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Dissecting the regulatory architecture of gene expression QTLs.doc

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Dissecting the regulatory architecture of gene expression QTLs

Gaffneyetal.GenomeBiology2012,13:R7 /2012/13/1/R7 RESEARCH OpenAccess Dissectingtheregulatoryarchitectureofgene expressionQTLs DanielJGaffney1,2,5*,Jean-BaptisteVeyrieras1,JacobFDegner1,RogerPique-Regi1,AthmaAPai1, GregoryECrawford3,MatthewStephens1,4,YoavGilad1andJonathanKPritchard1,2 Abstract Background:Expressionquantitativetraitloci(eQTLs)arelikelytoplayanimportantroleinthegeneticsof complextraits;however,theirfunctionalbasisremainspoorlyunderstood.UsingtheHapMaplymphoblastoidcell lines,wecombine1000Genomesgenotypesandanextensivecatalogueofhumanfunctionalelementsto investigatethebiologicalmechanismsthateQTLsperturb. Results:WeuseaBayesianhierarchicalmodeltoestimatetheenrichmentofeQTLsinawidevarietyofregulatory annotations.Wefindthatapproximately40%ofeQTLsoccurinopenchromatin,andthattheyareparticularly enrichedintranscriptionfactorbindingsites,suggestingthatmanydirectlyimpactprotein-DNAinteractions. AnalysisofcorepromoterregionsshowsthateQTLsalsofrequentlydisruptsomeknowncorepromotermotifsbut, surprisingly,arenotenrichedinotherwell-knownmotifssuchastheTATAbox.Wealsoshowthatinformation fromregulatoryannotationsalone,whenweightedbythehierarchicalmodel,canprovideameaningfulrankingof theSNPsthataremostlikelytodrivegeneexpressionvariation. Conclusions:OurstudydemonstrateshowregulatoryannotationandtheassociationsignalderivedfromeQTL- mappingcanbecombinedintoasingleframework.Weusedthisapproachtofurtherourunderstandingofthe biologythatdriveshumangeneexpressionvariation,andoftheputativelycausalSNPsthatunderlieit. Background PreviousstudieshaveshownthateQTLstendtoclus- Changesingeneexpressionarelikelytoplayimportant ter near the transcription start sites (TSSs) of target roles in adaptive evolution and human disease [1-5]. genes[14,15,17,18];eQTLsmayalsobeenrichedwithin Muchresearchisfocusedonunderstandingexactlyhow thetranscriptregionsofthetargetgenes,inexonsrela- changes in gene expression are encoded at the level of tivetointrons[15],andinconservedregions[