COLD SPRING HARBOR, NEW YORK—Hundreds of genes influence how tall a person is, but most make an imperceptible difference—perhaps a millimeter, for example. Now, a group studying the genetics of Peruvians, one of the world's shortest populations, has turned up a gene variant that cuts a person's height by more than 2 centimeters, on average. "It's amazing that they saw such a change," says Emma Farley, a genomicist at the University of California, San Diego. "It's quite a large effect."
Geneticists have diligently pursued genes for height; a 2014 analysis called GIANT examined 250,000 people. "That you can still pull out new players is very exciting," says Elaine Ostrander, a geneticist at the National Human Genome Research Institute in Bethesda, Maryland. "It speaks to the value of looking at isolated populations." So far, the gene variant is not known outside Peru, where the demands of living at high altitude may have driven its evolution, but it could offer clues about how other mutations influence height.
Postdoc Samira Asgari and Soumya Raychaudhuri's team, all at Harvard Medical School in Boston, originally wanted to know how a person's DNA influences the severity of tuberculosis. Together with epidemiologist Megan Murray's team at Partners in Health in Lima, they collected genetic information from 4002 residents there, along with other data including height. Peruvians are among the shortest people in the world, with men averaging 165 centimeters and women reaching about 153 centimeters—in both cases about 10 centimeters shorter than average people in the United States and 15 centimeters shorter than the Dutch, generally regarded as among the world's tallest people. So the team decided to search the DNA data for genetic factors underlying this short stature.
First, Asgari assessed the ancestry of their subjects by comparing their DNA to genomes of Africans, Europeans, and Native Americans. Peruvians are about 80% Native American, 16% European, and 3% African, she reported last week at the Biology of Genomes meeting here. "The more Native American ancestry, the shorter they were," she said. By correlating variation in the Native American portion of each person's genome with their height, Asgari found a specific gene variant that seems to influence the trait.
Short Peruvians have a version, or allele, of a gene called FBN1 that differs by one base from the gene's usual DNA sequence. That subtle shift alters an amino acid in a carbohydrate-coated protein called fibrillin-1, which provides structural support in connective tissue. Other FBN1 mutations are known to affect height in rare disorders: Marfan syndrome, which affects the skeleton, heart, and eyes and generally produces tall, thin people; and "stiff skin" syndrome, marked by shortness and a very thick, hard skin. This gene's new link to overall height "logically connects to [its] biology," Farley says.
Most of the 700 or so other genes tied to height can, with their individually small effects, together explain only about 7% of a Peruvian's height. The new allele accounts for another 1% all by itself, the researchers estimate. A person carrying just one copy of this FBN1 variant is about 2.2 centimeters shorter than people with different versions of the gene and those with two copies can be more than 4 centimeters shorter, Asgari reported.
Her group estimates that 5% of Peruvians carry the newly identified FBN1 allele, suggesting that evolution has favored short stature and perhaps thick skin among Peruvians. Many live at high altitudes, and animal studies show that species living at such elevations tend to be smaller, an apparent evolutionary adaptation to the scarcity of food in those places. Thick skin might also protect the body from the strong ultraviolet light at high altitudes.
Kousik Kundu, a genomicist at the Wellcome Sanger Institute in Hinxton, U.K., remains cautious about the role of this gene variant, calling for Asgari to get more detailed sequence data from her Peruvian subjects and to study larger populations there. Asgari also wants to study other short people, such as some groups in the Middle East, to see whether the same allele is at work elsewhere. With further genetic analysis, says geneticist Sarah Tishkoff at the University of Pennsylvania, Asgari might be able to say when the shortness variant arose. "It's a really cool story in the making."