Scientists Unveil Genetic Linkage Map for Rhesus Macaque

Dr. Jeff Rogers and his colleagues recently published a genetic linkage map for the rhesus macaque monkey, the nonhuman primate most widely used in biomedical research (Genomics: Volume 87, Issue 1, January 2006). It is only the second such genetic map of any nonhuman primate, with the first being of the baboon. That map, published in 2000, also was developed at SFBR by Dr. Rogers and Dr. Michael Mahaney. The baboon linkage map has already facilitated progress toward the identification of numerous genes influencing cardiovascular disease, diabetes, obesity, osteoporosis, infectious diseases, and mental disorders.

Both efforts were funded by the National Center for Research Resources, part of the National Institutes of Health. Work on the rhesus map also received funding from the NIH's Office of AIDS Research, and work on the baboon linkage map benefited from support from and collaboration with Sequana Therapeutics, Inc., a biotech company based in La Jolla, CA.

Rogers explains two reasons why the rhesus genetic map is poised to have an even greater impact. First, because the rhesus is the most commonly used nonhuman primate in biomedical research, this tool should be useful to a larger number of investigators studying an even broader range of diseases.

Second, it coincides with the February 9 announcement by the National Human Genome Research Institute that the rhesus macaque genome has been sequenced by a multi-center team, and that information has been deposited in free public databases for use by the world research community.

The sequencing of the rhesus genome was conducted at the Baylor College of Medicine Human Genome Sequencing Center in Houston, the Genome Sequencing Center at Washington University in St. Louis and the J. Craig Venter Institute, Rockville, Md., which are part of the NHGRI-supported Large-Scale Sequencing Research Network. The DNA samples used in the sequencing came from a female rhesus macaque at the Southwest Foundation for Biomedical Research in San Antonio.

Together, the genome sequence and the genetic linkage map make powerful tools for genetic discovery. "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 lightposts to help you figure out which general area you need to look in. In genetic jargon, we call these lightposts '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. "Now, with this tool, we geneticists can study large families of rhesus monkeys and look for the co-inheritance of a specific genetic marker and a specific disease trait, whether it be high blood pressure, insulin resistance, low bone density, or anything else we're investigating. Then we know where along a particular chromosome we need to focus our efforts to find the specific gene affecting that trait. In essence, the marker is like a lightpost that illuminates a section of a long, dark highway and helps us see the gene we're trying to find. With enough markers, we can illuminate the entire length of the sequence." Rogers expects Baylor's work on the rhesus DNA sequence and SFBR's work on the genetic linkage map to benefit genetic research with rhesus monkeys as the human DNA sequence and gene map have propelled genetic research with people. "Development of the human linkage map has led to the identifications of 100s 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 tool that will allow people to use all the power and all the strategies developed through human genetics for research with rhesus monkeys, as we already have for baboons."

While the baboon gene map has been especially valuable for investigators at SFBR and its Southwest National Primate Research Center, which has the world's largest colony of baboons for research and a unique pedigreed baboon colony, the rhesus map could be equally or even more valuable to investigators worldwide. "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."

They also are studied in such diverse fields as reproductive biology, aging, endocrinology and metabolism, cardiovascular disease, and obesity. "So we fully expect the linkage map that we've built for the rhesus to be valuable for studies on a wide range of different health problems being investigated by scientists all across the country and even around the world," said Rogers.

About Southwest Foundation for Biomedical Research

The Southwest Foundation for Biomedical Research is one of the leading independent biomedical research institutions in the United States. It is recognized within scientific and academic communities worldwide for the quality of its basic research into the nature, causes, prevention and treatment of disease. SFBR's staff of more than 70 doctoral-level scientists conducts nearly 180 research projects, with marked success in the areas of genetics, neonatal development, and infectious and metabolic diseases.