JAX Notes April 01, 2009

The Collaborative Cross: a powerful systems genetics tool

JAX Professor Gary Churchill helped design the Collaborative Cross

Genetic analysis is experiencing a new dawn — systems genetics, the study of the interactions among the genes in a biochemical pathway. A relatively new concept, systems genetics will help scientists better understand how genes function in the context of the entire biochemical pathway to which they belong. To realize the potential of systems genetics, researchers conducting mouse-based biomedical research need new tools — tools that will allow them to better resolve Quantitative Trait Loci (QTL) intervals and identify the underlying genes. The Collaborative Cross (CC) promises to be such a tool.

Partly conceived and developed by JAX Professor Gary Churchill, the Collaborative Cross approach will consist of a thousand recombinant inbred mouse lines — products of an eight-way funnel breeding design involving eight genetically diverse JAX® mice founder strains: A/J (000646), C57BL/6J (000664), 129S1/SvImJ (002448) NOD/ShiLtJ (001976)  NZO/HiLtJ (002105), CAST/EiJ (000928), PWK/PhJ (003715), and WSB/EiJ (001145). The autosomal genomes of each line will have equal contributions from each founder strain, and the recombinations that accumulate during the breeding process will be independent between lines.

The ability of the Collaborative Cross to support systems genetics analysis will be attributable to the following features: high genetic diversity, large size (for high statistical power), and large number of independent recombinations (for high mapping resolution). The average distance between CC recombinations will be approximately 12 Mb, with a QTL mapping resolution of 1 Mb, a substantial improvement over the mapping resolution possible in conventional mouse crosses.

The Collaborative Cross was possible through a community effort by the Complex Trait Consortium at three separate sites: 650 lines at Oak Ridge National Laboratory, Tennessee; 110 lines at Tel Aviv University, Israel; and hundreds more at the Animal Resources Centre, Western Australia. All are being extensively phenotyped and genotyped.

CC mouse lines will be distributed free of any intellectual property constraint. They will be a powerful tool for genomic studies, helping researchers better understand and develop more effective therapies and preventatives for complex polygenic diseases.

References

Chesler EJ, Miller DR, Branstetter LR, Galloway LD, Jackson BL, Philip VM, Voy BH, Culiat CT, Threadgill DW, Williams RW, Churchill GA, Johnson DK, Manly KF. 2008. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome 19:382-9.

Iraqi FA, Churchill G, Mott R. 2008. The Collaborative Cross, developing a resource for mammalian systems genetics: a status report of the Wellcome Trust cohort. Mamm Genome 19:379-81.