Harnessing a High Cargo-Capacity Transposon for Genetic Applications in Vertebrates 英文参考文献.docVIP

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Harnessing a High Cargo-Capacity Transposon for Genetic Applications in Vertebrates 英文参考文献.doc

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Harnessing a High Cargo-Capacity Transposon for Genetic Applications in Vertebrates 英文参考文献

HarnessingaHighCargo-CapacityTransposon forGeneticApplicationsinVertebrates Darius Balciunas1,2,Kirk J.Wangensteen1,3[,Andrew Wilber1,4[,Jason Bell1,Aron Geurts1,2,5,Sridhar Sivasubbu1,2 Xin Wang1,6,Perry B.Hackett1,2,4,6,David A.Largaespada1,2,5,R.Scott McIvor1,2,4,5,Stephen C.Ekker1,2,3,5,6* , 1TheArnoldandMabelBeckmanCenterforTransposonResearch,InstituteofHumanGenetics,UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesofAmerica, 2 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America, 3 Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America, 4 Gene Therapy Program, University of Minnesota, Minneapolis, Minnesota, United States of America, 5 Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America, 6 Stem Cell Institute, UniversityofMinnesota,Minneapolis,Minnesota,UnitedStatesofAmerica Viruses and transposons are efficient tools for permanently delivering foreign DNA into vertebrate genomes but exhibitdiminishedactivitywhencargoexceeds8kilobases(kb).Thissizerestrictionlimitstheirmoleculargeneticand biotechnological utility, such as numerous therapeutically relevant genes that exceed 8 kb in size. Furthermore, a greaterpayloadcapacityvectorwouldaccommodatemoresophisticatedciscargodesignstomodulatetheexpression andmutagenicriskofthesemoleculartherapeutics.WeshowthattheTol2transposoncanefficientlyintegrateDNA sequences larger than 10 kb into human cells. We characterize minimal sequences necessary for transposition (miniTol2) in vivo in zebrafish and in vitro in human cells. Both the 8.5-kb Tol2 transposon and 5.8-kb miniTol2 engineeredelementsreadilyfunctiontorevertthedeficiencyoffumarylacetoacetatehydrolaseinananimalmodelof hereditary tyrosinemia type 1. Together, Tol2 provides a novel nonviral vector for the delivery of large genetic payloadsforgenetherapyandothe