Discovering Transcription Factor Binding Sites in Highly Repetitive Regions of Genomes with Multi-Read Analysis of ChIP-Seq Data 英文参考文献.docVIP

DiscoveringTranscriptionFactorBindingSitesinHighly RepetitiveRegionsofGenomeswithMulti-ReadAnalysis ofChIP-SeqData DongjunChung1,2,PeiFenKuan3,BoLi4,RajendranSanalkumar5,KunLiang1,2,EmeryH.Bresnick5, ColinDewey2,4,Su¨ndu¨zKeles1,2 * 1Department ofStatistics,UniversityofWisconsin,Madison,Wisconsin, UnitedStatesofAmerica, 2Department ofBiostatisticsandMedicalInformatics, Universityof Wisconsin,Madison,Wisconsin,UnitedStatesofAmerica,3DepartmentofBiostatistics,UniversityofNorthCarolina,ChapelHill,NorthCarolina,UnitedStatesofAmerica, 4Department ofComputerSciences,UniversityofWisconsin,Madison,Wisconsin,UnitedStatesofAmerica, 5WisconsinInstitutesforMedicalResearch,UWCarbone CancerCenter,DepartmentofCellandRegenerativeBiology,UniversityofWisconsinSchoolofMedicineandPublicHealth,Madison,Wisconsin,UnitedStatesofAmerica Abstract Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is rapidly replacing chromatin immunoprecipitationcombinedwithgenome-widetilingarrayanalysis(ChIP-chip)asthepreferredapproachformapping transcription-factor binding sites and chromatin modifications. The state of the art for analyzing ChIP-seq data relies on usingonlyreadsthatmapuniquelytoarelevantreferencegenome(uni-reads).Thiscanleadtotheomissionofupto30% of alignable reads. We describe a general approach for utilizing reads that map to multiple locations on the reference genome (multi-reads). Our approach is based on allocating multi-reads as fractional counts using a weighted alignment scheme. Using human STAT1 and mouse GATA1 ChIP-seq datasets, we illustrate that incorporation of multi-reads significantlyincreasessequencingdepths,leadstodetectionofnovelpeaksthatarenototherwiseidentifiablewithuni- reads,andimprovesdetectionofpeaksinmappableregions.Weinvestigatevariousgenome-widecharacteristicsofpeaks detected only by utilization of multi-reads via computational experiments. Overall, peaks from multi-read analysis have similar characteristics to peaks th