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Find Genes With Small Effect

Find Genes With Small Effect. Association. Genetic Architecture. Very large number of QTLS, each of small effect Complex interactions with other genes and with the environment. QTL Detection Works in Animals. And It Replicates. F2 Analysis. Inbred Strain 1. Inbred Strain 2. F1. F2.

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Find Genes With Small Effect

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  1. Find Genes With Small Effect • Association

  2. Genetic Architecture • Very large number of QTLS, each of small effect • Complex interactions with other genes and with the environment

  3. QTL Detection Works in Animals

  4. And It Replicates

  5. F2 Analysis Inbred Strain 1 Inbred Strain 2 F1 F2

  6. Map the Genes 1. Genotype a few hundred animals 2. Classify animals as heterozygote or homozygote for either allele 3. Associate genotype with phenotype (e.g. ANOVA)

  7. Do It Yourself • Files in F:jonathaf\PhenosAndGenos.xls

  8. Why Is It So Easy? • Simple genetics

  9. Genetic Architecture • Small number of QTLs with relatively large effect • Genetic effect mostly additive • Little evidence for epistasis GO CLONE!

  10. Subsequent Problems • Interpret the phenotype • Find the gene

  11. Mapping Anxiety in Mice • A complex battery of psychological tests

  12. Neophobia

  13. Elevated Plus Maze

  14. All Knock Out Studies Use a Limited Repertoire of Tests

  15. Rats

  16. Shuttle Box

  17. What Happens If You Map a Lot of Tests?

  18. Behavioural Tests • Shuttle box • Open field • Elevated plus maze • Fear conditioning • Acoustic Startle Response

  19. QTLs for Standard Measures of Anxiety

  20. Shuttle Box

  21. Complex Genetics

  22. QTL Cloning • Fine map the locus • Identify some candidates • Find sequence variants

  23. Poor Resolution of QTL Detection Genetic effects are usually mapped to a region of between a quarter and a half the size of a chromosome

  24. Step 1: Fine Mapping • Chromosome dissection • Historical recombination

  25. Congenics

  26. One locus on chromosome 2 influencing seizure susceptibility contains at least three genes

  27. Recombinant Inbreds F2 Brother Sister Mating Recombinant Inbred

  28. Cross Recombinant Inbreds QTL

  29. Recombinant Inbred Segregation Test

  30. Results of RIST C = Homozygote 1 H = Homozygote 2 C/H = Heterozygote Non Significant

  31. Interpret the Test • Where is the QTL? • Does it make a difference if I use a different marker?

  32. Recombinant Inbred Segregation Test

  33. Chromosome Dissection Techniques Don’t Work • A single large QTL almost always turns out to be due to the joint effect of many smaller QTLs

  34. Historical Recombinations F0 F1 F2 F3 F4

  35. Increasing Generations Increases Resolution F2 F6 Sub centimorgan mapping needs about 30 generations of breeding

  36. Two Strains

  37. Genetically Heterogeneous Mice A/J AKR Balb C3H C57 DBA IS RIII HS Random Breeding HS generations >50

  38. Eight Strains

  39. QTL Cloning

  40. Drosophila

  41. Association Tests in Drosophila • If a molecular marker and a site contributing to variationin a quantitative trait (QTN) are physically close to one another, they are likely tobe in linkage disequilibrium. This linkage disequilibrium willresult from the two sites only rarely recombining from one anotherand hence sharing a common evolutionary history Disequilibriumbetween the marker site and QTN can be detected as a significantregression of marker site allelic state on the phenotypic measure Use a permutation-based statisticalapproach for assessing marker/phenotype associations that isrobust with respect to the number of correlated molecular markersused Test for marker/phenotype associations ina number of different genetic backgrounds to increase the powerof detecting significant associations

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