The Collaborative Cross
Why Do We Need a New Mouse Resource?
Genetically defined mouse models offer a tractable experimental system for mapping the genes underlying disease and for examining their function in the context of a complex, living organism. However, the current paradigm of using a small number of genetic backgrounds does not address the important role of genetic variation as a determinant of individual response and fails to provide strong mapping resolution. What is needed is a new mouse resource that has genetic diversity comparable to or greater than the common human genetic variants; that, unlike fully inbred strains, has a genetic constitution more similar to humans; and provides an ability to map genetic loci at level of resolution that can identify individual genes.
Developing the Collaborative Cross (CC)
The Collaborative Cross is a large panel of new inbred mouse strains that are currently being developed through a community effort (Churchill et al. 2004). The CC was designed to address some of the perceived shortcoming of available mouse strain resources, including small numbers of strains, limited genetic diversity, and a complex history that results in unknown confounding relationships among common inbred strains. The CC strains are derived from an eight way cross using a set of founder strains that include three wild-derived strains. The wild strains contribute 75% of the genetic diversity of the CC. Without relevant genetic diversity, forward genetic approaches cannot make discoveries.
The Collaborative Cross captures a substantial proportion of the genetic diversity available in laboratory mouse strains, estimated to be roughly twice the number of common SNPs in the human population (Yang et al., 2007). This diversity is approximately 4 times that in the widely used “classical” inbred strains.
The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems. It will be a genetically defined panel and, as all the strains are fully reproducable, genotyping need only be done once.
[ Collaborative Cross Breeding Status and Availability ]
Using the Diversity Outbred Mouse Population (DO)
As a further advance in gene mapping resources, The Jackson Laboratory is developing a new variety of mice that are designed to maximize allelic diversity (Diversity Outbred Mice). The mouse diversity outcross is an eight-way heterogeneous stock (HS) population. Motivation for creating the DO was derived from the success of fine mapping in other multi-way HS populations (e.g., Valdar et al., 2006). The founders of the DO are animals from breeding lines of the Collaborative Cross. This strategy allowed us to capture recombination events that occurred in the early generations of Collaborative Cross breeding to effectively jump-start recombination density in the DO population. The DO population is designed to produce and maintain a balanced mixture of the founder genomes. DO mice are maintained by random breeding with avoidance of sib mating. At each generation each mating pair contributes one male and female offspring the next generation. Numbers of mating pairs used to maintain the DO population are critical to avoid allelic loss and inbreeding. Simulations showed that with a population of at least 100 breeding pairs, the DO could be maintained for up to 300 generations with negligible losses of allelic diversity.
[ Diversity Outbred Breeding Status and Availability ]
Harnessing the Complementary Resources of the CC and DO
The CC strains are being inbred to produce stable clones. The DO mice, on the other hand, are being maintained as an outbred stock. Advantages of outbreeding include, normal levels of heterozygosity, similar to the human genetic condition, and substantially increased mapping resolution. A drawback of the DO is that each animal is genetically unique and thus not reproducible. Combinations of genetic loci that are discovered in the DO mice can be replicated in CC strains or in their reproducible F1 progeny. In this regard, the CC and DO populations are complementary. Together these new resources will revolutionize our understanding, treatment and ultimately, prevention of pervasive human diseases.