'It's complicated'

Modeling human diversity... in mice!

How can scientific research get answers when there's so much human diversity? Mice, of course!

Genetically diverse research animal models are key to understanding complex disease.

A 21st-century approach to using animal models is gaining traction in the research community and revealing unprecedented insights in human biology, aging and disease, and response to drugs, environmental toxins, diet and exercise.

The National Institute of General Medical Sciences has made a four-year grant totaling $2,003,367 to Jackson Laboratory Professor Gary Churchill, Ph.D.Employs a systems approach to investigate the genetics of health and disease and complex disease-related traits in the mouse.Gary Churchill to develop statistical methods and software to analyze genetic and physiological data from studies of special, genetically diverse populations of mice and other laboratory organisms.

“Populations formed by the inter-mating of multiple strains are supplanting traditional studies, based on crosses between a strain that is susceptible to disease and one that is resistant,” Churchill says. “Through this research effort, we will develop improved statistical methods and software for the analysis of systems of molecular and clinical traits in such multi-parent populations of model organisms.”

In the 20th century, model organisms ranging from yeast to mice were carefully bred into genetically uniform strains, standardization that enabled reproducible experiments to locate genes for a particular trait. But inbred strains do a poor job of representing humans, who are “outbred” and thus have a great deal of genetic variation. 

Enter multi-parent populations such as Collaborative Cross mice. Crossing eight founder strains, each with a distinctly different genetic background, over several generations results in a population in which each mouse is as genetically unique as any human.

So, a multi-parent mouse population can literally stand in for all of humanity. Unlike studies of human research subjects, every aspect of the mouse environment can be controlled, making it possible to isolate the effects of diet, exercise and other “lifestyle” components. Sequencing technology enables researchers to peg physiological and behavioral characteristics in the mice to specific genetic variants, which have analogs in the human genome.

Churchill’s collaborator on the grant is Karl Broman, professor of biostatistics and medical informatics at the University of Wisconsin Madison. It’s been 15 years since Churchill, Broman and researchers at 94 academic research institutions around the world published a commentary in Nature Genetics setting out the rationale for the Collaborative Cross. Since then, multi-parent populations have provided new and more efficient ways to explore complex genetic diseases and other traits:

Not surprisingly, studies using multi-parent animal model populations generate massive quantities of data, requiring analysis and organization to be of greatest value to the research community.

Churchill, Broman and their collaborators will develop next-generation software tools to implement the best analysis methods and make them readily accessible, along with interactive data analysis and visualization tools. Their work will enable exploration of these high-dimensional data and empower researchers to explore systems genetics data on multi-parent populations.

National Institute of General Medical Sciences: Systems Genetic Analysis of Multi-Parent Crosses, Grant Number 2R01GM070683-13