Office hours 304A Stanley Hall next week 3 4pm Monday Nov 24 Heritability in exptal organisms Genetically identical Genetically different Heritability in exptal organisms e t Genetic variance total var environmental var g t e Heritability H2 g t http www sciam com media inline 15DD5B0E AB4123B8 2B1E53E8573428C5 1 jpg http www twinsrealm com othrpics twins16 jpg http www twinsrealm com othr pics sarahandsandra jpg http www twinsinsurance net images twins jpg Heritability in humans MZ twins Mean each pair zi Each individual zij Total mean sq zij z 2 T Within pairs mean sq zij zi 2 N Between pairs mean sq zi z 2 N 1 t2 w2 b 2 h2 b2 w2 t2 mRNA expression Significance of heritability all progeny P1 P2 progeny marker genotype P1 progeny marker genotype P2 How to find genetic determinants of naturally varying traits Thus far we have only found linkage to a marker The causal variant is still unknown Mapping imprecision wide mapped interval Mapping imprecision wide mapped interval You should now know from the first problem set why the LOD score is highest for markers close to the causal variant locus Mapping imprecision wide mapped interval But why not just look at the single marker with the best LOD score Single best locus isn t the answer True distance 30 cM Diseasecausing mutation 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 True variant is under peak Fig 11 17 Submergence tolerance in rice Variation in submergence tolerance QuickTime and a TIFF Uncompressed decompressor are needed to see this picture http www a2mediagroup com data images news categories riceplant jpg Linkage mapping ime and a ssed decompressor o see this picture intolerant tolerant Finding the causative variant Finding the causative variant QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Finding the causative variant QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Transgenic test QuickTime and a TIFF Uncompressed decompressor are needed to see this picture http www plantsci cam ac uk Haseloff SITEGRAPHICS Agrotrans GIF Transgenic test From Prof Garriga problem set QuickTime and a TIFF Uncompressed decompressor are needed to see this picture http www plantsci cam ac uk Haseloff SITEGRAPHICS Agrotrans GIF Transgenic test QuickTime and a Uncompressed decompressor needed to see this picture Time and a essed decompressor to see this picture Transgenic test Time and a essed decompressor to see this picture Transgenic test Only expressed upon submergence Time and a essed decompressor to see this picture Transgenic test Expressed all the time Now in a real crop strain Swarna INTOL x IR49830 TOL F1 x Swarna INTOL Check for Sub1A Now in a real crop strain Swarna INTOL x IR49830 TOL F1 x Swarna INTOL B1 x Swarna INTOL Check for Sub1A Now in a real crop strain Swarna INTOL x IR49830 TOL F1 x Swarna INTOL B1 x Swarna INTOL B2 x Swarna INTOL Now in a real crop strain Swarna INTOL x IR49830 TOL F1 x Swarna INTOL B1 x Swarna INTOL B2 x Swarna INTOL Result Sub1A in Swarna genome Common in plant breeding Wild resistant to fungus Cultivated bred for yield etc QuickTime and a TIFF Uncompressed decompressor are needed to see this picture http www anbg gov au cpbr program sc barl mole htm Naturally genetically modified QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Every linkage study faces this problem What is the causative variant linked to the marker How to formulate a guess How to formulate a guess Here a very obvious hypothesis Often not such a large gain or loss QuickTime and a TIFF Uncompressed decompressor Fine mapping Fig 11 17 Fine mapping new markers Fig 11 17 Fine mapping new markers Between two humans 1 polymorphism every 1000 bp linkage study probably started with a tiny fraction of total Fine mapping new markers Position of true causal variant A simulation of a qualitative trait in a large mouse cross sparse marker set Best marker Fine mapping new markers Position of true causal variant Peak looks pretty close why bother improving resolution Best marker Fine mapping new markers Position of true causal variant Because you have to hunt through by hand to find the causal gene and test experimentally The smaller the region the better Best marker Fine mapping new markers Position of true causal variant Increased marker density Fine mapping new markers Position of true causal variant Why did the LOD score go up A More markers increases multiple testing which boosts LODs in the region B Closer markers have more significant linkage increasing their LODs C Peak is narrower so LODs increase in the region D The LOD score scales with the number of markers so actually it isn t different if you normalize correctly What do functional e g disease causing variants look like Rearrangements large gain and loss QuickTime and a TIFF Uncompressed decompressor are needed to see this picture Rearrangements large gain and loss Coding variants Fig 7 25 http homepages strath ac uk dfs99109 BB310 CFTRgene jpg Coding variants Fig 2B http homepages strath ac uk dfs99109 BB310 CFTRgene jpg Coding variants New amino acid Fig 2B http homepages strath ac uk dfs99109 BB310 CFTRgene jpg Coding variants Premature STOP Fig 2B http homepages strath ac uk dfs99109 BB310 CFTRgene jpg Coding variants Regulatory change not coding Fig 2B http graphics jsonline com graphi cs badger img may02 5martin506 j pg Nucleotide repeat diseases Fig 11 13 http geneticsmodules duhs duke edu Design Print asp Nucleotide repeat diseases Fig 7A B Think about it most identified variants are rare alleles with strong effect Most likely to be coding changes Old school Promoter variants Fig 9 22 Promoter variants Fig 9 22 Promoter mutations can cause misregulation and disease phenotype Promoter variants DOC Promoter variants Subtle single nucleotide promoter variants probably very common but hard to find Stay tuned DOC
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