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QTL Mapping in Diversity Outbred Mice

This paper discusses the use of quantitative trait locus mapping in Diversity Outbred mice, including genotyping and association mapping techniques. The study aims to narrow QTL intervals and analyze genotype probabilities using Hidden Markov Models. It also explores the incorporation of kinship into the analysis and demonstrates QTL mapping for neutrophil counts.

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QTL Mapping in Diversity Outbred Mice

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  1. QTL Mapping in Diversity Outbred Mice Daniel M. Gatti, Ph.D Berlin, Germany May 2014

  2. Outline Introduction Genotyping Diversity Outbred Mice Quantitative Trait Locus mapping in DO mice

  3. Motivation for producing the DO Known founders to perform linkage mapping Founders have been sequenced Can impute founder sequences onto DO and perform association mapping Fine recombination block structure Narrower QTL intervals (hopefully). Heterozygosity.

  4. DO Founders A B C D E F G H A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/HlLtJ CAST/EiJ PWK/PhJ WSB/EiJ

  5. Mouse Collaborative Cross Brynn Voy

  6. Mouse Collaborative Cross

  7. Mouse Collaborative Cross

  8. Mouse Collaborative Cross http://csbio.unc.edu/CCstatus/index.py

  9. Diversity Outbred Mice Collaborative Cross Funnel Diversity Outbred Mice from 144 different funnels Random Outbreeding

  10. Diversity Outbred Mice

  11. Outline Introduction Genotyping Diversity Outbred Mice Quantitative Trait Locus mapping in DO mice

  12. Overview of Genotyping

  13. MegaMUGA 77,800 markers ~ 33 Kb spacing ~$100 per sample

  14. Output from the MegaMUGA

  15. Genotyping Array Intensities A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/LtJ CAST/EiJ PWK/PhJ WSB/EiJ T T A G

  16. Genotyping Array Intensities A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/LtJ CAST/EiJ PWK/PhJ WSB/EiJ C C A G

  17. Genotyping Array Intensities A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/LtJ CAST/EiJ PWK/PhJ WSB/EiJ C T A G

  18. Complex Allele A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/LtJ CAST/EiJ PWK/PhJ WSB/EiJ

  19. Genotyping Array Intensities T T A C

  20. Genotyping Array Intensities G G A C

  21. Genotyping Array Intensities G T A C

  22. Genotyping Array Intensities G T A C

  23. Genotyping Array Intensities T G A C

  24. Genotyping Array Intensities G T A C

  25. Complex alleles are common A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/HlLtJ CAST/EiJ PWK/PhJ WSB/EiJ

  26. Genotype States Founders DO 36 possible genotype states

  27. Estimating Transition Probabilities • Must be modified by the distance between markers.

  28. Transition Probability Matrix 0 1 2 high low lowest

  29. HMM Overview Estimate genotype probabilities using HMM (assuming genotype means are true) Estimate initial genotype means & covariances using founder/F1 data Update genotype means & covariances (assuming genotypes are true) Repeat until convergence

  30. HMM Example

  31. HMM Example

  32. HMM Example

  33. Genotype Probabilities for one sample (Probs are rounded to single digit)

  34. Reconstructed DO Genome A/J C57BL/6J 129S1/SvImJ NOD/ShiLtJ NZO/HlLtJ CAST/EiJ PWK/PhJ WSB/EiJ

  35. QTL Mapping with Founder Haplotypes • For each sample, we have 36 genotype probabilities at each SNP. • We condense these down to 8 state founder probabilities.

  36. Outline Introduction Genotyping Diversity Outbred Mice Quantitative Trait Locus mapping in DO mice

  37. Kinship

  38. QTL Mapping Example 742 mice DO (410 M & 332F) Constitutive neutrophil counts Fit sex as an additive covariate Incorporate kinship into the model

  39. QTL Mapping

  40. Neutrophil Genome Scan

  41. Neutrophil QTL on Chr 1 High Alleles Low Alleles

  42. Association Mapping Baud et.al, Nat.Gen, 2013

  43. Association Mapping

  44. Acknowledgements Univ. of Wisc., Madison Karl Broman Univ. of Chicago Abraham Palmer Riyan Cheng • The Jackson Laboratory • Gary Churchill • Neal Goodwin • Karen Svenson • Elissa Chesler • Petr Simicek • Churchill Group • UNC-Chapel Hill • Leonard McMillan • Fernando Pardo-Manuel de Villena • Catherine Welsh • Chen-ping Fu

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