Autism, depression, anxiety. Antipsychotic drug side effects. What are the genetic and environmental factors that underlie and contribute to these complex problems? And how do genes and environment interact to shape them?
To seek answers, the National Human Genome Research Institute and the National Institute of Mental Health has named the University of North Carolina at Chapel Hill a Center of Excellence in Genomic Science and awarded UNC $8.6 million over five years to fund a new Center for Integrated Systems Genetics, or CISGen.
In funding the grant to UNC for the first two years, NIMH will contribute about $6 million through the 2009 American Recovery and Reinvestment Act.
The new center will require "an exceptional diversity of scientific expertise - from psychiatry to mouse genetics to computational biology," says CISGen co-director Fernando Pardo-Manuel de Villena, Ph.D., associate professor of genetics at the Carolina Center for Genome Sciences. "UNC is one of the few places in the US where this sort of project is possible, and the Center of Excellence award recognizes this."
Pardo-Manuel de Villena says that the crux of the problem is that "the genome is enormous, and there are billions of ways in which the pieces can act together. It's easier to win the PowerBall lottery than to get the right answer in humans." The centerpiece of the UNC Center of Excellence is to use laboratory mice to screen all the possibilities to find the few that are likely. "We can use the mouse to narrow the search space from billions of possibilities to only hundreds or even dozens. It's like the PowerBall when you know four or five of the six numbers for sure."
The CISGen team, co-directed by Patrick Sullivan, M.D., Ray M. Hayworth and Family Distinguished Professor of Psychiatry in the department of genetics at the UNC School of Medicine, will integrate the study of genetics and neurobehavior using unique strains of laboratory mice derived from a mouse resource housed at UNC known as the Collaborative Cross. Sullivan also is a member of the Carolina Center for Genome Sciences, the Center under which CISGen will operate.
The Collaborative Cross is designed to be a vital mouse reference population for scientists exploring the genetic underpinnings of complex traits. The team will generate novel strains of mice to study relevant behavioral traits. The resulting mouse models will then be used to focus genomic studies of human psychiatric disorders and predicting treatment outcomes.
"We chose the hardest problems out there, the ones that have been most resistant to scientific inquiry in humans," Sullivan says. "We chose to study mouse versions of psychiatric traits potentially relevant to autism, depression and anxiety, and antipsychotic drug side effects and response to treatment."
Sullivan says the team also chose the hardest twist on this problem, how the environment interacts with the genome. "We want to understand how genes and environments interact to influence these traits so well that we can predict whether they will occur in mice never before studied. These sorts of studies are straight-forward in mouse but exceptionally hard in people."