How to find genetic determinants of naturally varying traits Mapping a disease locus Autosomal dom phenotype variation in locus 1 A1 A2 marker genotype variation in locus 2 Fig 11 A Mapping a disease locus A1 A2 D d A1 A1 A1 A2 A2 Fig 11 A d d d Mapping a disease locus A1 A2 D d A1 A1 A1 A2 A1 Fig 11 A D d d Mapping a disease locus A1 A2 D d A1 A1 sperm A1 A2 A2 Fig 11 A D d d LOD scores r 0 1 0 2 0 3 0 4 0 5 odds 12 244 10 737 6 325 2 867 1 Odds P pedigree r P pedigree r 0 5 Odds 1 r n rk 0 5 total meioses A computational search through many r values observed RF is single best estimate 1 8 0 125 A computational search through many r values observed RF is single best estimate 1 8 0 125 But we already knew that What s the point More realistic situation in dad phase of alleles unknown A1 A2 D d or A1 A2 A1 A1 d D A1 A2 d d Dad phase unknown P pedigree r Odds 1 2 1 r n rk 1 2 1 r n rk assume one phase for dad A1 D A2 d 7 non recomb 1 recomb k recomb n non recomb A1 A2 Dad phase unknown P pedigree r Odds 1 2 1 r n rk 1 2 1 r n rk assume the other phase for dad A1 d A2 D 1 non recomb 7 recomb A1 A2 Dad phase unknown P pedigree r Odds 1 2 1 r n rk 1 2 1 r n rk Odds 1 2 1 r 7 r1 1 2 1 r 1 r7 A1 A2 Dad phase unknown oddsOdds ratio 1 2 1 r n rk 1 2 1 r n rk 0 5 total meioses A1 A2 1 2 P pedigree r phase 1 1 2 P pedigree r phase 2 Dad phase unknown oddsOdds ratio 1 2 1 r n rk 1 2 1 r n rk 0 5 total meioses Now there are two k s one for each phase We could ask for observed r would be 1 8 or 7 8 A1 A2 Dad phase unknown oddsOdds ratio 1 2 1 r n rk 1 2 1 r n rk 0 5 total meioses Now there are two k s one for each phase We could ask for observed r would be 1 8 or 7 8 What single r value best explains the data A1 A2 Now you really need the computational search maximum likelihood r 0 13 Now you really need the computational search maximum likelihood r 0 13 between the observed r s 1 8 and 7 8 Maximization method was invented to map mammalian diseases in complex pedigrees Cystic fibrosis mapping 1985 Cystic fibrosis mapping 1985 What does this mean Arylesterase activity Cystic fibrosis mapping 1985 homozyg low homozyg high Paraoxonase activity Metabolizes insecticide Cystic fibrosis mapping 1985 Cystic fibrosis mapping 1985 via somatic cell hybrid mapping Cystic fibrosis mapping 1985 Cystic fibrosis mapping 1985 Best model is r 0 what does this mean Cystic fibrosis mapping 1985 Fig 5A How did they get 27 kids Combining families 1 2 2 3 2 3 1 2 2 3 1 3 1 2 2 3 1 2 1 2 1 3 1 3 2 3 1 3 1 3 2 3 1 3 1 2 2 3 2 3 2 2 2 2 Combining families 1 2 2 3 1 2 Given r 2 3 Given r Odds1 2 3 1 2 2 3 1 3 1 2 1 3 1 2 1 3 2 3 1 3 1 3 2 3 1 3 1 2 2 3 Odds2 Given r Odds3 2 3 2 2 2 2 Combining families 1 2 2 3 1 2 Given r 2 3 Given r Odds1 2 3 1 2 2 3 1 3 1 2 1 3 How to get an overall estimate of probability of linkage A Multiply odds together B Add odds together C Take the largest odds D Take the average odds 1 2 1 3 2 3 1 3 1 3 2 3 1 3 1 2 2 3 Odds2 Given r Odds3 2 3 2 2 2 2 How do you know which marker to test Modern genetic scans Modern genetic scans Fig 11 17 Modern genetic scans Genotype 1000 s of markers for each individual test each marker at various r s across all individuals Fig 11 17 Modern genetic scans Genotype 1000 s of markers for each individual test each marker at various r s across all individuals Fig 11 17 Modern genetic scans single family QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Modern genetic scans single family QuickTime and a TIFF Uncompressed decompressor are needed to see this picture QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Modern genetic scans single family QuickTime and a TIFF Uncompressed decompressor are needed to see this picture What does the max in max LOD score refer to A The strongest linking marker B The most probable recombination fraction C The most severe phenotype Remember maximum likelihood r 0 13 Modern genetic scans r 0 1 0 2 0 3 0 4 0 5 odds 12 244 10 737 6 325 2 867 1 Max LOD score is the one from the best r value Modern genetic scans single family QuickTime and a TIFF Uncompressed decompressor are needed to see this picture What is the simplest explanation for so many tall black lines around Chr 13 A Multiple markers in the region which makes LOD higher B Multiple markers are all linked to a single disease mutation C Multiple mutations on Chr 13 cause the disease D Higher LOD is counted by the number of linking markers Modern genetic scans single family QuickTime and a TIFF Uncompressed decompressor are needed to see this picture What is the simplest explanation for so many tall black lines around Chr 13 A Multiple markers in the region which makes LOD higher B Multiple markers are all linked to a single disease mutation C Multiple mutations on Chr 13 cause the disease D Higher LOD is counted by the number of linking markers Modern genetic scans 22 families Modern genetic scans 22 families Smooth curve inferred genotype at positions between markers Modern genetic scans Fit model twice 22 families But 779 small families or sib pairs Why would an experiment fail to observe linkage Marker density matters Try to minimize genotyping cost But if the only marker you test is 50 cM away will get no linkage Number of families matters If low number of patients no statistical significance Tune in next lecture for more about this Improper statistics Can make noise look like a fabulously significant linkage peak Locus heterogeneity Fig 3 16 Locus heterogeneity Fig 3 16 Age of onset in breast cancer Age of onset in breast cancer age of …
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