1Heritability 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 = zijTotal mean sq = Σ Σ(zij - z)2TMean each pair = ziWithin pairs mean sq = Σ Σ(zij - zi)2NBetween pairs mean sq = 2 Σ(zi - z)2N-1= σb2= σw2= σt2h2 = σb2 − σw2σt2NO progeny as extreme as diploid hybridThree mutant genesFrom pathogenic strainFrom pathogenic strainFrom pathogenic strainAlleles from thesame strain atdifferent genes/locican have differenteffects.Linked mutations of opposite effectPathLabVery unlikelyLab parent Pathogenic parentWhy is distribution of progeny so skewed?Diploid hybridWhy is distribution of progeny so skewed?Hypothesis:interaction betweenloci (see problemset)2Golden mutationFine-mappingInject into golden larvae85 kbslc24a5 mRNANo truncation in humans, but…No other species have the Thr allele: what does this mean?Could be deleterious, just an accidental mutation.Could be advantageous for some humans, no other species.Correlates with human differencesAAAGGGNote that this isnot linkageanalysis.Individuals areunrelated.Genetic association studiesWhat is a haplotype?Fig. 11.253What is a haplotype?Fig. 11.25What is a haplotype?Fig. 11.25What is a haplotype?Fig. 11.25What is a haplotype?Fig. 11.25Fig. 11.26Association mapping (qualitative)Fig. 11.26Association mapping (qualitative)4Fig. 11.26Association mapping (qualitative)Fig. 11.26Association mapping (qualitative)Fig. 11.26Association mapping (qualitative)Association mapping (qualitative)Fig. 11.26Only have markers, not true underlyingdisease mutation (duh)Linkage disequilibriumLinkage disequilibriumMarker allelesappear togetherin diseasepopulation morethan you wouldexpect5In association, we don’tcalculate a recombinationfraction; we aren’t countingrecombinants.Association mapping (qualitative)In association, we don’tcalculate a recombinationfraction; we aren’t countingrecombinants. Eachindividual could represent adifferent number ofgenerations (and recomb)since mutation arose.Association mapping (qualitative)The association revolutionGet markers by (re-)sequencingAssociation scan, qualitative43347G’s797141C’scontrolsosteoarthritisχ2 testFine-mapping-log(χ2 p-value)rs3774726Beginnings of molecular confirmationBeginnings of molecular confirmationcodingpolymorphismsAnother example: qualitativehttp://www.encyclopedia.com/topic/myasthenia_gravis.a spxAnother example: qualitativeEarly onsetAnother example: qualitativeNormal onsetA promoter SNP (at last)7AAAGGGQuantitative test for associationhttp://w ww.nature.co m/nrg/journal /v7/n10/full/n rg1916.htmlAssociation scan, quantitativeRice yield: start with linkageNipponbare x KasalathF1F2Narrow down by backcrossTransgenic testAssociation across 100cultivars (quant)8Association across 100cultivars (quant)Conclude thatthese alleles arecommon acrossmany cultivars, notjust in linkagecross.Association vs. linkageAssociation vs. linkageUnrelatedindividuals (usually)RelatedindividualsAssociation vs. linkageUnrelatedindividuals (usually)RelatedindividualsExtreme of linkage study is one large family; lesslikely that phenotype has multiple genetic causes(locus heterogeneity).Association vs. linkageStrong, easy to detectUnrelatedindividualsRelatedindividualsAssociation vs. linkageStrong, easy to detect,but rare in populationUnrelatedindividualsRelatedindividuals9Association vs. linkageStrong, easy to detect,but rare in population;may not be reflective ofcommon disease.UnrelatedindividualsRelatedindividualsAssociation vs. linkageStrong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.UnrelatedindividualsRelatedindividualsAssociation vs. linkageStrong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.Common but weakeffectsUnrelatedindividualsRelatedindividualsAssociation vs. linkageStrong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.Common but weakeffects; need 1000’sof samples to detectUnrelatedindividualsRelatedindividualsAssociation vs. linkageStrong, easy to detect,but rare in population;may not be reflective ofcommon disease.Also, hard to collect familydata.Common but weakeffects; need 1000’sof samples to detect.If no common cause,can fail.UnrelatedindividualsRelatedindividualsAnother key feature ofassociation mapping:resolution10Association vs. linkagemanyrecombinationshave happenedsince commonancestor;shared regionis small; nosignal fordistant markersAssociation vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can getsignal atdistantmarkersmanyrecombinationshave happenedsince commonancestor;shared regionis small; nosignal fordistant markersAssociation vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can getsignal atdistantmarkersmanyrecombinationshave happenedsince commonancestor;shared regionis small; nosignal fordistant markersSo you need very high densityof markers to get signal in anassociation study, but you getvery high spatial resolution.Association vs. linkagesmallnumber ofgenerations;individualsshare bigchunks ofgenome;can getsignal atdistantmarkersmanyrecombinationshave happenedsince commonancestor;shared regionis small; nosignal fordistant markersIn the “old days” of sparsemarkers, linkage analysis wasthe best strategy.But there is a pitfall ofassociation tests: “populationstructure”Diabetes in Native Americans11(1971)Diabetes in Native Americans(1971)Family studiesindicate it is atleast partlygenetic, notenvironmental.Diabetes in Native AmericansAssociation mapping causal lociTyped IgG heavy chains with protein assay.Phenotypes can serve as markers too…Association mapping causal lociTyped IgG heavy chains with protein assay.Phenotypes can serve as markers too…(Multiple proteins from chr 14 region: haplotype)Association mapping causal loci32841343no Gm27023GmcontroldiabetesAssociation mapping causal loci1232841343no Gm27023GmcontroldiabetesAssociation mapping causal loci32841343no Gm27023GmcontroldiabetesAssociation mapping causal loci“Gm is protective against diabetes?”Association mapping causal lociSelf-identified heritageSelf-identified heritageMost “full heritage”members don’t havethe
View Full Document
Unlocking...