The Collaborative Cross
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. For information
regarding research opportunities, contact Elissa Chesler
(cheslerej@ornl.gov).
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