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News — The most widely used nonhuman primate model in research on human health and disease has just become even more valuable, thanks in part to scientists " and a monkey " at Southwest Foundation for Biomedical Research (SFBR) in San Antonio.

A multi-center team funded by the National Human Genome Research Institute (NHGRI) has published in the April 13 issue of the prestigious journal Science the complete sequence for the genome of the rhesus macaque monkey.

Work on the genetic sequence, which details more than 98 percent of the "clonable" DNA along the rhesus genome, was conducted at the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC) in Houston, the Genome Sequencing Center at Washington University in St. Louis, and the J. Craig Venter Institute in Rockville, Md. " all part of the NHGRI-supported Large-Scale Sequencing Research Network " under the direction of Dr. Richard Gibbs, director of the BCM-HGSC.

The consortium had assistance in this effort from Dr. Jeff Rogers, a geneticist at SFBR and a co-author on the publication in Science. Rogers was lead author on a white paper that nominated this species as the second nonhuman primate to be selected by the NHGRI for whole genome sequencing. The first was the chimpanzee.

Rogers reasoned that the rhesus monkey DNA sequence would be especially valuable because of the monkey's genetic closeness to humans and because scientists have spent the last century accumulating a wealth of research data on the rhesus, dating back to early infectious disease research. Today, the rhesus serves as the primary animal model for the study of HIV and AIDS as well as for studies on neuroscience. It also is a vital animal model for research on metabolic disorders such as cardiovascular disease, diabetes and obesity, reproductive biology, aging, vision, mental health and addictive disorders, pharmacology, and a host of other human health issues.

"Because so much is already known about the rhesus, this genetic sequence is poised to have a more immediate impact than it would with an animal that was less understood," said Rogers. "That was a big part of why we urged the National Human Genome Research Institute to select the rhesus monkey for sequencing, because there already is so much data, so much information, that researchers can build upon for the advancement of human health."

When NHGRI approved the project, Rogers served as a liaison between genome sequencing centers and primatology centers.

The DNA sequence was derived from a female rhesus macaque monkey that was part of the colony at SFBR's Southwest National Primate Research Center, where Rogers also is a faculty member.

Gibbs said that Rogers and the Southwest National Primate Research Center at SFBR were pivotal in the project's success.

"There is no question about that," Gibbs said. "Jeff first championed the request to sequence the rhesus genome, and throughout the whole process, he has brought the perspective of the primatologist as well as the molecular biologist to the project."

Potential impact

Gibbs said the sequencing of the rhesus genome is poised to have a dramatic impact on three key areas of research.

"It should enhance research on human diseases by providing a better understanding of this commonly used animal model," he said. "In the evolutionary context, it also will help researchers identify genes that are key players in determining the differences between primate species. And finally, the sequence should improve studies on the rhesus itself, which is a fascinating animal, by providing new genetic tools," Said Gibbs.

Rogers is particularly enthused about how this breakthrough will benefit worldwide research on human health and disease, ultimately leading to new and improved methods of disease prevention and treatment.

"From the perspective of the national biomedical research effort, rhesus monkeys are the most widely used and most significant nonhuman primate model for biomedical research," Rogers said. "As the best animal model for investigations on AIDS, rhesus monkeys are particularly important to that research effort, but they also are the primary model for neuroscience, addiction research, vision research, diabetes, and pharmacology." Offering examples of how the rhesus sequence could benefit AIDS research, he said it should help further understanding of such things as why certain animals can withstand the virus so much longer than others, what happens to cells when they are infected by the virus, what genes are turned on or off when someone is infected with the virus, and what the virus does to the function of those genes in the cell.

The sequence and the map

The sequence should be even more valuable to efforts to find disease-influencing genes when used in conjunction with the rhesus genetic linkage map developed by Rogers and published in 2006 (Genomics; Vol. 87, Issue 1).

Gibbs pointed out the genetic linkage map actually was instrumental in the final assembly of the rhesus genome sequence. "As part of the assembly process, we have to decide where things go at the very highest level, and Jeff's genetic map was useful for that," he said.

Explaining the difference between the sequence and the map, Rogers illustrated how each is more powerful for genetic research when paired with the other. "The genome contains 3 billion base pairs of DNA," Rogers explained. "If you think of the entire genome stretched out as a long highway going from New York to Los Angeles, the DNA sequence tells you every detail of everything you're going to see as you go down that highway, down to every blade of grass you'll pass. "That's obviously valuable information, but it's a lot to sift through if you're trying to find a particular blade of grass " or in reality, a genetic variation " that influences a certain disease or trait. So the genetic linkage map essentially gives you landmarks or lampposts to help you figure out which general area you need to look in [to find a gene influencing a certain trait, such as the color of your eyes or susceptibility to high blood pressure]. In genetic jargon, we call these lampposts 'markers.' By combining the linkage map and its markers with the whole genome sequence, we can look in more detail within that one most important area."

To create the linkage map, Rogers and his team used genetic samples from 900 rhesus monkeys at both the Southwest National Primate Research Center and the Oregon National Primate Research Center. They analyzed short stretches of DNA that showed variation, or polymorphisms, from animal to animal, then placed a marker at each of those locations, creating the map of 250 markers across the genome.

The genetic linkage map Rogers developed for the rhesus monkey is only the second linkage map developed for a nonhuman primate. The first, for the baboon, also was developed at SFBR's Southwest National Primate Research Center by Rogers and fellow SFBR scientist Dr. Michael Mahaney. The map is continually updated by a team that includes Rogers and Mahaney and their colleague Dr. Laura Cox. Already, the baboon linkage map has facilitated progress toward the identification of numerous genes influencing cardiovascular disease, diabetes, obesity, osteoporosis, infectious diseases, and mental disorders.

Rogers says that, together, the DNA sequence and the genetic linkage map for the rhesus macaque should benefit genetic research with rhesus monkeys in the same way that the human DNA sequence and gene map have propelled genetic research with people. "Development of the human linkage map has led to the identification of hundreds of different genes that influence different health-related traits, everything from diabetes to schizophrenia," he said. "Human genetics is now largely based on the DNA sequence and the linkage map to tie the sequence to the individual variation for specific diseases. So what we've done here is build a combination of tools that will allow people to use many of the same strategies developed through human genetics for research with rhesus monkeys."