Estimated Comparative Integration Hotspots Identify Different Behaviors of Retroviral Gene Transfer Vectors 英文参考文献.docVIP

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Estimated Comparative Integration Hotspots Identify Different Behaviors of Retroviral Gene Transfer Vectors 英文参考文献.doc

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Estimated Comparative Integration Hotspots Identify Different Behaviors of Retroviral Gene Transfer Vectors 英文参考文献

EstimatedComparativeIntegrationHotspotsIdentify DifferentBehaviorsofRetroviralGeneTransferVectors AlessandroAmbrosi1,IngridK.Glad2,DaniloPellin1,ClaudiaCattoglio3,4,FulvioMavilio3,5,CleliaDi Serio1,ArnoldoFrigessi6* 1University Center of Statistics for the Biomedical Sciences, Vita-Salute San Raffaele University, Milan, Italy, 2Department of Mathematics, University of Oslo, Oslo, Norway,3DivisionofGeneticsandCellBiology,IstitutoScientificoH.SanRaffaele,Milan,Italy, 4DepartmentofMolecularandCellBiology,UniversityofCaliforniaat Berkeley, Berkeley, California, United States of America, 5Center for Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy, 6Department of Biostatistics,UniversityofOslo,Oslo,Norway Abstract Integrationofretroviralvectorsinthehumangenomefollowsnonrandompatternsthatfavorinsertionalderegulationof geneexpressionandmaycauserisksofinsertionalmutagenesiswhenusedinclinicalgenetherapy.Understandinghow viralvectorsintegrateintothehumangenomeisakeyissueinpredictingtheserisks.Weprovideanewstatisticalmethod to compare retroviral integration patterns. We identified the positions where vectors derived from the Human ImmunodeficiencyVirus(HIV)andtheMoloneyMurineLeukemiaVirus(MLV)showdifferentintegrationbehaviorsinhuman hematopoieticprogenitorcells.Non-parametricdensityestimationwasusedtoidentifycandidatecomparativehotspots, which were then tested and ranked. We found 100 significative comparative hotspots, distributed throughout the chromosomes.HIVhotspotswerewiderandcontainedmoregenesthanMLVones.AGeneOntologyanalysisofHIVtargets showedenrichmentofgenesinvolvedinantigenprocessingandpresentation,reflectingthehighHIVintegrationfrequency observed at the MHC locus on chromosome 6. Four histone modifications/variants had a different mean density in comparativehotspots(H2AZ,H3K4me1,H3K4me3,H3K9me1),whilegeneexpressionwithinthecomparativehotspotsdid not differ from background. These findings suggest the existence of epigenetic or nu