Chimp DNA Unraveled - Clues on Alzheimer's?

Scientists said yesterday they had determined the precise order of the 3 billion bits of genetic code that carry the instructions for making a chimpanzee, humankind's closest cousin.

The fresh unraveling of chimpanzee DNA allows an unprecedented gene-to-gene comparison with the human genome, mapped in 2001, and makes plain the evolutionary processes through which chimps and humans arose from a common ancestor about 6 million years ago.

By placing the two codes alongside each other, scientists identified all 40 million molecular changes that today separate the two species and pinpointed the mere 250,000 that seem most responsible for the difference between chimpness and humanness.

"Now we can peek into evolution's lab notebook to see what went on there," said Francis Collins, director of the National Human Genome Research Institute, which funded the $25 million effort at 18 institutions in five countries.

On a practical level, researchers said, the work is likely to explain why chimps are resistant to several human diseases such as AIDS, hepatitis, malaria and Alzheimer's disease - information that could lead to new ways to prevent or treat many human ills.

More profoundly, however, the achievement promises to help answer the alluring but loaded question of what, exactly, makes us truly human.
But the answer will not come easily.

"We're not going to stand up and say that these 14 things make us human," said Eric Lander of the Broad Institute in Cambridge, Mass., a facility run by the Massachusetts Institute of Technology and Harvard, which along with Washington University in St. Louis led the chimpanzee genome sequencing effort. "But it's not trivial to be able to say, 'Here is an inventory of the most important differences, and now go at it and figure out which of these differences contain the signatures of what is distinctively human.'"

As predicted by preliminary studies, the human and chimpanzee genetic codes are essentially 99 percent identical, a testament to how fundamentally similar the two species remain. At the same time, it is powerful evidence that seemingly modest changes in molecular code can lead to very different stations in the web of life.

Because of that 1 percent difference, experts noted, humans now dominate every ecosystem on Earth while chimpanzees and other great apes - a group that also includes bonobos, gorillas and orangutans - are at risk of becoming extinct within the next few decades, largely because of human activities.

Well aware of that awkward reality, several scientists yesterday used the occasion of the chimp genome's unveiling to focus attention on the creatures' plight, calling for renewed conservation efforts and new rules governing the use of great apes in research.

"There is a deep irony in the fact that the sequencing of the chimpanzee genome coincides with the potential demise of great apes in the wild," wrote Ajit Varki of the University of California at San Diego, and colleagues, in a commentary accompanying the main research report in today's issue of the journal Nature.

The DNA analysis - the first of a non-human primate and the fourth of a mammal (after human, mouse and rat) - was done on blood drawn from a chimp named Clint, who lived at a research center in Atlanta until dying in January from causes unrelated to the project. Key scientific findings and related commentaries fill about 100 pages in today's Natureand tomorrow's issue of the journal Science.

The human and chimpanzee genomes are distinguished by 35 million differences in individual DNA "letters"- each the result of a tiny, random mutation - and another 5 million larger differences in which entire chunks of DNA were either added to or deleted from one genome or the other.

All told, the two sequences differ by 4 percent. But three-quarters of the differences seem to be in nonfunctional parts of the genome, suggesting that a mere 1 percent variation makes all the difference.

Put another way, the difference between the human and chimp genomes is 10 times as great as the difference between any two humans.

Among the genes that appear unique to humans are some involved in brain development and body plan and one that has been postulated as being crucial to the development of language. But most of the differences between chimpanzees and humans seem attributable not so much to the genes themselves but to how genes that both species share are regulated - that is, the timing and level of intensity under which those shared genes operate.

"The class of genes that has changed the fastest in humans compared to chimps are the genes that control other genes," said Tarjei Mikkelsen of the Broad Institute.

Developmental changes are behind many of the differences between human and chimp brains. Human brain cells divide several more times than chimp brain cells during fetal development, a fact that contributes to the adult human brain's growth to three times the size of the chimpanzee's. Much of that increase is in the cerebral cortex, home to higher cognition.

But scientists confess to knowing little about how such changes might add up to differences in intellect and behavior.

"We are woefully ignorant about how genes build brains, and how the electrical activity of the brain builds thoughts and emotions," wrote Marc Hauser, co-director of Harvard's Mind, Brain and Behavior Program, in Nature.

Chimpanzees have repeatedly toppled conceptions about the ways in which humans are purportedly unique.

They fashion and use tools, including hammers, anvils, probes for fishing termites from the ground and seats to rest on, though unlike humans, they make all their tools by modifying found objects and never by putting complementary pieces together.

Chimps also medicate themselves, swallowing rough leaves and chewing on bitter stems to treat a type of intestinal infection.

And in perhaps their cheekiest aping of humanity, chimpanzees display remarkable political acumen. They form complex alliances and trade grooming services, sex and food. Like many denizens of the world's great cities, they lobby, demand bribes, repay favors and, when crossed, extract revenge.

Yet precisely because chimpanzees are so similar to humans (most medicines are absorbed, metabolized and excreted by chimps just as they are in people, for example), they make excellent stand-ins for humans in medical labs.

Medical studies on chimpanzees are no longer done in most countries other than the United States, where about 1,100 are now in research labs. Several scientists predicted Wednesday that release of the chimp genome would escalate a debate as to whether U.S. research restrictions - including an eight-year-old federal moratorium on breeding chimps for research - should be tightened or loosened.

Pascal Gagneux of the Zoological Society of San Diego and two colleagues wrote in a Nature commentary that a stricter code of ethics for chimpanzee research is needed. They recommend rules similar to those now in place for research on humans who cannot give meaningful informed consent because of their age or mental status.

Others, recalling the initial importance of chimpanzees as research tools when AIDS first emerged, argue that newly emerging medical challenges demand renewed breeding for research.

Acknowledging recent challenges by proponents of intelligent design, a proposition that posits the need for an intelligent creator, several scientists said the genome study offered elegant confirmation of Darwin's vision of evolution.

One analysis, for example, showed that the accumulation of deleterious mutations in the human and chimp genomes is greater than in the mouse and rat genomes in just the proportion predicted by one of the mathematical corollaries of the theory of evolution.

"I can't imagine Darwin hoping for a stronger confirmation of his ideas," said Robert Waterston, who led the Washington University team.

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