Project Leader: E. J. Chesler

The Collaborative Cross is a randomized cross of eight inbred mouse strains designed by members of the Complex Trait Consortium. Oak Ridge National Laboratory is the North American site of the collaborative cross, designed to be the ultimate mouse reference population. The cross features a randomized assortment of 8 inbred strains, A/J, C57BL/6J, 129S1/SvImJ, NOD/LtJ, NZO, CAST/Ei, PWK/Ph, WSB/Ei. The lines are first crossed pairwise to make all 56 possible G1 parents. A set of possible 4-way crosses is performed, keeping Y-chromosome and mitochondrial balance. Finally, all 8 genomes are brought together in G2:F1, and the offspring of this cross are inbred. 90% inbreeding is expected at G2:F20 based on theoretical results.

History

The collaborative cross was first proposed at the Edinburgh Meeting of the IMGC in October of 2001 and in print by Threadgill, Hunter and Williams in 2002, motivated by the need for an affordable, retrievable, high-precision resource for the analysis of complex traits. The idea was developed further with the research community at the first Annual Meeting of the Complex Trait Consortium in Memphis, TN, May 15-17, 2002. A workgroup met at Johns Hopkins University in 2002 to refine the design of such a resource Strain selection was discussed at the CTC satellite meeting of the IMGC in San Antonio Texas on November 17, 2002. The Collaborative Cross was presented at the NIH on March 17th, 2004 by Gary A. Churchill and Robert W. Williams.

Enthusiasm for the cross was developing, and ideal strategies for breeding, randomization and implementation were discussed. Meanwhile, powerful demonstrations of the utility of a systems genetics approach such as www.genenetwork.org were being developed. Simulations of the power and precision of genetic analysis and for the structure of the population were also performed to estimate the optimal number of strains for breeding. Initial proposals for implementing the collaborative cross called for a grass-roots distributed breeding effort, but the advantages of phenotyping mice from a single location and the consistency of a population that would be bred under a single selection environment became clear. The cross needed a large facility capable of consistent, randomized matings.

In May 2005 the Collaborative Cross found a home at the William and Liane Russell Functional Genomics Laboratory. At this high-capacity breeding facility, all lines can be bred and maintained simultaneously and consistently. Early support for the cross came from Robert W. Williams and Gary A. Churchill who contributed mouse resources for the progenitor population. The Department of Energy provided critical support in the form of subsidized husbandry for the cross, and several hundred funnels were initiated. The Ellison Medical Foundation provided major external support for this project in the interest of developing a research tool for the study of aging.

Present status of the cross

Faithful implementation of the randomized mating strategy described in Churchill et al, is being performed using the husbandry management tool, CCDB, developed for the collaborative cross by Dr. Kenneth Manly.

Getting involved

There are many ways to access the collaborative cross and participate in this community endeavor. The Oak Ridge National Laboratory has many established opportunities for visiting scientists, faculty and student teams, graduate students, undergraduates and high-school students. Recent teams have participated in phenotyping of RI and progenitor stocks and analytic tool development. Many other collaborative and sub-contract research opportunities exist, fulfilling our mission as a DOE User Facility. While the cross is being inbred, the mice can be used as a heterogeneous stock population. Individuals can be phenotyped and genotyped to facilitate high-precision/high-polymorphic information QTL mapping using methods developed by Richard Mott and colleagues. To obtain mice or for information regarding research opportunities, contact Darla Miller (millerdr@ornl.gov).

Support

• The Ellison Medical Foundation
• U.S. DOE