Of Mice and Men
Genetically diverse mice will shed light on how human genes function.
Understanding how genes and the environment interact to control complex genetic traits, such as resistance to certain diseases, is among the most important challenges of biological research. Simulating the genetic diversity of the human population is a critical tool that will help answer this question.
The Collaborative Cross project in ORNL's Life Sciences Division will provide researchers worldwide with a pool of genetically diverse mice that mimics the genetic profile of a typical human population. Because researchers have sequenced the entire mouse genome, which is identical to 85% of the human genome, the mouse genome is an ideal slate for studying complex processes, such as the body's response to chemical, biological, and viral agents.
The ORNL project aims to produce 1000 viable strains of mice from eight original strains over the next seven years. "Part of the goal is to share mice with facilities all over the world," says Dabney Johnson, a genetics researcher at ORNL who headed up the team that wrote the proposal that won $1.3 million from the Ellison Medical Foundation. The Collaborative Cross has already attracted international attention. Several institutions, including the University of Tennessee, the University of North Carolina, and Jackson Laboratory in Bar Harbor, Maine, are participating in the project.
ORNL's $14 million Russell Laboratory for Comparative and Functional Genomics, a 36,000-square-foot facility completed in 2004, is a pathogen-free facility for breeding mice. A key part of ORNL's modernization plan, the "mouse house" has space for 80,000 mice, cryogenic storage, and an ideal environment for producing uncontaminated lab specimens.
"Controlling environmental factors ensures that any differences in a complex process in the mice are genetic," Johnson says. "As an example, exposure to parasites, viruses, and bacteria can change the way a mouse behaves or responds."
Biologists using "clean" mice from the Collaborative Cross can confidently attribute response differences to genetic factors. Researchers say this mouse population is critical to the development of a community resource for understanding the genetic and environmental complexity of human disease.
Johnson notes that the project generates large amounts of data for use with predictive models and simulations that can be run only by the largest supercomputers. In 2004, ORNL was selected as the site for DOE's National Leadership Computing Facility, which by 2007 will be capable of performing 250 trillion calculations per second and providing a previously unavailable computational capability for genome research.
One complex trait on which these mice can shed light is the human response to pathogens that might be used as weapons. "Los Alamos National Laboratory has discovered a gene that plays a part in the human response to anthrax," Johnson says. "We can change that gene in mice."
Based on their genetic makeup, some people are more susceptible or more resistant than others to infection by a disease agent. If researchers can determine how cells react when exposed to a pathogen, the genes that guide the reaction can be located. How these specific genes differ from person to person might allow biologists to gauge each person's susceptibility to a disease agent.
"We can find biomarkers that point to the first gene in the pathway and confirm it sets off the genetic chain reaction," Johnson says. Pharmaceutical companies can then develop a drug that targets the specific links in the chain and functions as the genetic firewall that protects against the disease agent.
Other potential benefits are emerging. "Suppose we could identify a susceptible population before its members were harmed," Johnson continues. "In a specific population, like military personnel that must be immunized against smallpox, identifying the individuals likely to have a strong response to the vaccine could alert us to the vaccinated soldiers that should be closely observed."
Armed with a modern mouse facility and one of the world's most powerful computers, ORNL researchers are confident they are just opening the door to a new era of biological discovery, where the secrets of humankind will be found among some of Earth's smallest creatures.—Eva Millwood
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