04/01/10University of North Carolina Techniques for Accelerating Inbreeding in the Collaborative...
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04/01/10 University of North Carolina
Techniques for Accelerating Inbreeding in the Collaborative Cross
1Department of Computer Science, University of North Carolina at Chapel Hill2Department of Genetics, University of North Carolina at Chapel Hill
Catie WelshCatie Welsh11, Ryan J. Buus, Ryan J. Buus22, Jennifer Shockley, Jennifer Shockley22, , Stephanie HansenStephanie Hansen22, Darla Miller, Darla Miller22,,
Fernando Pardo-Manuel de VillenaFernando Pardo-Manuel de Villena22, Leonard McMillan, Leonard McMillan11
Observations
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• 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.
Backcross
Sib-Mating Pedigree Diagram
Parent-Child Backcross Pedigree Diagram
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Change breeding scheme after 10 generations of random sib-matings to cross offspring with their parent; alternating sex of parent at each generation.
G2:F10
Marker-Assisted Inbreeding (MAI)
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• 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
MAI
DD
Ss
DS
Each of the marked regions is some form of heterozygosity between the 2 animals.
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SS
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
SS
Ss = Opposite Homozygous DD = Both HeterozygousDS = One Heterozygous, One HomozygousSS = Same Homozygous
MAI Metrics
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Ss = Opposite Homozygous DD = Both HeterozygousDS = One Heterozygous, One HomozygousSS = Inbred
Relationship between a potential breeding pair at 1 allele
Interval 1 2 3 Probability
Breeding Pair 1 DD DS DD = 1/8 x ¼ x 1/8 = 1/256
Breeding Pair 2 Ss DS DD = 0 x ¼ x 1/8 = 0
MAI
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Model is very conservative; assume every location fully informative
100,000 simulations
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23.5
33.5
38.2
137.5141.2
145.1
99% Fixation
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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
Maximizing Mapping Power
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Advanced Intercross – Maximize # of segments for x generations, thereafter minimize heterozygosity until inbred.
Impact on Number of Segments
Impact on Number of Generations
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
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Acknowledgements
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UNC Computer ScienceWei WangYi LiuJeremy 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 GeneticsWill Valdar
Funding SourcesNIH 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”