Finding the gene for cystic fibrosis Finding the gene for cystic fibrosis Why is this in quotes A CF is not caused by a gene it s caused by multiple genes B CF is not caused by genetic factors C CF is not caused by a gene it s caused by a mutation How to find genetic determinants of naturally varying traits 1 Genetic markers Genetic markers microsatellite microsatellite Fig 10 3 Fig 10 3 Table 11 1 How do you find polymorphisms Lots of benign variation between us Fig 11 6 2 How do you find polymorphisms How do you find polymorphisms Introduced in lecture 9 15 Fig 11 6 How do you find polymorphisms Fig 11 6 Fig 11 6 How do you find polymorphisms Fig 11 6 3 How do you find polymorphisms Fig 11 6 How do you find polymorphisms Fig 11 6 Hybrid mapping location of probe mouse Hybrid mapping location of probe human mouse hybrid Back then no technique to see 6kb at cytological resolution www3 mdanderson org depts cellab fish1 htm 4 Who cares about benign polymorphisms Who cares about benign polymorphisms Remember Sturtevant We are going to do a twopoint cross One of our genetic loci is represented by phenotype the other is a DNA marker Fig 5 10 Mapping a disease locus Autosomal dom Fig 11 A Mapping a disease locus Autosomal dom phenotype variation in locus 1 A1 A1 A2 A2 Fig 11 A 5 Mapping a disease locus Autosomal dom phenotype variation in locus 1 Mapping a disease locus Autosomal dom phenotype variation in locus 1 A1 A1 A2 A2 marker genotype variation in locus 2 marker genotype variation in locus 2 Fig 11 A How close are they in genetic distance Fig 11 A Mapping a disease locus Mapping a disease locus Autosomal dom A1 A2 D d Autosomal dom A1 A2 D d assume phase Fig 11 A A1 A1 A2 A2 Fig 11 A 6 Mapping a disease locus A1 A2 D d A1 A1 d d Mapping a disease locus A1 A2 D d A1 A1 A1 A1 A2 A2 A2 Fig 11 A D d A1 A1 d d Mapping a disease locus A1 A2 D d A1 A1 A1 A1 A2 A2 A1 Fig 11 A d Fig 11 A Mapping a disease locus A1 A2 d d D A2 d d d Fig 11 A 7 Mapping a disease locus A1 A2 D d A1 A1 d d Mapping a disease locus A1 A2 D d A1 A1 d d sperm A1 A1 A2 A2 Fig 11 A Fig 11 A Mapping a disease locus A1 A2 D d A1 A1 d d Mapping a disease locus A1 A2 D d A1 A1 d d sperm A1 A1 A2 A2 A2 Fig 11 A D In total 7 of the kids are non recombinants and 1 is a recombinant Fig 11 A 8 Mapping a disease locus Mapping a disease locus 1 8 12 5 m u A1 A2 Fig 11 A What is the apparent RF between the DNA marker and the disease mutation A1 In total 7 of the kids are non recombinants and 1 is a recombinant A 1 10 B 1 8 C 1 20 A2 Fig 11 A What is the apparent RF between the DNA marker and the disease mutation In total 7 of the kids are non recombinants and 1 is a recombinant A 1 10 B 1 8 C 1 20 What if True distance 30 cM Diseasecausing mutation Why do I say apparent RF Restriction fragment length polymorphism observed recombination fraction 1 8 12 5 cM 9 What if What if True distance 30 cM Diseasecausing mutation observed recombination fraction 1 8 12 5 cM True distance 30 cM Diseasecausing mutation Restriction fragment length polymorphism You could say this will never happen But What if Restriction fragment length polymorphism observed recombination fraction 1 8 12 5 cM this is our observation 12 cM 18 cM who cares True distance 30 cM Diseasecausing mutation Restriction fragment length polymorphism observed recombination fraction 1 8 12 5 cM Further experiments need to find the causal variant not just a marker If distances are wrong could be hunting for years this is our observation The observed number of recombinants is just a point estimate with some error associated 10 Mapping a disease locus Mapping a disease locus marker known 1 8 12 5 m u 1 8 12 5 m u A1 A1 A2 A2 We now know the mutation is near linked to the marker We now know the mutation is near linked to the marker Mapping a disease locus Mapping a disease locus Fig 11 A marker known 1 8 12 5 m u A1 window containing causative mutation A2 We now know the mutation is near linked to the marker 1 8 12 5 m u A1 A2 How significant 11 Mapping a disease locus If RF 0 5 unlinked would be like flipping a coin 8 times How likely would you be to get 7 heads and 1 tail How much MORE likely is a model of RF 0 5 1 8 12 5 m u A1 A2 How significant If RF 0 5 unlinked would be like flipping a coin 8 times How likely would you be to get 7 heads and 1 tail LOD scores If RF 0 5 unlinked would be like flipping a coin 8 times How likely would you be to get 7 heads and 1 tail r genetic distance between marker and disease locus How much MORE likely is a model of RF 0 5 For large cross between known parents would use 2 to evaluate significance Here we can t 1 recomb 7 non recomb A1 A2 12 LOD scores LOD scores r genetic distance between marker and disease locus r genetic distance between marker and disease locus Odds Odds P pedigree r P pedigree r 0 5 P pedigree r P pedigree r 0 5 1 recomb 7 non recomb How likely are the data given our model 1 recomb 7 non recomb A1 A1 A2 A2 LOD scores LOD scores r genetic distance between marker and disease locus r genetic distance between marker and disease locus Odds Odds P pedigree r P pedigree r 0 5 Odds 1 r n rk 0 5n P pedigree r P pedigree r 0 5 Odds 0 5k 1 r n rk 0 5 total meioses k 1 recomb n 7 non recomb k 1 recomb n 7 non recomb A1 A1 A2 A2 13 Remember LOD scores r genetic distance between marker and disease locus Odds True distance 30 cM P pedigree r Diseasecausing mutation P pedigree r 0 5 Odds 1 r n rk 0 5 total meioses We have an idea of true r but it is imprecise Restriction fragment length polymorphism observed recombination fraction 1 8 12 5 cM this is our observation The observed number of recombinants is just a point estimate with some error associated k 1 recomb n 7 non recomb A1 A2 LOD scores LOD scores r genetic distance between …
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