Helping hand. Blue stains indicate where HACSN1 spurred gene activity in a developing mouse limb.

James Noonan

Fingering What Make Us Human

You are not a chimpanzee. Your relatively flat face and lack of body fur are dead giveaways. But what makes us so different from our primate relatives, when we share so many of the same genes? Scientists have found a tantalizing clue in a short sequence of DNA, which may have given us our human limbs and hands.

Researchers trying to explain the anatomical discrepancies between humans look at more than just genes. They also home in on so-called noncoding genetic sequences, DNA regions that don't make proteins. Although these regions are sometimes referred to as "junk DNA,” scientists have begun to realize that they have important functions, such as switching certain genes on and off. About 200,000 of these sequences have been found in mammals so far, and 1000 are unique to humans.

Now researchers have found out what one of these human-specific sequences--called HACSN1--does. Yale University geneticist James Noonan and colleagues paired the DNA fragment with a gene that produces a blue protein when HACSN1 switches it on. The researchers then injected the combination into single-celled mouse embryos. Eleven-and-a-half days into the experiment, they found that the gene was active throughout the embryos' developing forelimbs, in areas analogous to the thumb and first couple of fingers of humans. When the team injected embryos with comparable sequences from chimps and macaques, the gene activity was confined to the base of the limb. That suggests that HACSN1 could be a "molecular component of humanness," says Noonan, whose team reports its findings tomorrow in Science.

It's unclear how the HACSN1 affects limb development because researchers don't know which gene it's influencing. The next step will be engineering mice with the right complement of human genes that would allow researchers to determine whether a particular sequence might alter the position of the digits, rotate the thumb, or do something completely different in humans. Still, "I don't expect the mouse to be able to pick up a wrench and go to work," Noonan says.

Douglas Epstein, a developmental geneticist at the University of Pennsylvania School of Medicine, says that the study could pave the way for many more discoveries of uniquely human sequences. "The experiments are wonderful; they're unique," he says. Eddy De Robertis, a biochemist at the University of California, Los Angeles, is impressed that human HACSN1, which is only slightly different from the other mammalian DNA sequences from the same genetic region, is able to produce a detectable, potentially functional change. Even if "they don't know what gene it's targeting yet," he says, "it's quite interesting."