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Macaque Genome Deciphered; May Herald Medical Breakthroughs

Stefan Lovgren
for National Geographic News
April 12, 2007
 
Scientists have finished sequencing the genome of the rhesus macaque monkey in work they say will enhance medical research in a wide range of areas, including HIV and neuroscience.

The findings will also advance scientists' understanding of primate evolution and what makes humans genetically distinct. (Read a genetics overview.)

An analysis comparing the macaque genome to the already sequenced chimpanzee and human genomes shows that the three primate species share about 93 percent of their DNA. But they have some significant differences among their genes.

"We really want to know what makes us humans—and different from our primate cousins," said Richard Gibbs, director of Baylor College of Medicine's Human Genome Sequencing Center in Houston, Texas.

"This study allows us to observe what has been added or deleted in each of these three primate genomes during their evolution."

Gibbs is the project leader for the Rhesus Macaque Genome Sequencing and Analysis Consortium, an international team of more than 170 scientists from 35 institutions whose findings are published in tomorrow's issue of the journal Science.

Evolutionary Pressures

The rhesus macaque is the second nonhuman primate, after the chimpanzee, to have its genome sequenced.

Chimps are believed to be the primates most closely related to humans. Compared to the human genome, the chimp genome is only about 1.5 percent different, while the macaque genome is about 7 percent different.

That divergence makes macaques ideal for the evolutionary study of primates, because important features that have been conserved in primates over time can be more easily seen by comparing rhesus monkeys to humans than by comparing chimps to humans.

"In some ways the chimp, which has already been sequenced, is a little too close for us to make easy sense of what the differences are" between humans and other primates, Gibbs said.

"It's a little easier to contrast the macaque with either chimp or human to make sense of what's going on," he added.

"If the chimp and the macaque share a feature and the human is different, you can say this is a human change."

Researchers say that humans and macaques had a common ancestor about 25 million years ago. About six million years ago, chimps split off from the human lineage.

"Once they diverge, other changes occur that reflect what the evolutionary pressures are on that particular species," Gibbs said. "What we see now are snapshots of the molecular fossils that reflect what had happened to that species since the divergence."

The researchers identified nearly 200 genes that probably play a key part in determining differences among primate species, including genes involved in hair formation, immune response, membrane-protein generation, and sperm-egg fusion.

Scientists were surprised to find some instances where the normal form of the macaque protein looks like a diseased human protein. One such example is phenylketonuria, a genetic disorder that can lead to brain damage and mental retardation because sufferers lack an important metabolic enzyme.

"The underlying question here is, What is what apparently looks like a human mutation that causes a devastating disease with early demise and severe mental retardation doing in an apparently normal macaque?" Gibbs asked.

AIDS Research

Because the rhesus macaque is both abundant and genetically and physiologically similar to humans, it is widely used in medical research, particularly in vaccine research and as a model for AIDS research.

Scientists expect the rhesus macaque genome sequence to enhance research in neuroscience, behavioral biology, reproductive physiology, endocrinology, and cardiovascular studies. (Related: "Dog Genome Mapped, Shows Similarities to Humans" [December 7, 2005].)

Some interesting findings are already coming from a study of variations within the macaque genome.

The complete genome sequencing of the macaque was done with the DNA of a single individual—a female rhesus macaque at the Southwest Foundation for Biomedical Research in San Antonio, Texas. But researchers also sequenced parts of the genomes of 16 other macaques, 8 from China and 8 from India.

The analysis suggests that the two populations, from India and China, separated about 162,000 years ago.

"We're able to say that the two subspecies of the macaques are very different from each other on a genetic level, probably much more different than human populations are [from each other]," said study leader Carlos Bustamante, an assistant professor of biological statistics and computational biology at Cornell University in Ithaca, New York.

The simian immunodeficiency virus (SIV) is used as a model for the human immunodeficiency virus (HIV). When exposed to SIV, Chinese macaques develop AIDS-like symptoms more slowly than Indian macaques, the researchers found.

"Indian animals came down with AIDS much faster than Chinese animals, so there's a huge interest in trying to figure out what are the genetic differences that may account for that," Bustamante said.

Researchers looking for a disease-causing gene don't usually find the exact location of the gene right away. Instead, the scientists first determine that the gene is situated somewhere along a particular DNA strand between two easily recognized sequences called markers, and then zero in from there.

"We found that for Indian macaques the number of markers you need to map a genetic disease will be much smaller than the number of markers that you need in Chinese macaques or even in humans," Bustamante said. "This means the search [for disease-causing genes] may be easier in Indian macaques."

Gibbs, the overall project leader, points out that sequencing the macaque genome doesn't mean more macaques should be used in laboratory research.

"I think we're doing something quite opposite," he said.

"We're entering into a new area where we can actually do much more rational and more informed experiments with macaques. We're knowing the macaque better instead of just advocating experimenting on the macaque."

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