Modeling the Evolution of Regulatory Elements by Simultaneous Detection and Alignment with Phylogenetic Pair HMMs 英文参考文献.docVIP

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Modeling the Evolution of Regulatory Elements by Simultaneous Detection and Alignment with Phylogenetic Pair HMMs 英文参考文献.doc

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Modeling the Evolution of Regulatory Elements by Simultaneous Detection and Alignment with Phylogenetic Pair HMMs 英文参考文献

ModelingtheEvolutionofRegulatoryElementsby SimultaneousDetectionandAlignmentwith PhylogeneticPairHMMs WilliamH.Majoros1*,UweOhler1,2* 1Institute for Genome Sciences Policy, Duke University, Durham, North Carolina, United States of America, 2Department of Biostatistics Bioinformatics, Duke University,Durham,NorthCarolina,UnitedStatesofAmerica Abstract ThecomputationaldetectionofregulatoryelementsinDNAisadifficultbutimportantproblemimpactingourprogressin understandingthecomplexnatureofeukaryoticgeneregulation.Attemptstoutilizecross-speciesconservationforthistask havebeenhamperedbothbyevolutionarychangesoffunctionalsitesandpoorperformanceofgeneral-purposealignment programs when applied to non-coding sequence. We describe a new and flexible framework for modeling binding site evolutioninmultiplerelatedgenomes,basedonphylogeneticpairhiddenMarkovmodelswhichexplicitlymodelthegain and loss of binding sites along a phylogeny. We demonstrate the value of this framework for both the alignment of regulatoryregionsandtheinferenceofprecisebinding-sitelocationswithinthoseregions.Astheunderlyingformalismisa stochastic,generativemodel,itcanalsobeusedtosimulatetheevolutionofregulatoryelements.Ourimplementationis scalableintermsofnumbersofspeciesandsequencelengthsandcanproducealignmentsandbinding-sitepredictions withaccuracyrivalingorexceedingcurrentsystemsthatspecializeinonlyalignmentoronlybinding-siteprediction.We demonstratethevalidityandpowerofvariousmodelcomponentsonextensivesimulationsofrealisticsequencedataand applyaspecificmodeltostudyDrosophilaenhancersinasmanyastenrelatedgenomesandinthepresenceofgainand lossofbindingsites.Differentmodelsandmodelingassumptionscanbeeasilyspecified,thusprovidinganinvaluabletool for the exploration of biological hypotheses that can drive improvements in our understanding of the mechanisms and evolutionofgeneregulation. Citation: Majoros WH, Ohler U (2010) Modeling the Evolution of Regulatory Elements by Simultaneous Detection and Alignment w