Churchill and Fernando Pardo-Manuel de Villena, Ph.D., of the University of North Carolina, Chapel Hill, leading an international research team, created a genome-wide, high-resolution map of most of the inbred mouse strains used today. Their conclusion, published in Nature Genetics: Most of the mice in use today represent only limited genetic diversity, which could be significantly expanded with the addition of more wild mouse populations.
The current array of laboratory mouse strains is the result of more than 100 years of selective breeding. In the early 20th century, America's first mammalian geneticists, including Jackson Laboratory founder Clarence Cook Little, sought to understand the genetic processes that lead to cancer and other diseases. Mice were the natural experimental choice as they breed quickly and prolifically and are small and easy to keep.
Lacking the tools of molecular genetics, those early scientists started by tracking the inheritance of physical traits such as coat color. A valuable source of diverse-looking mouse populations were breeders of "fancy mice," a popular hobby in Victorian and Edwardian England and America as well as for centuries in Asia.
In their paper, Churchill and Pardo-Manuel de Villena report that "classical laboratory strains are derived from a few fancy mice with limited haplotype diversity." In contrast, strains that were derived from wild-caught mice "represent a deep reservoir of genetic diversity," they write.
The team created an online tool, the Mouse Phylogeny Viewer, for the research community to access complete genomic data on 162 mouse strains. "The viewer provides scientists with a visual tool where they can actually go and look at the genome of the mouse strains they are using or considering, compare the differences and similarities between strains and select the ones most likely to provide the basis for experimental results that can be more effectively extrapolated to the diverse human population," said Pardo-Manuel de Villena.
"As scientists use this resource to find ways to prevent and treat the genetic changes that cause cancer, heart disease, and a host of other ailments, the diversity of our lab experiments should be much easier to translate to humans," he noted.
Churchill and Pardo-Manuel de Villena have been working for almost a decade with collaborators around the world to expand the genetic diversity of the laboratory mouse. In 2004 they launched the Collaborative Cross, a project to interbreed eight different strains--five of the classic inbred strains and three wild-derived strains. In 2009 Churchill's lab started the Diversity Outbred mouse population with breeding stock selected from the Collaborative Cross project.
The research team estimates that the standard laboratory mouse strains carry about 12 million single nucleotide polymorphisms (SNPs), single-letter variations in the A, C, G or T bases of DNA. The Collaborative Cross mice deliver a whopping 45 million SNPs, as much as four times the genetic variation in the human population. "All these variants give us a lot more handles into understanding the genome," Churchill says.
"This work creates a remarkable foundation for understanding the genetics of the laboratory mouse, a critical model for studying human health," said James Anderson, Ph.D., who oversees bioinformatics grants at the National Institutes of Health. "Knowledge of the ancestry of the many strains of this invaluable model vertebrate will not only inform future experimentation but will allow a retrospective analysis of the huge amounts of data already collected."
Other team members include Hyuna Yang, Ph.D., from The Jackson Laboratory; Leonard McMillan, Ph.D., two graduate students Jeremy Wang and Catherine Welsh from the UNC-Chapel Hill Department of Computer Science; Timothy Bell, Ryan Buus and graduate student John Didion from the UNC-Chapel Hill Department of Genetics, UNC Lineberger and the Carolina Center for Genome Sciences; Francois Bonhomme, Ph.D., and Pierre Boursot, Ph.D., from the Université Montpellier (France); Alex Yu, Ph.D., from the National Taiwan University; Michael Nachman, Ph.D., from the University of Arizona; Jaroslav Pialek, Ph.D., from the Academy of Sciences of the Czech Republic, and Priscilla Tucker, Ph.D., from the University of Michigan.
The research was supported by the National Institute of General Medical Sciences (part of the National Institutes of Health), and several additional National Institutes of Health grants, a Czech Science Foundation grant and a University of North Carolina Bioinformatics and Computational Biology training grant.
Yang et al.: Subspecific origin and haplotype diversity in the laboratory mouse. Nature Genetics, advance online publication Sunday, May 29, 2011, http://dx.doi.org/10.1038/847.
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