What Makes Us Different?

Sunday, Oct. 01, 2006 By MICHAEL D. LEMONICK AND ANDREA DORFMAN
ILLUSTRATION FOR TIME BY TIM O'BRIEN
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ZEROING IN ON THE GENES

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Even before the chimp genome was published, researchers had begun teasing out our genetic differences. As long ago as 1998, for example, glycobiologist Ajit Varki and colleagues at the University of California, San Diego, reported that humans have an altered form of a molecule called sialic acid on the surface of their cells. This variant is coded for by a single gene, which is damaged in humans. Since sialic acids act in part as a docking site for many pathogens, like malaria and influenza, this may explain why people are more susceptible to these diseases than, say, chimpanzees are.

A few years later, a team led by Paabo announced that the human version of a gene called FOXP2, which plays a role in our ability to develop speech and language, evolved within the past 200,000 years—after anatomically modern humans first appeared. By comparing the protein coded by the human FOXP2 gene with the same protein in various great apes and in mice, they discovered that the amino-acid sequence that makes up the human variant differs from that of the chimp in just two locations out of a total of 715—an extraordinarily small change that may nevertheless explain the emergence of all aspects of human speech, from a baby's first words to a Robin Williams monologue. And indeed, humans with a defective FOXP2 gene have trouble articulating words and understanding grammar.

Then, in 2004, a team led by Hansell Stedman of the University of Pennsylvania identified a tiny mutation in a gene on chromosome 7 that affects the production of myosin, the protein that enables muscle tissue to contract. The mutant gene prevents the expression of a myosin variant, known as MYH16, in the jaw muscles used in biting and chewing. Since the same mutation occurs in all of the modern human populations the researchers tested—but not in seven species of nonhuman primates, including chimps—the researchers suggest that lack of MYH16 made it possible for our ancestors to evolve smaller jaw muscles some 2 million years ago. That loss in muscle strength, they say, allowed the braincase and brain to grow larger. It's a controversial claim, one disputed by anthropologist C. Owen Lovejoy of Kent State University. "Brains don't expand because they were permitted to do so," he says. "They expand because they were selected"—because they conferred extra reproductive success on their owners, perhaps by allowing them to hunt more effectively than the competition.

BEYOND THE GENES

Still, the principle of gene-by-gene comparison remains a powerful one, and just a year ago geneticists got hold of a long-awaited tool for making those comparisons in bulk. Although the news was largely overshadowed by the impact of Hurricane Katrina, which hit the same week, the publication of a rough draft of the chimp genome in the journal Nature immediately told scientists several important things. First, they learned that overall, the sequences of base pairs that make up both species' genomes differ by 1.23%—a ringing confirmation of the 1970s estimates—and that the most striking divergence between them occurs, intriguingly, in the Y chromosome, present only in males. And when they compared the two species' proteins—the large molecules that cells construct according to blueprints embedded in the genes—they found that 29% of the proteins were identical (most of the proteins that aren't the same differ, on average, by only two amino-acid substitutions).

The genetic differences between chimps and humans, therefore, must be relatively subtle. And they can't all be due simply to a slightly different mix of genes. Even before the human genome was sequenced back in 2000, says biologist Sean Carroll of the University of Wisconsin, Madison, "it was estimated that humans had 100,000 genes. When we got the genome, the estimate dropped to 25,000. Now we know the overall number is about 22,000, and it might even come down to 19,000."

This shockingly small number made it clear to scientists that genes alone don't dictate the differences between species; the changes, they now know, also depend on molecular switches that tell genes when and where to turn on and off. "Take the genes involved in creating the hand, the penis and the vertebrae," says Lovejoy. "These share some of the same structural genes. The pelvis is another example. Humans have a radically different pelvis from that of apes. It's like having the blueprints for two different brick houses. The bricks are the same, but the results are very different."

Those molecular switches lie in the noncoding regions of the genome—once known dismissively as junk DNA but lately rechristened the dark matter of the genome. Much of the genome's dark matter is, in fact, junk—the residue of evolutionary events long forgotten and no longer relevant. But a subset of the dark matter known as functional noncoding DNA, comprising some 3% to 4% of the genome and mostly embedded within and around the genes, is crucial. "Coding regions are much easier for us to study," says Carroll, whose new book, The Making of the Fittest: DNA and the Ultimate Forensic Record of Evolution, delves deep into the issue. "But it may be the dark matter that governs a lot of what we actually see."