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News — Being announced this week in the journal Nature is the sequencing of the genome of the gray, short-tailed opossum, Monodelphis domestica, an animal originally developed as a model for scientific studies at Southwest Foundation for Biomedical Research (SFBR) in San Antonio and now utilized by researchers around the globe for a wide variety of research on human health and disease. The tiny Monodelphis domestica is the first marsupial to be sequenced.

SFBR Chief Scientific Officer John L. VandeBerg, who first developed the animal as a scientific model and who serves as a co-author on the Nature article, explained that the genome sequencing is poised to have a significant impact on biomedical research.

"The Monodelphis has unique properties that make it particularly useful in studies of fetal development, genetic factors related to high cholesterol and melanoma, as well as the quest to find ways to repair injured spinal cords, among other areas of research," he said. "Having the animal's genetic sequence will accelerate the rate of research developments in all these areas."

Scientists in Cambridge, Mass., at the Broad Institute Sequencing Center of the Massachusetts Institute of Technology and Harvard University led the multi-institutional project sponsored by the National Institute of Human Genome Research, part of the National Institutes of Health. Kerstin Linblad-Toh oversaw the project at the Broad Institute.

The opossum that was sequenced came from SFBR's fully pedigreed Monodelphis colony, the largest such colony in the world. SFBR scientists also contributed to the white paper nominating the Monodelphis domestica as the first marsupial to have its genome sequenced.

The scientists' reasoning was that the Monodelphis sequence would have a far-reaching impact because of the breadth of scientific research programs in which the animal is utilized. In addition, the fact that inbred strains of the animal had been developed meant it would be easier and quicker to sequence. And the fact that SFBR scientists have already developed a genetic linkage map for the Monodelphis will help researchers make better use of the full genome sequence.

VandeBerg, who previously worked with captive colonies of large marsupials such as kangaroos and wallabies in Australia, began developing the Monodelphis as a research model in 1979, realizing that its small size made it a more practical laboratory animal.

"Since marsupials have very different characteristics from eutherian, or placental mammals, particularly in their early stage of birth, my thinking was that any marsupial that could be produced in large numbers in the laboratory would become extraordinarily valuable for research on early mammalian development," he said.

VandeBerg brought 27 animals with him to San Antonio when he joined SFBR in 1980 and soon developed a colony that became a worldwide resource. Today SFBR's Monodelphis colony numbers about 2,400 animals, all fully pedigreed. It produces 6,000 progeny a year " totaling about 80,000 animals over 30 generations. SFBR has supplied many of these animals to others laboratories that have established their own colonies.

All this has been possible because of several years of NIH funding in the 1980s followed by strong and consistent grant support from the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation to sustain and enhance the SFBR colony since 1990.

Particularly beneficial characteristics and resulting research programs with the Monodelphis domestica include:

"¢ It is the only mammal known to develop melanoma skin cancer solely from exposure to ultraviolet light, the cause of melanoma in most human cases.

"¢ With NIH funding, VandeBerg's team of scientists at SFBR has developed the Monodelphis for research on dietary-induced hypercholesterolemia (high blood cholesterol), a major contributor to heart disease. Some animals are genetically predisposed to high blood cholesterol that is only manifested when the animal is fed a human-style high-cholesterol diet. The SFBR team has been working to identify genes that cause some animals to be susceptible to that type of diet and others to be resistant.

"¢ The Monodelphis offers insight into fetal development, because the animal is born at a stage that would be the equivalent of about a six-week human fetus and continues its development outside the uterus, where it can easily be monitored without any invasive procedures.

"¢ Because the baby Monodelphis can regenerate a severed or crushed spinal cord, up to about one week of age, this species offers insight into therapies for spinal cord injury, an area of research where SFBR researchers are collaborating with others. They are studying the expression of genes that make this healing possible, and what genetic or physiological changes occur that cause the animal to lose this ability as it matures. Identifying and understanding those changes could lead to new ideas for treatment of human spinal cord injuries.

Speeding up the pace of scientific research

VandeBerg is encouraged by the sequencing of the Monodelphis genome, which he expects to dramatically speed the pace of genetic research investigations with this unique animal model. "Trying to find these genes has been extremely difficult without having the sequence of the animal," he said. "But now that the sequence is available, I expect it to eliminate as much as one to three years of preliminary work required before a researcher can zero in on a gene or set of genes that appears to play a role in a certain disease or illness."

He explained, "Now, when we identify a Monodelphis gene that we suspect influences a physiologic process, we can go straight to the Monodelphis genome and find out the exact sequence of that gene without doing the incredibly painstaking lab work it once required. Instead, we can now go straight to this database and in an hour or two learn what we want to learn, match it up with the human database, find out where that gene is located on a human chromosome and what genes are surrounding it on a human chromosome, go back and see if the same genes are around it on the Monodelphis chromosome, and then launch straight into experiments on the function of the gene. In the past, it would take one year, two years, or even three years, to go from the idea of having one or more candidate genes for a process to where you could actually do functional experiments."

He cited the example of the search for genes that make some more susceptible to a high-cholesterol diet.

"For years we've been doing genome scans, that is, tracking marker genes through generations, together with physiologic characters such as high blood cholesterol," VandeBerg said. "We get signals on particular chromosomes where we know there must be a gene, let's say chromosome 8, that influences blood cholesterol. So we know there's a gene in one segment of chromosome 8 that controls blood cholesterol.

"The narrowest we can get through that technology is maybe 200 genes or 300 genes. In the past, we never even knew what genes were in that segment. It was so hard to go from there to finding the gene that we were interested in. Now we'll be able to go to the Monodelphis gene map, find all the genes that are in that chromosomal segment of Monodelphis, get some ideas of function of those genes from research with humans, mice and so on, and be able to target the ones that we want to investigate. Before, we had this pool of 200 or 300 genes with no efficient way to get a handle on which ones we might want to look at."

The availability of this genome sequence will contribute greatly to the collage of animals needed for biomedical research to progress.

"The opossum does not displace any other laboratory animal, but it has brought to the table some new capabilities, particularly in developmental biology," he said.

The Monodelphis domestica is found in the wild in Brazil, Bolivia, and Guyana. An adult weighs three to four ounces and is about twice the size of a mouse, and usually lives no longer than two years in the wild.