Genome-Wide Association between Branch Point Properties and Alternative Splicing 英文参考文献.docVIP

Genome-WideAssociationbetweenBranchPoint PropertiesandAlternativeSplicing Andre′ Corvelo1,2,MartinaHallegger3,ChristopherW.J.Smith3,EduardoEyras1,4* 1Computational Genomics, Universitat Pompeu Fabra, Barcelona, Spain, 2Graduate Program in Areas of Basic and Applied Biology, Universidade do Porto, Porto, Portugal,3DepartmentofBiochemistry,UniversityofCambridge,Cambridge,UnitedKingdom,4CatalanInstitutionforResearchandAdvancedStudies,Barcelona,Spain Abstract Thebranchpoint(BP)isoneofthethreeobligatorysignalsrequiredforpre-mRNAsplicing.Inmammals,thedegeneracyof themotifcombinedwiththelackofalargesetofexperimentallyverifiedBPscomplicatesthetaskofmodelingitinsilico, andthereforeofpredictingthelocationofnaturalBPs.Consequently,BPshavebeendisregardedinaconsiderablefraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreementwithU2snRNAbindingstability.UsingaSupportVectorMachinealgorithm,wecreatedamodelcomplemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods.Applyingouralgorithmtohumanintrons,weshowthatBPpositionishighlydependentonthepresenceofAG dinucleotidesinthe39endofintrons,withdistancetothe39splicesiteandBPstrengthstronglycorrelatingwithalternative splicing.Furthermore,experimentalBPmappingforfiveexonsprecededbylongAG-dinucleotideexclusionzonesrevealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previouslyassumed,anditappearshighlydependentonthepresenceofdownstreampolypyrimidinetracts.Thereported associationbetweenBPfe