Dad phase unknown 2050 VLSB oddsOdds ratio 1 2 1 r n rk 1 2 1 r n rk 0 5 total meioses What single r value best explains the data A1 D A2 d or A1 A2 d D A1 A2 For this you need to search r s maximum likelihood r 0 13 Oops a numerical mistake thanks to Jonathan for detective work In real life this correction does matter family 1 10 meioses 1 or 9 apparent recombinants family 2 10 meioses 4 or 6 apparent recombinants family 3 10 meioses 3 or 7 apparent recombinants family 4 10 meioses 3 or 7 apparent recombinants total LOD LOD family 1 LOD family 2 LOD family 3 LOD family 4 Using only one phase best r 0 2771 Accounting for both phases best r 0 2873 1 Locus heterogeneity Coins age of onset r intrinsic probability of coming up heads bias Odds P your flips r P your flips r 0 5 Odds 1 r n rk 0 5 total flips Odds ratio of model that coin is biased relative to null Significance cutoff Coins r intrinsic probability of coming up heads bias single family 0 heads 1 heads 2 heads 3 heads 4 heads r odds r odds r odds r odds r odds 0 16 0 0 0 0 0 0 0 0 0 1 10 498 0 1 1 1664 0 1 0 1296 0 1 0 0144 0 1 0 0016 0 2 6 5536 0 2 1 6384 0 2 0 4096 0 2 0 1024 0 2 0 0256 0 3 3 8416 0 3 1 6464 0 3 0 7056 0 3 0 3024 0 3 0 1296 0 4 2 0736 0 4 1 3824 0 4 0 9216 0 4 0 6144 0 4 0 4096 0 5 1 0 5 1 0 5 1 0 5 1 0 5 1 0 6 0 4096 0 6 0 6144 0 6 0 9216 0 6 1 3824 0 6 2 0736 0 7 0 1296 0 7 0 3024 0 7 0 7056 0 7 1 6464 0 7 3 8416 0 8 0 0256 0 8 0 1024 0 8 0 4096 0 8 1 6384 0 8 6 5536 0 9 0 0016 0 9 0 0144 0 9 0 1296 0 9 1 1664 0 9 10 498 1 0 1 0 1 0 1 0 1 16 2 The analogy again The analogy again Testing lots of markers for linkage to a trait is analogous to having lots of students each flipping a coin Testing lots of markers for linkage to a trait is analogous to having lots of students each flipping a coin The search for the coin s bias parameter is analogous to the search for recombination distance between markers and disease locus The search for the coin s bias parameter is analogous to the search for recombination distance between markers and disease locus Each student is analogous to a marker The analogy again Testing lots of markers for linkage to a trait is analogous to having lots of students each flipping a coin The search for the coin s bias parameter is analogous to the search for recombination distance between markers and disease locus Each student is analogous to a marker Each coin flip is analogous to a family member in pedigree Multiple testing shown another way 1 Simulate thousands of markers inherited from parents to progeny 2 Assign some family members to have a disease others not 3 Test for linkage between disease and markers knowing there is none E Lander and L Kruglyak Nature Genetics 11 241 1995 3 Simulation Simulation Every marker is analogous to a student flipping A real world scenario Simulation theory You have invested a bolus of research money in a linkage mapping study of a genetic disease segregating in families For each family member you do genotyping at a bunch of markers When you finally run the linkage calculation the strongest marker gives a LOD of 2 You desperately want to believe this is significant You simulate a fake trait with no genetic control 1000 times You find that in 433 of these simulations the fake trait had a LOD 2 This means that in your real data the probability of your precious linkage peak being a false positive is 433 1000 0 433 If you spent more money and time to follow this up it could be a complete waste Essential to know 4 Simulation theory Simulate 1000 times ask how frequently you get a peak over a certain threshold Simulation theory With modest marker spacing in a human study LOD of 3 is 9 likely to be a false positive Simulation theory But this would change in a different organism with different number of markers etc Simulation theory But this would change in a different organism with different number of markers etc So in practice everyone does their own simulation specific to their own study 5 More markers more tests more chance for spurious high linkage score More markers more tests more chance for spurious high linkage score Not true when you add individuals patients Always improves results Multiple testing in genetics Multiple markers not necessary Marker density matters But if the only marker you test is 50 cM away will get no linkage 6 But if the only marker you test is 50 cM away will get no linkage So a mapping experiment is a delicate balance between too much testing and not enough Candidate gene approach apple pigment Candidate gene approach apple pigment http waynesword palomar edu images apple3b jpg Marker density matters Candidate gene approach Hypothesize that causal variant will be in known pigment gene or regulator NOT randomly chosen markers genome wide 7 Candidate gene approach Candidate gene approach Red progeny have RFLP pattern like red parent Candidate gene approach But if you can beat multiple testing why not do the whole genome Unpigmented progeny have RFLP pattern like unpigmented parent 8 Back to week 4 Testing for linkage doesn t always mean counting recombinants Fig 3 12 Qualitative but polygenic A simulated cross test one locus AAbb aaBB AaBb inter mate Two loci Need one dominant allele at each locus to get phenotype Flower color Two loci Fig 3 12 Need one dominant allele at each locus to get phenotype Genotype at marker close to A locus 9 A simulated cross test one locus AAbb A simulated cross test one locus AAbb aaBB AaBb AABb AaBb aaBb aaBB inter mate AaBB aaBB AaBb inter mate Two loci Two loci Need one dominant allele at each locus to get phenotype Need one dominant allele at each locus to get phenotype Aabb AABb AaBb Flower color aaBb AaBB aaBB Aabb Flower color Genotype at marker close to A locus Genotype at marker close to A locus A simulated cross test one locus No need to count recombinants AAbb AAbb aaBB AaBb AABb AaBb aaBb aaBB inter mate AaBB aaBB AaBb Two loci Two loci Need one dominant allele at each locus to get phenotype Need one dominant allele at each …
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