PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Thus far, we have only found linkage to a marker. The causal variant is still unknown.Mapping imprecisionSlide 9Slide 10Single best locus isn’t the answerTrue variant is “under” peakSubmergence tolerance in riceVariation in submergence toleranceLinkage mappingFinding the causative variantSlide 17Slide 18Transgenic testSlide 20Slide 21Slide 22Slide 23Slide 24Now in a real crop strainSlide 26Slide 27Slide 28Common in plant breeding“Naturally genetically modified”Every linkage study faces this problemHow to formulate a guess?Slide 33Fine-mappingFine-mapping: new markersSlide 36Slide 37Slide 38Slide 39Slide 40Slide 41What do functional (e.g. disease-causing) variants look like?Rearrangements/large gain and lossSlide 44Coding variantsSlide 46Slide 47Slide 48Slide 49Nucleotide repeat diseasesSlide 51Think about it: most identified variants are rare alleles with strong effect. Most likely to be coding changes.Old schoolPromoter variantsSlide 55Slide 56Slide 57Office hours304A Stanley Hallnext week 3-4pm Monday Nov 24Genetically identicalGenetically differentHeritability in exptal organismsHeritability in exptal organismsGenetic variance = total var - “environmental var”Heritability H2 = etg = t - eg/tHeritability in humans: MZ twinshttp://www.sciam.com/media/inline/15DD5B0E-AB41-23B8-2B1E53E8573428C5_1.jpghttp://www.twinsinsurance.net/images/twins.jpghttp://www.twinsrealm.com/othrpics/sarahandsandra.jpghttp://www.twinsrealm.com/othrpics/twins16.jpgEach individual = zij Total mean sq = (zij - z)2TMean each pair = zi Within pairs mean sq = (zij - zi)2NBetween pairs mean sq = (zi - z)2N-1= b2= w2= t2h2 = b2w2t2Significance of heritability?mRNA expressionall progenyP1 P2progeny, marker genotype P1progeny, marker genotype P2How 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 imprecisionwide mapped intervalMapping imprecisionwide mapped intervalYou should now know from the first problem set why the LOD score is highest for markers close to the causal variant locus…Mapping imprecisionwide mapped intervalBut why not just look at the single marker with the best LOD score?Single best locus isn’t the answerobserved recombination fraction = 1/8 = 12.5 cMDisease-causing mutationRestriction fragment length polymorphismTrue distance 30 cMThe observed number of recombinants is just a point estimate, with some error associated. this is our observationTrue variant is “under” peakFig. 11.17Submergence tolerance in riceVariation in submergence toleranceQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.http://www.a2mediagroup.com/data/images/news/categories/riceplant.jpgLinkage mappingQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.intolerant tolerantFinding the causative variantFinding the causative variantQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Finding the causative variantQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Transgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.http://www.plantsci.cam.ac.uk/Haseloff/SITEGRAPHICS/Agrotrans.GIFTransgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.http://www.plantsci.cam.ac.uk/Haseloff/SITEGRAPHICS/Agrotrans.GIFFrom Prof. Garriga problem setTransgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Transgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Transgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Only expressed upon submergenceTransgenic testQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Expressed all the time…Now in a real crop strainSwarna INTOL x IR49830 TOLF1x Swarna INTOLCheck for Sub1A+Now in a real crop strainSwarna INTOL x IR49830 TOLF1x Swarna INTOLB1x Swarna INTOLCheck for Sub1A+Now in a real crop strainSwarna INTOL x IR49830 TOLF1x Swarna INTOLB1x Swarna INTOLB2x Swarna INTOL…Now in a real crop strainSwarna INTOL x IR49830 TOLF1x Swarna INTOLB1x Swarna INTOLB2x Swarna INTOL…Result: Sub1A in Swarna genomeCommon in plant breedingQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.http://www.anbg.gov.au/cpbr/program/sc/barl_mole.htmWild: resistant to fungusCultivated: bred for yield, etc.“Naturally genetically modified”QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Every linkage study faces this problemWhat is the causative variant linked to the marker?How to formulate a guess?How to formulate a guess?QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Here a very obvious hypothesis. Often not such a large gain or loss.Fine-mappingFig. 11.17Fine-mapping: new markersFig. 11.17Fine-mapping: new markersBetween two humans, 1 polymorphism every 1000 bp; linkage study probably started with a tiny fraction of total.Fine-mapping: new markersBest markerPosition of true causal variantA simulation of a qualitative trait in a large mouse cross; sparse marker setFine-mapping: new markersBest markerPosition of true causal variantPeak looks pretty close—why bother improving resolution?Fine-mapping: new markersBest markerPosition of true causal variantBecause you have to hunt through by hand to find the causal gene, and test experimentally. The smaller the region, the better.Fine-mapping: new markersPosition of true causal variantIncreased marker densityFine-mapping: new markersWhy did the LOD score go up?Position of true causal variantA. 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?QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.Rearrangements/large gain and lossRearrangements/large gain and lossCoding variantsFig. 7.25Coding
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