Genetic analysis in the Collaborative Cross breeding population (original) (raw)

  1. Greta Sokoloff3,
  2. Cheryl L. Ackert-Bicknell4,
  3. Martin Striz5,
  4. Lisa Branstetter1,
  5. Melissa A. Beckmann1,2,
  6. Jason S. Spence1,2,
  7. Barbara L. Jackson6,
  8. Leslie D. Galloway7,
  9. Paul Barker1,
  10. Ann M. Wymore1,
  11. Patricia R. Hunsicker1,
  12. David C. Durtschi1,2,
  13. Ginger S. Shaw1,2,
  14. Sarah Shinpock1,
  15. Kenneth F. Manly8,
  16. Darla R. Miller1,
  17. Kevin D. Donohue9,
  18. Cymbeline T. Culiat1,2,
  19. Gary A. Churchill4,
  20. William R. Lariviere10,
  21. Abraham A. Palmer3,11,
  22. Bruce F. O'Hara5,
  23. Brynn H. Voy1,2 and
  24. Elissa J. Chesler1,2,4,12
  25. 1Systems Genetics Group, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA;
  26. 2Genome Science and Technology Program, University of Tennessee, Knoxville, Tennessee 37996, USA;
  27. 3Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA;
  28. 4The Jackson Laboratory, Bar Harbor, Maine 04609, USA;
  29. 5Department of Biology, University of Kentucky, Lexington, Kentucky 40506, USA;
  30. 6Statistics and Data Sciences Group, Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA;
  31. 7Ecology and Evolutionary Biology Department, University of Tennessee, Knoxville, Tennessee 37996, USA;
  32. 8Center of Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA;
  33. 9Department of Electrical and Computer Engineering, University of Kentucky, Lexington, Kentucky 40506, USA;
  34. 10Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA;
  35. 11Department of Psychiatry and Behavioral Neurosciences, University of Chicago, Chicago, Illinois 60637, USA

Abstract

Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Five of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations.

Footnotes

Freely available online through the Genome Research Open Access option.