin and into the genes, however, can yield surprises. Pygmies have just gotten such a close look. And being short--their most obvious feature--may actually be a sort of evolutionary side effect: What they really needed were genes that confer resistance to disease, and those same genes happened to disrupt growth.

“When I think about natural selection, diseases will kill them off much faster than being tall,” says Sarah A. Tishkoff, a professor of genetics at the University of Pennsylvania.

Ms. Tishkoff has led a new genetic analysis of Pygmies in Cameroon—a group with an average height of 4 feet 11 inches—that has identified a “master gene” for immune response that is much more common in Pygmies than in their taller neighbors, the Bantu. In Thursday’s PLoS Genetics, she and Joseph P. Jarvis, a senior research scientist at the independent Coriell Institute for Medical Research, in Camden, N.J., and several other colleagues point out that this same gene can disrupt growth-hormone pathways.

“I can’t say for sure this is what’s going on,” Ms. Tishkoff says. “But in our bodies there is such intricate cross-talk among different systems that I’d be surprised if one gene didn’t alter different traits.”

Anthropologists who have studied Pygmies for decades—and puzzled over their stature—are not giving up on competing theories but agree that genetics is adding valuable new tools to their field. “We’ve been trying to link Pygmy height to something in their environment, and we haven’t been able to do that. That’s a knock on my discipline,” says Edward H. Hagen, an associate professor of anthropology at Washington State University at Vancouver who has studied Aka Pygmies in the Central African Republic. “Sarah’s paper doesn’t give us an answer, but it gives us a lot of new clues. It’s a different way of thinking about the problem.”

Pygmies have drawn the attention of scientists because they are such a clear example of human variation—they are under five feet while the rest of the world is well over it, on average—and they are all over the place. In addition to Africa, there are Pygmies in Asia and South America. Plus there is fossil evidence. The celebrated “hobbit” fossils of Indonesia date from 18,000 years ago and are about 3 feet 4 inches tall, says Geroge W. Perry, an assistant professor of anthropology and biology at Pennsylvania State University. There are even pygmy animals, such as elephants and mammoths, whose remains have been found on islands.

Scientists have offered a long list of explanations for shortness. Food limits are one, says Mr. Perry, who is studying the population genetics of a Pygmy group called the Bataa in Uganda. Pygmies live in dense rain forests where food is hard to obtain, and less body requires fewer calories to keep it going; however, today’s hunter-gatherers don’t search constantly for food, indicating they get enough. Then there is heat regulation: Small bodies generate less heat during exercise. But that idea also has a counterargument, Mr. Perry says. Some of the shortest populations live in cooler or drier areas.

In 2007 scientists proposed yet another theory: Pygmies in the Philippines usually die by their mid-20s, so they must put their metabolic energy into reaching reproductive age quickly rather than growing tall. That one got criticized because recent cultural changes among those Pygmies—which the researchers used for their calculations of energy use—probably didn’t represent their historical state.

Ms. Tishkoff and Mr. Jarvis and their team thought genetics might provide a better answer. They examined 67 Pygmies, and for comparison used 58 Bantu “because they literally lived right next door” but were 6 inches taller, on average, Ms. Tishkoff says. The populations do mix and marry, so the researchers first identified genes that were predominantly Pygmy and those that came from Bantu. “The more Pygmy ancestry, the shorter the people were, and that supported this as a genetic trait,” Ms. Tishkoff says.

Then they looked for regions of the genome that seemed highly selected for, which they did by finding stretches of DNA that were much more common in Pygmies than in Bantu or Masai comparison groups. They found one, a short piece of Chromosome 3. And one of the genes on it was called DOCK3, which affects height among Europeans. That gave the scientists confidence they were looking in the right place. “And right next to it was this other gene, CISH, which is a master regulator of immune response,” Ms. Tishkoff says. It is associated with resistance to tuberculosis, malaria, and bacteremia.

Mr. Jarvis, looking at genetic databases, found that CISH does something else extremely intriguing. It interrupts growth hormones in the body. Mice with overactive versions of this gene are exceptionally small. Furthermore, CISH was part of an entire network of genes and hormones that affect body size in people, part of a growth hormone pathway called insulin growth factor 1. Again, this package of genes cropped up most often in the shortest people, even within the Pygmy groups.

“It was like a bunch of giant arrows, all pointing in the same direction,” Ms. Tishkoff says.

And they pointed to disease and height. Pygmies in Cameroon carry a lot of parasites, so they need a strong immune system. There are also a lot of potent viruses in the region; HIV is theorized to have come from this area. So Ms. Tishkoff says that genes like CISH could have been very important, and very active, in this population. And their activity, as an offshoot, could have slowed down other genes responsible for body growth.

The next step is to test the function of these genes, to see if CISH is really hyperactive in Pygmies, and if it does interfere with growth-factor genes. Until someone demonstrates that, genetics doesn’t knock out any competing notions.

The idea is fascinating, Mr. Perry says, and actually could include the environmental explanations. There could have been various ecological pressures on Pygmy body size, some pushing for more height, some pushing less. And then the need for disease resistance arose, and tipped the balance towards the short end of the scale.

[Photo courtesy Alain Froment]