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04/01/10

Techniques for Accelerating Inbreeding in the Collaborative Cross. Catie Welsh 1 , Ryan J. Buus 2 , Jennifer Shockley 2 , Stephanie Hansen 2 , Darla Miller 2 , Fernando Pardo -Manuel de Villena 2 , Leonard McMillan 1.

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04/01/10

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  1. Techniques for Accelerating Inbreeding in the Collaborative Cross Catie Welsh1, Ryan J. Buus2, Jennifer Shockley2, Stephanie Hansen2, Darla Miller2, Fernando Pardo-Manuel de Villena2, Leonard McMillan1 1Department of Computer Science, University of North Carolina at Chapel Hill2Department of Genetics, University of North Carolina at Chapel Hill 04/01/10 University of North Carolina

  2. Motivation 2 Figures Courtesy of Karl Broman

  3. Motivation 3

  4. Observations • Large difference between selfing and random sibling mating. • Randomization was an important design decision in the CC. • Attempt to accelerate inbreeding using marker-assisted techniques. • Study impact of marker-assisted inbreeding on the genetic structure of the CC. 4

  5. Backcross G2:F10 Change breeding scheme after 10 generations of random sib-matings to cross offspring with their parent; alternating sex of parent at each generation. Sib-Mating Pedigree Diagram Parent-Child Backcross Pedigree Diagram 5

  6. Backcross 100,000 Simulations were done. No genotyping necessary. 33.5 38.2 141.2 145.1 6

  7. Marker-Assisted Inbreeding (MAI) • Random sib-matings for 10 generations • Starting at generation 11: • Generate 4 female and 4 male offspring • Consider all 16 pair matings • Choose the “best” breeding pair 7

  8. MAI DD Choosing the “Best” Breeding Pair • Consider all heterozygous regions • Calculate fraction of the genome that segregates in each pair of mice. • Take into account the different types of heterozygosity Each of the marked regions is some form of heterozygosity between the 2 animals. SS Ss = Opposite Homozygous DD = Both Heterozygous DS = One Heterozygous, One Homozygous SS = Same Homozygous Ss DS SS 8

  9. MAI Metrics Relationship between a potential breeding pair at 1 allele Ss = Opposite Homozygous DD = Both Heterozygous DS = One Heterozygous, One Homozygous SS = Inbred 9

  10. MAI Model is very conservative; assume every location fully informative 100,000 simulations 23.5 141.2 137.5 145.1 33.5 38.2 10 10

  11. 99% Fixation • 25.7 generations to reach 99% inbred with a regular 8-way cross • 23.5 generations to be 99% inbred using Backcrosses • 17.5 generations to be 99% inbred using MAI 17.6 23.5 25.7 11

  12. MAI Impact Regular 8-way MAI 8-way 12

  13. Starting Earlier Impact on Number of Generations Impact on Number of Segments 13

  14. Maximizing Mapping Power • Advanced Intercross – Maximize # of segments for x generations, thereafter minimize heterozygosity until inbred. Impact on Number of Generations Impact on Number of Segments 14

  15. Conclusion • 2 approaches to accelerating inbreeding • Backcrosses – slight speedup • MAI – dramatic acceleration • Both have small impact on # of segments (slight decrease) • Use of advanced intercross will increase # of segments • MAI techniques are currently being used at UNC with CC lines • 8 lines in various stages • Considering the use of backcrosses in more lines 15

  16. Acknowledgements UNC Computer Science • Wei Wang • Yi Liu • Jeremy Wang FPMV Lab • David Aylor • Tim Bell • John Calaway • Mark Calaway • John Didion • Justin Gooch • Ginger Shaw • Jason Spence Churchill Lab • Gary Churchill • Hyuna Yang • UNC Genetics • Will Valdar • Funding Sources • NIH U01 CA105417 “Integrative Genetics of Cancer Susceptibility” • NSF IIS 0534580 “Visualizing and Exploring High-dimensional Data” • NIH GM 076468 “The Center for Genome Dynamics at Jackson Laboratory: An NIGMS National Center of Systems Biology” 16

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