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Exogenous enzymes upgrade transgenesis and genetic engineering of farm animals

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Abstract

Transgenic farm animals are attractive alternative mammalian models to rodents for the study of developmental, genetic, reproductive and disease-related biological questions, as well for the production of recombinant proteins, or the assessment of xenotransplants for human patients. Until recently, the ability to generate transgenic farm animals relied on methods of passive transgenesis. In recent years, significant improvements have been made to introduce and apply active techniques of transgenesis and genetic engineering in these species. These new approaches dramatically enhance the ease and speed with which livestock species can be genetically modified, and allow to performing precise genetic modifications. This paper provides a synopsis of enzyme-mediated genetic engineering in livestock species covering the early attempts employing naturally occurring DNA-modifying proteins to recent approaches working with tailored enzymatic systems.

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Abbreviations

Cas9:

CRISPR-associated protein 9

CPI:

Cytoplasmic injection

Ct:

Chromatin transfer

CRISPR:

Clustered regularly interspaced short palindromic repeats

DSB:

Double-strand break

GOI:

Gene of interest

HR:

Homologous recombination

HDR:

Homology-directed repair

ICSI:

Intracytoplasmic sperm injection

ICSI-Tr:

Intracytoplasmic sperm injection-mediated transgenesis

iPS:

Induced pluripotent stem (cell)

I-SceI:

Homing endonuclease

ITR:

Inverted terminal repeat

KO:

Knockout

NHEJ:

Non-homologous end joining

PB:

piggyBac transposon system

PNI:

Pronuclear injection

RE:

Restriction enzyme

RecA:

Recombinase A

REMI:

Restriction enzyme-mediated integration

RMCE:

Recombinase-mediated cassette exchange

RMDI:

Recombinase-mediated DNA insertion

SB:

Sleeping Beauty transposon system

SCNT:

Somatic cell nuclear transfer

sgRNA:

Single-guide RNA

SMGT:

Sperm-mediated gene transfer

SV40:

Simian virus 40

TALEN:

Transcription activator-like element nuclease

Tol2:

Tol2 transposon system

ZFN:

Zinc finger nuclease

References

  1. Miao X (2013) Recent advances in the development of new transgenic animal technology. Cell Mol Life Sci 70(5):815–828. doi:10.1007/s00018-012-1081-7

    CAS  PubMed  Google Scholar 

  2. Laible G, Wei J, Wagner S (2014) Improving livestock for agriculture: technological progress from random transgenesis to precision genome editing heralds a new era. Biotechnol J. doi:10.1002/biot.201400193

    PubMed  Google Scholar 

  3. Prather RS (2013) Pig genomics for biomedicine. Nat Biotechnol 31(2):122–124. doi:10.1038/nbt.2490

    CAS  PubMed  Google Scholar 

  4. Segal DJ, Meckler JF (2013) Genome engineering at the dawn of the golden age. Annu Rev Genomics Hum Genet 14:135–158. doi:10.1146/annurev-genom-091212-153435

    CAS  PubMed  Google Scholar 

  5. Cibelli J, Emborg ME, Prockop DJ, Roberts M, Schatten G, Rao M, Harding J, Mirochnitchenko O (2013) Strategies for improving animal models for regenerative medicine. Cell Stem Cell 12(3):271–274. doi:10.1016/j.stem.2013.01.004

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Shinohara ET, Kaminski JM, Segal DJ, Pelczar P, Kolhe R, Ryan T, Coates CJ, Fraser MJ, Handler AM, Yanagimachi R, Moisyadi S (2007) Active integration: new strategies for transgenesis. Transgenic Res 16(3):333–339

    CAS  PubMed  Google Scholar 

  7. Garrels W, Ivics Z, Kues WA (2012) Precision genetic engineering in large mammals. Trends Biotechnol 30(7):386–393. doi:10.1016/j.tibtech.2012.03.008

    CAS  PubMed  Google Scholar 

  8. Keravala A, Liu D, Lechman ER, Wolfe D, Nash JA, Lampe DJ, Robbins PD (2006) Hyperactive Himar1 transposase mediates transposition in cell culture and enhances gene expression in vivo. Hum Gene Ther 17(10):1006–1018. doi:10.1089/hum.2006.17.1006

    CAS  PubMed  Google Scholar 

  9. Zayed H, Izsvák Z, Walisko O, Ivics Z (2004) Development of hyperactive sleeping beauty transposon vectors by mutational analysis. Mol Ther 9(2):292–304. doi:10.1016/j.ymthe.2003.11.024

    CAS  PubMed  Google Scholar 

  10. Mates L, Chuah MK, Belay E, Jerchow B, Manoj N, Acosta-Sanchez A, Grzela DP, Schmitt A, Becker K, Matrai J, Ma L, Samara-Kuko E, Gysemans C, Pryputniewicz D, Miskey C, Fletcher B, VandenDriessche T, Ivics Z, Izsvak Z (2009) Molecular evolution of a novel hyperactive sleeping beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet 41(6):753–761. doi:10.1038/ng.343

    CAS  PubMed  Google Scholar 

  11. Yusa K, Zhou L, Li MA, Bradley A, Craig NL (2011) A hyperactive piggyBac transposase for mammalian applications. Proc Natl Acad Sci USA 108(4):1531–1536. doi:10.1073/pnas.1008322108

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Kim H, Kim JS (2014) A guide to genome engineering with programmable nucleases. Nat Rev Genet 15(5):321–334. doi:10.1038/nrg3686

    CAS  PubMed  Google Scholar 

  13. Jakobsen JE, Johansen MG, Schmidt M, Dagnaes-Hansen F, Dam K, Gunnarsson A, Liu Y, Kragh PM, Li R, Holm IE, Callesen H, Mikkelsen JG, Nielsen AL, Jorgensen AL (2013) Generation of minipigs with targeted transgene insertion by recombinase-mediated cassette exchange (RMCE) and somatic cell nuclear transfer (SCNT). Transgenic Res 22(4):709–723. doi:10.1007/s11248-012-9671-6

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Yu Y, Wang Y, Tong Q, Liu X, Su F, Quan F, Guo Z, Zhang Y (2013) A site-specific recombinase-based method to produce antibiotic selectable marker free transgenic cattle. PLoS ONE 8(5):e62457. doi:10.1371/journal.pone.0062457

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Whitelaw CB, Lillico SG, King T (2008) Production of transgenic farm animals by viral vector-mediated gene transfer. Reprod Domest Anim 43(Suppl 2):355–358. doi:10.1111/j.1439-0531.2008.01184.x

    PubMed  Google Scholar 

  16. Park F (2007) Lentiviral vectors: are they the future of animal transgenesis? Physiol Genomics 31(2):159–173. doi:10.1152/physiolgenomics.00069.2007

    CAS  PubMed  Google Scholar 

  17. Pfeifer A, Hofmann A (2009) Lentiviral transgenesis. Methods Mol Biol 530:391–405. doi:10.1007/978-1-59745-471-1_21

    CAS  PubMed  Google Scholar 

  18. Lillico S, Vasey D, King T, Whitelaw B (2011) Lentiviral transgenesis in livestock. Transgenic Res 20(3):441–442. doi:10.1007/s11248-010-9448-8

    CAS  PubMed  Google Scholar 

  19. Carlson DF, Tan W, Hackett PB, Fahrenkrug SC (2013) Editing livestock genomes with site-specific nucleases. Reprod Fertil Dev 26(1):74–82. doi:10.1071/RD13260

    PubMed  Google Scholar 

  20. Tan W, Carlson DF, Lancto CA, Garbe JR, Webster DA, Hackett PB, Fahrenkrug SC (2013) Efficient nonmeiotic allele introgression in livestock using custom endonucleases. Proc Natl Acad Sci USA 110(41):16526–16531. doi:10.1073/pnas.1310478110

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Gun G, Kues WA (2014) Current progress of genetically engineered pig models for biomedical research. Biores Open Access 3(6):255–264. doi:10.1089/biores.2014.0039

    PubMed Central  PubMed  Google Scholar 

  22. Carroll D (2014) Genome engineering with targetable nucleases. Annu Rev Biochem 83:409–439. doi:10.1146/annurev-biochem-060713-035418

    CAS  PubMed  Google Scholar 

  23. Schiestl RH, Petes TD (1991) Integration of DNA fragments by illegitimate recombination in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 88(17):7585–7589

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Black M, Seeber F, Soldati D, Kim K, Boothroyd JC (1995) Restriction enzyme-mediated integration elevates transformation frequency and enables co-transfection of Toxoplasma gondii. Mol Biochem Parasitol 74(1):55–63

    CAS  PubMed  Google Scholar 

  25. Maier FJ, Schafer W (1999) Mutagenesis via insertional- or restriction enzyme-mediated-integration (REMI) as a tool to tag pathogenicity related genes in plant pathogenic fungi. Biol Chem 380(7–8):855–864. doi:10.1515/BC.1999.105

    CAS  PubMed  Google Scholar 

  26. Marsh-Armstrong N, Huang H, Berry DL, Brown DD (1999) Germ-line transmission of transgenes in Xenopus laevis. Proc Natl Acad Sci USA 96(25):14389–14393

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Cavolina P, Agnese C, Maddalena A, Sciandrello G, Di Leonardo A (1989) Induction of CAD gene amplification by restriction endonucleases in V79, B7 Chinese hamster cells. Mutat Res 225(1–2):61–64

    CAS  PubMed  Google Scholar 

  28. Costa ND, Masson WK, Thacker J (1993) The effectiveness of restriction endonucleases in cell killing and mutation. Somat Cell Mol Genet 19(5):479–490

    CAS  PubMed  Google Scholar 

  29. Seo BB, Kim CH, Yamanouchi K, Takahashi M, Sawasaki T, Tachi C, Tojo H (2000) Co-injection of restriction enzyme with foreign DNA into the pronucleus for elevating production efficiencies of transgenic animals. Anim Reprod Sci 63(1–2):113–122

    CAS  PubMed  Google Scholar 

  30. Wall RJ (1996) Transgenic livestock: progress and prospects for the future. Theriogenology 45:57–68

    Google Scholar 

  31. Abella Columna E, Giaccia AJ, Evans JW, Yates BL, Morgan WF (1993) Analysis of restriction enzyme-induced chromosomal aberrations by fluorescence in situ hybridization. Environ Mol Mutagen 22(1):26–33

    CAS  PubMed  Google Scholar 

  32. Dewey WC, Miller HH, Leeper DB (1971) Chromosomal aberrations and mortality of x-irradiated mammalian cells: emphasis on repair. Proc Natl Acad Sci USA 68(3):667–671

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Obe G, Von der Hude W, Scheutwinkel-Reich M, Basler A (1986) The restriction endonuclease Alu I induces chromosomal aberrations and mutations in the hypoxanthine phosphoribosyltransferase locus, but not in the Na+/K+ ATPase locus in V79 hamster cells. Mutat Res 174(1):71–74. doi:10.1016/0165-7992(86)90079-5

    CAS  PubMed  Google Scholar 

  34. Singh B, Bryant PE (1991) Induction of mutations at the thymidine kinase locus in CHO cells by restriction endonucleases. Mutagenesis 6(3):219–223

    CAS  PubMed  Google Scholar 

  35. Hafez M, Hausner G (2012) Homing endonucleases: DNA scissors on a mission. Genome 55(8):553–569. doi:10.1139/g2012-049

    CAS  PubMed  Google Scholar 

  36. Jacquier A, Dujon B (1985) An intron-encoded protein is active in a gene conversion process that spreads an intron into a mitochondrial gene. Cell 41(2):383–394

    CAS  PubMed  Google Scholar 

  37. Ogino H, McConnell WB, Grainger RM (2006) Highly efficient transgenesis in Xenopus tropicalis using I-SceI meganuclease. Mech Dev 123(2):103–113

    CAS  PubMed  Google Scholar 

  38. Thermes V, Grabher C, Ristoratore F, Bourrat F, Choulika A, Wittbrodt J, Joly JS (2002) I-SceI meganuclease mediates highly efficient transgenesis in fish. Mech Dev 118(1–2):91–98

    CAS  PubMed  Google Scholar 

  39. Bevacqua RJ, Canel NG, Hiriart MI, Sipowicz P, Rozenblum GT, Vitullo A, Radrizzani M, Fernandez Martin R, Salamone DF (2013) Simple gene transfer technique based on I-SceI meganuclease and cytoplasmic injection in IVF bovine embryos. Theriogenology 80(2):104–113. doi:10.1016/j.theriogenology.2013.03.017

    CAS  PubMed  Google Scholar 

  40. Ortega MN, Benítez SB, Barrionuevo BE, Olmos Nicotra MF, Alessio AP, Fili AE, Forcato DO, Stice SL, Bosch P (2012) Meganuclease I-SceI enhances stable transgene integration in cultured bovine fetal fibroblasts. Reprod Fertil Dev 25(1):170–171. doi:10.1071/RDv25n1Ab46

    Google Scholar 

  41. Wang Y, Zhou XY, Xiang PY, Wang LL, Tang H, Xie F, Li L, Wei H (2014) The meganuclease I-SceI containing nuclear localization signal (NLS-I-SceI) efficiently mediated mammalian germline transgenesis via embryo cytoplasmic microinjection. PLoS ONE 9(9):e108347. doi:10.1371/journal.pone.0108347

    PubMed Central  PubMed  Google Scholar 

  42. Brackett BG, Baranska W, Sawicki W, Koprowski H (1971) Uptake of heterologous genome by mammalian spermatozoa and its transfer to ova through fertilization. Proc Natl Acad Sci USA 68(2):353–357

    PubMed Central  CAS  PubMed  Google Scholar 

  43. Lavitrano M, Camaioni A, Fazio VM, Dolci S, Farace MG, Spadafora C (1989) Sperm cells as vectors for introducing foreign DNA into eggs: genetic transformation of mice. Cell 57(5):717–723

    CAS  PubMed  Google Scholar 

  44. Brinster RL, Sandgren EP, Behringer RR, Palmiter RD (1989) No simple solution for making transgenic mice. Cell 59(2):239–241

    CAS  PubMed  Google Scholar 

  45. Tsai HJ (2000) Electroporated sperm mediation of a gene transfer system for finfish and shellfish. Mol Reprod Dev 56(2 Suppl):281–284. doi:10.1002/(SICI)1098-2795(200006)56:2+<281:AID-MRD15>3.0.CO;2-B

    CAS  PubMed  Google Scholar 

  46. Shamila Y, Mathavan S (2000) Sperm/DNA interaction: DNA binding proteins in sperm cell of silkworm Bombyx mori. Mol Reprod Dev 56(2 Suppl):289–291. doi:10.1002/(SICI)1098-2795(200006)56:2+<289:AID-MRD17>3.0.CO;2-Y

    CAS  PubMed  Google Scholar 

  47. Fernandez MA, Mani SA, Rangarajan PN, Seshagiri PB (1999) Sperm-mediated gene transfer into oocytes of the golden hamster: assessment of sperm function. Indian J Exp Biol 37(11):1085–1092

    CAS  PubMed  Google Scholar 

  48. Cappello F, Stassi G, Lazzereschi D, Renzi L, Di Stefano C, Marfe G, Giancotti P, Wang HJ, Stoppacciaro A, Forni M, Bacci ML, Turchi V, Sinibaldi P, Rossi M, Bruzzone P, Pretagostini R, Della Casa G, Cortesini R, Frati L, Lavitrano M (2000) hDAF expression in hearts of transgenic pigs obtained by sperm-mediated gene transfer. Transplant Proc 32(5):895–896

    CAS  PubMed  Google Scholar 

  49. Shemesh M, Gurevich M, Harel-Markowitz E, Benvenisti L, Shore LS, Stram Y (2000) Gene integration into bovine sperm genome and its expression in transgenic offspring. Mol Reprod Dev 56(S2):306–308

    CAS  PubMed  Google Scholar 

  50. Sciamanna I, Piccoli S, Barberi L, Zaccagnini G, Magnano AR, Giordano R, Campedelli P, Hodgson C, Lorenzini R, Spadafora C (2000) DNA dose and sequence dependence in sperm-mediated gene transfer. Mol Reprod Dev 56(2 Suppl):301–305. doi:10.1002/(SICI)1098-2795(200006)56:2+<301:AID-MRD20>3.0.CO;2-B

    CAS  PubMed  Google Scholar 

  51. Perry AC, Wakayama T, Kishikawa H, Kasai T, Okabe M, Toyoda Y, Yanagimachi R (1999) Mammalian transgenesis by intracytoplasmic sperm injection. Science 284(5417):1180–1183

    CAS  PubMed  Google Scholar 

  52. Umeyama K, Saito H, Kurome M, Matsunari H, Watanabe M, Nakauchi H, Nagashima H (2012) Characterization of the ICSI-mediated gene transfer method in the production of transgenic pigs. Mol Reprod Dev 79(3):218–228. doi:10.1002/mrd.22015

    CAS  PubMed  Google Scholar 

  53. Hirabayashi M, Kato M, Ito J, Hochi S (2005) Viable rat offspring derived from oocytes intracytoplasmically injected with freeze-dried sperm heads. Zygote 13(1):79–85

    PubMed  Google Scholar 

  54. Pereyra-Bonnet F, Fernandez-Martin R, Olivera R, Jarazo J, Vichera G, Gibbons A, Salamone D (2008) A unique method to produce transgenic embryos in ovine, porcine, feline, bovine and equine species. Reprod Fertil Dev 20(7):741–749

    CAS  PubMed  Google Scholar 

  55. Bevacqua RJ, Pereyra-Bonnet F, Fernandez-Martin R, Salamone DF (2010) High rates of bovine blastocyst development after ICSI-mediated gene transfer assisted by chemical activation. Theriogenology 74(6):922–931. doi:10.1016/j.theriogenology.2010.04.017

    PubMed  Google Scholar 

  56. Chan AW, Luetjens CM, Dominko T, Ramalho-Santos J, Simerly CR, Hewitson L, Schatten G (2000) Foreign DNA transmission by ICSI: injection of spermatozoa bound with exogenous DNA results in embryonic GFP expression and live rhesus monkey births. Mol Hum Reprod 6(1):26–33

    CAS  PubMed  Google Scholar 

  57. Mizushima S, Takagi S, Ono T, Atsumi Y, Tsukada A, Saito N, Sasanami T, Okabe M, Shimada K (2010) Novel method of gene transfer in birds: intracytoplasmic sperm injection for green fluorescent protein expression in quail blastoderms. Biol Reprod 83(6):965–969. doi:10.1095/biolreprod.110.085860

    CAS  PubMed  Google Scholar 

  58. Henikoff S (1998) Conspiracy of silence among repeated transgenes. Bioessays 20(7):532–535. doi:10.1002/(sici)1521-1878(199807)20:7<532:aid-bies3>3.0.co;2-m

    CAS  PubMed  Google Scholar 

  59. Kues WA, Schwinzer R, Wirth D, Verhoeyen E, Lemme E, Herrmann D, Barg-Kues B, Hauser H, Wonigeit K, Niemann H (2006) Epigenetic silencing and tissue independent expression of a novel tetracycline inducible system in double-transgenic pigs. FASEB J 20(8):1200–1202. doi:10.1096/fj.05-5415fje

    CAS  PubMed  Google Scholar 

  60. Kaneko T, Moisyadi S, Suganuma R, Hohn B, Yanagimachi R, Pelczar P (2005) Recombinase-mediated mouse transgenesis by intracytoplasmic sperm injection. Theriogenology 64(8):1704–1715

    CAS  PubMed  Google Scholar 

  61. Suganuma R, Pelczar P, Spetz JF, Hohn B, Yanagimachi R, Moisyadi S (2005) Tn5 transposase-mediated mouse transgenesis. Biol Reprod 73(6):1157–1163

    CAS  PubMed  Google Scholar 

  62. Maga EA, Sargent RG, Zeng H, Pati S, Zarling DA, Oppenheim SM, Collette NM, Moyer AL, Conrad-Brink JS, Rowe JD, BonDurant RH, Anderson GB, Murray JD (2003) Increased efficiency of transgenic livestock production. Transgenic Res 12(4):485–496

    CAS  PubMed  Google Scholar 

  63. Mason JB, Najarian JG, Anderson GB, Murray JD, Maga EA (2006) The effect of coating single- and double-stranded DNA with the recombinase A protein of Escherichia coli on transgene integration in mice. Transgenic Res 15(6):703–710. doi:10.1007/s11248-006-9005-7

    CAS  PubMed  Google Scholar 

  64. Moisyadi S, Kaminski JM, Yanagimachi R (2009) Use of intracytoplasmic sperm injection (ICSI) to generate transgenic animals. Comp Immunol Microbiol Infect Dis 32(2):47–60. doi:10.1016/j.cimid.2008.05.003

    PubMed Central  PubMed  Google Scholar 

  65. Garrels W, Mates L, Holler S, Dalda A, Taylor U, Petersen B, Niemann H, Izsvak Z, Ivics Z, Kues WA (2011) Germline transgenic pigs by sleeping beauty transposition in porcine zygotes and targeted integration in the pig genome. PLoS ONE 6(8):e23573. doi:10.1371/journal.pone.0023573

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Ivics Z, Garrels W, Mátés L, Yau TY, Bashir S, Zidek V, Landa V, Geurts A, Pravenec M, Rülicke T, Kues WA, Izsvák Z (2014) Germline transgenesis in pigs by cytoplasmic microinjection of sleeping beauty transposons. Nat Protoc 9(4):810–827. doi:10.1038/nprot.2014.010

    CAS  PubMed  Google Scholar 

  67. Kawakami K (2007) Tol2: a versatile gene transfer vector in vertebrates. Genome Biol 8(Suppl 1):S7. doi:10.1186/gb-2007-8-s1-s7

    PubMed Central  PubMed  Google Scholar 

  68. Suster ML, Abe G, Schouw A, Kawakami K (2011) Transposon-mediated BAC transgenesis in zebrafish. Nat Protoc 6(12):1998–2021. doi:10.1038/nprot.2011.416

    CAS  PubMed  Google Scholar 

  69. Schnutgen F, Stewart AF, von Melchner H, Anastassiadis K (2006) Engineering embryonic stem cells with recombinase systems. Methods Enzymol 420:100–136. doi:10.1016/s0076-6879(06)20007-7

    PubMed  Google Scholar 

  70. Mali P, Esvelt KM, Church GM (2013) Cas9 as a versatile tool for engineering biology. Nat Methods 10(10):957–963. doi:10.1038/nmeth.2649

    PubMed Central  CAS  PubMed  Google Scholar 

  71. McClintock B (1950) The origin and behavior of mutable loci in maize. Proc Natl Acad Sci USA 36(6):344–355

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Makałowski W, Pande A, Gotea V, Makałowska I (2012) Transposable elements and their identification. Methods Mol Biol 855:337–359. doi:10.1007/978-1-61779-582-4_12

    PubMed  Google Scholar 

  73. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, Szustakowki J, Consortium IHGS (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921. doi:10.1038/35057062

    CAS  PubMed  Google Scholar 

  74. Muñoz-López M, García-Pérez JL (2010) DNA transposons: nature and applications in genomics. Curr Genomics 11(2):115–128. doi:10.2174/138920210790886871

    PubMed Central  PubMed  Google Scholar 

  75. Ostertag EM, Kazazian HH (2001) Biology of mammalian L1 retrotransposons. Annu Rev Genet 35:501–538. doi:10.1146/annurev.genet.35.102401.091032

    CAS  PubMed  Google Scholar 

  76. Gilbert N, Lutz-Prigge S, Moran JV (2002) Genomic deletions created upon LINE-1 retrotransposition. Cell 110(3):315–325

    CAS  PubMed  Google Scholar 

  77. Plasterk RH, Izsvák Z, Ivics Z (1999) Resident aliens: the Tc1/mariner superfamily of transposable elements. Trends Genet 15(8):326–332

    CAS  PubMed  Google Scholar 

  78. Ivics Z, Li MA, Mates L, Boeke JD, Nagy A, Bradley A, Izsvak Z (2009) Transposon-mediated genome manipulation in vertebrates. Nat Methods 6(6):415–422. doi:10.1038/nmeth.1332

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Ivics Z, Hackett PB, Plasterk RH, Izsvak Z (1997) Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91(4):501–510

    CAS  PubMed  Google Scholar 

  80. van Luenen HG, Colloms SD, Plasterk RH (1994) The mechanism of transposition of Tc3 in C. elegans. Cell 79(2):293–301

    PubMed  Google Scholar 

  81. Mátés L, Izsvák Z, Ivics Z (2007) Technology transfer from worms and flies to vertebrates: transposition-based genome manipulations and their future perspectives. Genome Biol 8(Suppl 1):S1. doi:10.1186/gb-2007-8-s1-s1

    PubMed Central  PubMed  Google Scholar 

  82. Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T (2005) Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122(3):473–483. doi:10.1016/j.cell.2005.07.013

    CAS  PubMed  Google Scholar 

  83. Horie K, Yusa K, Yae K, Odajima J, Fischer SE, Keng VW, Hayakawa T, Mizuno S, Kondoh G, Ijiri T, Matsuda Y, Plasterk RH, Takeda J (2003) Characterization of Sleeping Beauty transposition and its application to genetic screening in mice. Mol Cell Biol 23(24):9189–9207

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Balciunas D, Wangensteen KJ, Wilber A, Bell J, Geurts A, Sivasubbu S, Wang X, Hackett PB, Largaespada DA, McIvor RS, Ekker SC (2006) Harnessing a high cargo-capacity transposon for genetic applications in vertebrates. PLoS Genet 2(11):e169. doi:10.1371/journal.pgen.0020169

    PubMed Central  PubMed  Google Scholar 

  85. Rostovskaya M, Naumann R, Fu J, Obst M, Mueller D, Stewart AF, Anastassiadis K (2013) Transposon mediated BAC transgenesis via pronuclear injection of mouse zygotes. Genesis 51(2):135–141. doi:10.1002/dvg.22362

    CAS  PubMed  Google Scholar 

  86. Curradi M, Izzo A, Badaracco G, Landsberger N (2002) Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol 22(9):3157–3173

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Carlson DF, Garbe JR, Tan W, Martin MJ, Dobrinsky JR, Hackett PB, Clark KJ, Fahrenkrug SC (2011) Strategies for selection marker-free swine transgenesis using the sleeping beauty transposon system. Transgenic Res 20(5):1125–1137. doi:10.1007/s11248-010-9481-7

    CAS  PubMed  Google Scholar 

  88. Ryding AD, Sharp MG, Mullins JJ (2001) Conditional transgenic technologies. J Endocrinol 171(1):1–14

    CAS  PubMed  Google Scholar 

  89. Woltjen K, Hämäläinen R, Kibschull M, Mileikovsky M, Nagy A (2011) Transgene-free production of pluripotent stem cells using piggyBac transposons. Methods Mol Biol 767:87–103. doi:10.1007/978-1-61779-201-4_7

    CAS  PubMed  Google Scholar 

  90. Yusa K, Rad R, Takeda J, Bradley A (2009) Generation of transgene-free induced pluripotent mouse stem cells by the piggyBac transposon. Nat Methods 6(5):363–369. doi:10.1038/nmeth.1323

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Li X, Burnight ER, Cooney AL, Malani N, Brady T, Sander JD, Staber J, Wheelan SJ, Joung JK, McCray PB, Bushman FD, Sinn PL, Craig NL (2013) piggyBac transposase tools for genome engineering. Proc Natl Acad Sci USA 110(25):E2279–E2287. doi:10.1073/pnas.1305987110

    PubMed Central  CAS  PubMed  Google Scholar 

  92. Sinzelle L, Vallin J, Coen L, Chesneau A, Du Pasquier D, Pollet N, Demeneix B, Mazabraud A (2006) Generation of trangenic Xenopus laevis using the Sleeping Beauty transposon system. Transgenic Res 15(6):751–760. doi:10.1007/s11248-006-9014-6

    CAS  PubMed  Google Scholar 

  93. Yergeau DA, Johnson Hamlet MR, Kuliyev E, Zhu H, Doherty JR, Archer TD, Subhawong AP, Valentine MB, Kelley CM, Mead PE (2009) Transgenesis in Xenopus using the sleeping beauty transposon system. Dev Dyn 238(7):1727–1743. doi:10.1002/dvdy.21994

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Kitada K, Ishishita S, Tosaka K, Takahashi R, Ueda M, Keng VW, Horie K, Takeda J (2007) Transposon-tagged mutagenesis in the rat. Nat Methods 4(2):131–133. doi:10.1038/nmeth1002

    CAS  PubMed  Google Scholar 

  95. Clark KJ, Carlson DF, Foster LK, Kong BW, Foster DN, Fahrenkrug SC (2007) Enzymatic engineering of the porcine genome with transposons and recombinases. BMC Biotechnol 7:42. doi:10.1186/1472-6750-7-42

    PubMed Central  PubMed  Google Scholar 

  96. Baus J, Liu L, Heggestad AD, Sanz S, Fletcher BS (2005) Hyperactive transposase mutants of the Sleeping Beauty transposon. Mol Ther 12(6):1148–1156. doi:10.1016/j.ymthe.2005.06.484

    CAS  PubMed  Google Scholar 

  97. Yant SR, Park J, Huang Y, Mikkelsen JG, Kay MA (2004) Mutational analysis of the N-terminal DNA-binding domain of sleeping beauty transposase: critical residues for DNA binding and hyperactivity in mammalian cells. Mol Cell Biol 24(20):9239–9247. doi:10.1128/MCB.24.20.9239-9247.2004

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Geurts AM, Yang Y, Clark KJ, Liu G, Cui Z, Dupuy AJ, Bell JB, Largaespada DA, Hackett PB (2003) Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol Ther 8(1):108–117

    CAS  PubMed  Google Scholar 

  99. Gordon JW, Scangos GA, Plotkin DJ, Barbosa JA, Ruddle FH (1980) Genetic transformation of mouse embryos by microinjection of purified DNA. Proc Natl Acad Sci USA 77(12):7380–7384

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Bondioli KR, Biery KA, Hill KG, Jones KB, De Mayo FJ (1991) Production of transgenic cattle by pronuclear injection. Biotechnology 16:265–273

    CAS  PubMed  Google Scholar 

  101. Hammer RE, Pursel VG, Rexroad CE Jr, Wall RJ, Bolt DJ, Ebert KM, Palmiter RD, Brinster RL (1985) Production of transgenic rabbits, sheep and pigs by microinjection. Nature 315(6021):680–683

    CAS  PubMed  Google Scholar 

  102. Iqbal K, Barg-Kues B, Broll S, Bode J, Niemann H, Kues W (2009) Cytoplasmic injection of circular plasmids allows targeted expression in mammalian embryos. Biotechniques 47(5):959–968. doi:10.2144/000113270

    PubMed  Google Scholar 

  103. Clark KJ, Urban MD, Skuster KJ, Ekker SC (2011) Transgenic zebrafish using transposable elements. Methods Cell Biol 104:137–149. doi:10.1016/B978-0-12-374814-0.00008-2

    PubMed Central  CAS  PubMed  Google Scholar 

  104. Marh J, Stoytcheva Z, Urschitz J, Sugawara A, Yamashiro H, Owens JB, Stoytchev I, Pelczar P, Yanagimachi R, Moisyadi S (2012) Hyperactive self-inactivating piggyBac for transposase-enhanced pronuclear microinjection transgenesis. Proc Natl Acad Sci USA 109(47):19184–19189. doi:10.1073/pnas.1216473109

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Jang CW, Behringer RR (2007) Transposon-mediated transgenesis in rats. CSH Protoc 2007:pdb.prot4866

    PubMed  Google Scholar 

  106. Li Z, Zeng F, Meng F, Xu Z, Zhang X, Huang X, Tang F, Gao W, Shi J, He X, Liu D, Wang C, Urschitz J, Moisyadi S, Wu Z (2014) Generation of transgenic pigs by cytoplasmic injection of piggyBac transposase based pmGENIE-3 plasmids. Biol Reprod 90(5):93–102. doi:10.1095/biolreprod.113.116905

    PubMed  Google Scholar 

  107. Jakobsen JE, Li J, Kragh PM, Moldt B, Lin L, Liu Y, Schmidt M, Winther KD, Schyth BD, Holm IE, Vajta G, Bolund L, Callesen H, Jorgensen AL, Nielsen AL, Mikkelsen JG (2011) Pig transgenesis by sleeping beauty DNA transposition. Transgenic Res 20(3):533–545. doi:10.1007/s11248-010-9438-x

    CAS  PubMed  Google Scholar 

  108. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813

    CAS  PubMed  Google Scholar 

  109. Campbell KH, McWhir J, Ritchie WA, Wilmut I (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature 380(6569):64–66

    CAS  PubMed  Google Scholar 

  110. Bosch P, Hodges CA, Stice SL (2004) Generation of transgenic livestock by somatic cell nuclear transfer. Biotecnologia Aplicada 21(3):128–136

    CAS  Google Scholar 

  111. Wu Z, Xu Z, Zou X, Zeng F, Shi J, Liu D, Urschitz J, Moisyadi S, Li Z (2013) Pig transgenesis by piggyBac transposition in combination with somatic cell nuclear transfer. Transgenic Res 22(6):1107–1118. doi:10.1007/s11248-013-9729-0

    CAS  PubMed  Google Scholar 

  112. Alessio A, Fili A, Forcato D, Olmos-Nicotra F, Alustiza F, Rodriguez N, Owens J, Moisyad S, Kues WA, Bosch P (2014) Efficient piggyBac transposon-mediated transgene integration into bovine fetal fibroblast genome. Reprod Dom Anim 49(S1):8

    Google Scholar 

  113. Wilson MH, Coates CJ, George AL Jr (2007) PiggyBac transposon-mediated gene transfer in human cells. Mol Ther 15(1):139–145. doi:10.1038/sj.mt.6300028

    CAS  PubMed  Google Scholar 

  114. Ikeda R, Kokubu C, Yusa K, Keng VW, Horie K, Takeda J (2007) Sleeping beauty transposase has an affinity for heterochromatin conformation. Mol Cell Biol 27(5):1665–1676. doi:10.1128/MCB.01500-06

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Yant SR, Wu X, Huang Y, Garrison B, Burgess SM, Kay MA (2005) High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 25(6):2085–2094. doi:10.1128/MCB.25.6.2085-2094.2005

    PubMed Central  CAS  PubMed  Google Scholar 

  116. Blakely G, Colloms S, May G, Burke M, Sherratt D (1991) Escherichia coli XerC recombinase is required for chromosomal segregation at cell division. New Biol 3(8):789–798

    CAS  PubMed  Google Scholar 

  117. Gellert M, Nash H (1987) Communication between segments of DNA during site-specific recombination. Nature 325(6103):401–404. doi:10.1038/325401a0

    CAS  PubMed  Google Scholar 

  118. Sadowski P (1986) Site-specific recombinases: changing partners and doing the twist. J Bacteriol 165(2):341–347

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Fukushige S, Sauer B (1992) Genomic targeting with a positive-selection lox integration vector allows highly reproducible gene expression in mammalian cells. Proc Natl Acad Sci USA 89(17):7905–7909

    PubMed Central  CAS  PubMed  Google Scholar 

  120. O’Gorman S, Fox DT, Wahl GM (1991) Recombinase-mediated gene activation and site-specific integration in mammalian cells. Science 251(4999):1351–1355

    PubMed  Google Scholar 

  121. Bestor TH (2000) Gene silencing as a threat to the success of gene therapy. J Clin Invest 105(4):409–411. doi:10.1172/JCI9459

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Whitelaw E, Sutherland H, Kearns M, Morgan H, Weaving L, Garrick D (2001) Epigenetic effects on transgene expression. Methods Mol Biol 158:351–368. doi:10.1385/1-59259-220-1:351

    CAS  PubMed  Google Scholar 

  123. Grindley ND, Whiteson KL, Rice PA (2006) Mechanisms of site-specific recombination. Annu Rev Biochem 75:567–605. doi:10.1146/annurev.biochem.73.011303.073908

    CAS  PubMed  Google Scholar 

  124. Stark WM, Boocock MR, Sherratt DJ (1992) Catalysis by site-specific recombinases. Trends Genet 8(12):432–439

    CAS  PubMed  Google Scholar 

  125. Dymecki SM (2000) Site-specific recombination in cells and mice. In: Joyner AL (ed) Gene targeting: a practical approach. The practical approach, 2nd edn. Oxford University Press, New York, pp 36–99

    Google Scholar 

  126. Wang Y, Yau YY, Perkins-Balding D, Thomson JG (2011) Recombinase technology: applications and possibilities. Plant Cell Rep 30(3):267–285. doi:10.1007/s00299-010-0938-1

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Grainge I, Jayaram M (1999) The integrase family of recombinase: organization and function of the active site. Mol Microbiol 33(3):449–456

    CAS  PubMed  Google Scholar 

  128. Branda CS, Dymecki SM (2004) Talking about a revolution: the impact of site-specific recombinases on genetic analyses in mice. Dev Cell 6(1):7–28

    CAS  PubMed  Google Scholar 

  129. Turan S, Zehe C, Kuehle J, Qiao J, Bode J (2013) Recombinase-mediated cassette exchange (RMCE): a rapidly-expanding toolbox for targeted genomic modifications. Gene 515(1):1–27. doi:10.1016/j.gene.2012.11.016

    CAS  PubMed  Google Scholar 

  130. Jones JR, Shelton KD, Magnuson MA (2005) Strategies for the use of site-specific recombinases in genome engineering. Methods Mol Med 103:245–257

    CAS  PubMed  Google Scholar 

  131. Turan S, Galla M, Ernst E, Qiao J, Voelkel C, Schiedlmeier B, Zehe C, Bode J (2011) Recombinase-mediated cassette exchange (RMCE): traditional concepts and current challenges. J Mol Biol 407(2):193–221. doi:10.1016/j.jmb.2011.01.004

    CAS  PubMed  Google Scholar 

  132. Araki K, Araki M, Yamamura K (1997) Targeted integration of DNA using mutant lox sites in embryonic stem cells. Nucleic Acids Res 25(4):868–872

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Araki K, Imaizumi T, Sekimoto T, Yoshinobu K, Yoshimuta J, Akizuki M, Miura K, Araki M, Yamamura K (1999) Exchangeable gene trap using the Cre/mutated lox system. Cell Mol Biol (Noisy-le-grand) 45(5):737–750

    CAS  Google Scholar 

  134. Senecoff JF, Rossmeissl PJ, Cox MM (1988) DNA recognition by the FLP recombinase of the yeast 2 mu plasmid. A mutational analysis of the FLP binding site. J Mol Biol 201(2):405–421

    CAS  PubMed  Google Scholar 

  135. Schlake T, Bode J (1994) Use of mutated FLP recognition target (FRT) sites for the exchange of expression cassettes at defined chromosomal loci. Biochemistry 33(43):12746–12751

    CAS  PubMed  Google Scholar 

  136. Kolb AF, Siddell SG (1996) Genomic targeting with an MBP-Cre fusion protein. Gene 183(1–2):53–60

    CAS  PubMed  Google Scholar 

  137. Baubonis W, Sauer B (1993) Genomic targeting with purified Cre recombinase. Nucleic Acids Res 21(9):2025–2029

    PubMed Central  CAS  PubMed  Google Scholar 

  138. de Wit T, Drabek D, Grosveld F (1998) Microinjection of cre recombinase RNA induces site-specific recombination of a transgene in mouse oocytes. Nucleic Acids Res 26(2):676–678

    PubMed Central  PubMed  Google Scholar 

  139. Braun T, Bober E, Rudnicki MA, Jaenisch R, Arnold HH (1994) MyoD expression marks the onset of skeletal myogenesis in Myf-5 mutant mice. Development 120(11):3083–3092

    CAS  PubMed  Google Scholar 

  140. Fiering S, Kim CG, Epner EM, Groudine M (1993) An “in-out” strategy using gene targeting and FLP recombinase for the functional dissection of complex DNA regulatory elements: analysis of the beta-globin locus control region. Proc Natl Acad Sci USA 90(18):8469–8473

    PubMed Central  CAS  PubMed  Google Scholar 

  141. Kim CG, Epner EM, Forrester WC, Groudine M (1992) Inactivation of the human beta-globin gene by targeted insertion into the beta-globin locus control region. Genes Dev 6(6):928–938

    CAS  PubMed  Google Scholar 

  142. Olson EN, Arnold HH, Rigby PW, Wold BJ (1996) Know your neighbors: three phenotypes in null mutants of the myogenic bHLH gene MRF4. Cell 85(1):1–4

    CAS  PubMed  Google Scholar 

  143. Pham CT, MacIvor DM, Hug BA, Heusel JW, Ley TJ (1996) Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci USA 93(23):13090–13095

    PubMed Central  CAS  PubMed  Google Scholar 

  144. Howard TH, Homan EJ, Bremel RD (2001) Transgenic livestock: regulation and science in a changing environment. J Anim Sci 79:E1–E11

    Google Scholar 

  145. Askew GR, Doetschman T, Lingrel JB (1993) Site-directed point mutations in embryonic stem cells: a gene-targeting tag-and-exchange strategy. Mol Cell Biol 13(7):4115–4124

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Stacey A, Schnieke A, McWhir J, Cooper J, Colman A, Melton DW (1994) Use of double-replacement gene targeting to replace the murine alpha-lactalbumin gene with its human counterpart in embryonic stem cells and mice. Mol Cell Biol 14(2):1009–1016

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Wu H, Liu X, Jaenisch R (1994) Double replacement: strategy for efficient introduction of subtle mutations into the murine Col1a-1 gene by homologous recombination in embryonic stem cells. Proc Natl Acad Sci USA 91(7):2819–2823

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Graham C, Cole S, Laible G (2009) Site-specific modification of the bovine genome using Cre recombinase-mediated gene targeting. Biotechnol J 4(1):108–118. doi:10.1002/biot.200800200

    CAS  PubMed  Google Scholar 

  149. Yu Y, Tong Q, Li Z, Tian J, Wang Y, Su F, Liu J, Zhang Y (2014) Improved site-specific recombinase-based method to produce selectable marker- and vector-backbone-free transgenic cells. Sci Rep 4:4240. doi:10.1038/srep04240

    PubMed Central  PubMed  Google Scholar 

  150. Yu H, Wang X, Zhu L, He Z, Liu G, Xu X, Chen J, Cheng G (2013) Establishment of a rapid and scalable gene expression system in livestock by site-specific integration. Gene 515(2):367–371. doi:10.1016/j.gene.2012.10.017

    CAS  PubMed  Google Scholar 

  151. Wang S, Sun X, Ding F, Zhang K, Zhao R, Li S, Li R, Tang B, Zhang L, Liu Y, Li J, Gao F, Wang H, Wang L, Dai Y, Li N (2009) Removal of selectable marker gene from fibroblast cells in transgenic cloned cattle by transient expression of Cre recombinase and subsequent effects on recloned embryo development. Theriogenology 72(4):535–541. doi:10.1016/j.theriogenology.2009.04.009

    CAS  PubMed  Google Scholar 

  152. Xu Y, Liu S, Yu G, Chen J, Xu X, Wu Y, Zhang A, Dowdy SF, Cheng G (2008) Excision of selectable genes from transgenic goat cells by a protein transducible TAT-Cre recombinase. Gene 419(1–2):70–74. doi:10.1016/j.gene.2008.04.020

    CAS  PubMed  Google Scholar 

  153. Zhang H, Hasty P, Bradley A (1994) Targeting frequency for deletion vectors in embryonic stem cells. Mol Cell Biol 14(4):2404–2410

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Nagy A, Moens C, Ivanyi E, Pawling J, Gertsenstein M, Hadjantonakis AK, Pirity M, Rossant J (1998) Dissecting the role of N-myc in development using a single targeting vector to generate a series of alleles. Curr Biol 8(11):661–664

    CAS  PubMed  Google Scholar 

  155. Ramírez-Solis R, Liu P, Bradley A (1995) Chromosome engineering in mice. Nature 378(6558):720–724. doi:10.1038/378720a0

    PubMed  Google Scholar 

  156. Zou YR, Müller W, Gu H, Rajewsky K (1994) Cre-loxP-mediated gene replacement: a mouse strain producing humanized antibodies. Curr Biol 4(12):1099–1103

    CAS  PubMed  Google Scholar 

  157. Gu H, Marth JD, Orban PC, Mossmann H, Rajewsky K (1994) Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science 265(5168):103–106

    CAS  PubMed  Google Scholar 

  158. Kühn R, Schwenk F, Aguet M, Rajewsky K (1995) Inducible gene targeting in mice. Science 269(5229):1427–1429

    PubMed  Google Scholar 

  159. Nagy A (2000) Cre recombinase: the universal reagent for genome tailoring. Genesis 26(2):99–109

    CAS  PubMed  Google Scholar 

  160. Chen L, Li L, Pang D, Li Z, Wang T, Zhang M, Song N, Yan S, Lai LX, Ouyang H (2010) Construction of transgenic swine with induced expression of Cre recombinase. Animal 4(5):767–771. doi:10.1017/S1751731109991571

    CAS  PubMed  Google Scholar 

  161. Li S, Flisikowska T, Kurome M, Zakhartchenko V, Kessler B, Saur D, Kind A, Wolf E, Flisikowski K, Schnieke A (2014) Dual fluorescent reporter pig for Cre recombination: transgene placement at the ROSA26 locus. PLoS ONE 9(7):e102455. doi:10.1371/journal.pone.0102455

    PubMed Central  PubMed  Google Scholar 

  162. Groth AC, Olivares EC, Thyagarajan B, Calos MP (2000) A phage integrase directs efficient site-specific integration in human cells. Proc Natl Acad Sci USA 97(11):5995–6000. doi:10.1073/pnas.090527097

    PubMed Central  CAS  PubMed  Google Scholar 

  163. Belteki G, Gertsenstein M, Ow DW, Nagy A (2003) Site-specific cassette exchange and germline transmission with mouse ES cells expressing phiC31 integrase. Nat Biotechnol 21(3):321–324. doi:10.1038/nbt787

    CAS  PubMed  Google Scholar 

  164. Smith MC, Brown WR, McEwan AR, Rowley PA (2010) Site-specific recombination by phiC31 integrase and other large serine recombinases. Biochem Soc Trans 38(2):388–394. doi:10.1042/BST0380388

    CAS  PubMed  Google Scholar 

  165. Thorpe HM, Wilson SE, Smith MC (2000) Control of directionality in the site-specific recombination system of the Streptomyces phage phiC31. Mol Microbiol 38(2):232–241

    CAS  PubMed  Google Scholar 

  166. Farruggio AP, Chavez CL, Mikell CL, Calos MP (2012) Efficient reversal of phiC31 integrase recombination in mammalian cells. Biotechnol J 7(11):1332–1336. doi:10.1002/biot.201200283

    PubMed Central  CAS  PubMed  Google Scholar 

  167. Thyagarajan B, Olivares EC, Hollis RP, Ginsburg DS, Calos MP (2001) Site-specific genomic integration in mammalian cells mediated by phage phiC31 integrase. Mol Cell Biol 21(12):3926–3934. doi:10.1128/MCB.21.12.3926-3934.2001

    PubMed Central  CAS  PubMed  Google Scholar 

  168. Groth AC, Fish M, Nusse R, Calos MP (2004) Construction of transgenic Drosophila by using the site-specific integrase from phage phiC31. Genetics 166(4):1775–1782

    PubMed Central  CAS  PubMed  Google Scholar 

  169. Yin Y, Cao G, Xue R, Gong C (2014) Construction of transformed, cultured silkworm cells and transgenic silkworm using the site-specific integrase system from phage φC31. Mol Biol Rep 41(10):6449–6456. doi:10.1007/s11033-014-3527-5

    CAS  PubMed  Google Scholar 

  170. Allen BG, Weeks DL (2005) Transgenic Xenopus laevis embryos can be generated using phiC31 integrase. Nat Methods 2(12):975–979. doi:10.1038/nmeth814

    PubMed Central  CAS  PubMed  Google Scholar 

  171. Hu ZP, Chen LS, Jia CY, Zhu HZ, Wang W, Zhong J (2013) Screening of potential pseudo att sites of Streptomyces phage ΦC31 integrase in the human genome. Acta Pharmacol Sin 34(4):561–569. doi:10.1038/aps.2012.173

    PubMed Central  CAS  PubMed  Google Scholar 

  172. Ma QW, Sheng HQ, Yan JB, Cheng S, Huang Y, Chen-Tsai Y, Ren ZR, Huang SZ, Zeng YT (2006) Identification of pseudo attP sites for phage phiC31 integrase in bovine genome. Biochem Biophys Res Commun 345(3):984–988. doi:10.1016/j.bbrc.2006.04.145

    CAS  PubMed  Google Scholar 

  173. Qu L, Ma Q, Zhou Z, Ma H, Huang Y, Huang S, Zeng F, Zeng Y (2012) A profile of native integration sites used by φC31 integrase in the bovine genome. J Genet Genomics 39(5):217–224. doi:10.1016/j.jgg.2012.03.004

    CAS  PubMed  Google Scholar 

  174. Ni W, Hu S, Qiao J, Wang Y, Shi H, He Z, Li G, Chen C (2012) ΦC31 integrase mediates efficient site-specific integration in sheep fibroblasts. Biosci Biotechnol Biochem 76(11):2093–2095. doi:10.1271/bbb.120439

    CAS  PubMed  Google Scholar 

  175. Ma H, Ma Q, Lu Y, Wang J, Hu W, Gong Z, Cai L, Huang Y, Huang SZ, Zeng F (2014) PhiC31 integrase induces efficient site-specific recombination in the Capra hircus genome. DNA Cell Biol 33(8):484–491. doi:10.1089/dna.2013.2124

    CAS  PubMed  Google Scholar 

  176. Bi Y, Liu X, Zhang L, Shao C, Ma Z, Hua Z, Li L, Hua W, Xiao H, Wei Q, Zheng X (2013) Pseudo attP sites in favor of transgene integration and expression in cultured porcine cells identified by Streptomyces phage phiC31 integrase. BMC Mol Biol 14:20. doi:10.1186/1471-2199-14-20

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Sadelain M, Papapetrou EP, Bushman FD (2012) Safe harbours for the integration of new DNA in the human genome. Nat Rev Cancer 12(1):51–58. doi:10.1038/nrc3179

    CAS  Google Scholar 

  178. Papapetrou EP, Lee G, Malani N, Setty M, Riviere I, Tirunagari LM, Kadota K, Roth SL, Giardina P, Viale A, Leslie C, Bushman FD, Studer L, Sadelain M (2011) Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells. Nat Biotechnol 29(1):73–78. doi:10.1038/nbt.1717

    PubMed Central  CAS  PubMed  Google Scholar 

  179. Keravala A, Lee S, Thyagarajan B, Olivares EC, Gabrovsky VE, Woodard LE, Calos MP (2009) Mutational derivatives of PhiC31 integrase with increased efficiency and specificity. Mol Ther 17(1):112–120. doi:10.1038/mt.2008.241

    PubMed Central  CAS  PubMed  Google Scholar 

  180. Sclimenti CR, Thyagarajan B, Calos MP (2001) Directed evolution of a recombinase for improved genomic integration at a native human sequence. Nucleic Acids Res 29(24):5044–5051

    PubMed Central  CAS  PubMed  Google Scholar 

  181. Xu Z, Thomas L, Davies B, Chalmers R, Smith M, Brown W (2013) Accuracy and efficiency define Bxb1 integrase as the best of fifteen candidate serine recombinases for the integration of DNA into the human genome. BMC Biotechnol 13:87. doi:10.1186/1472-6750-13-87

    PubMed Central  PubMed  Google Scholar 

  182. Olivares EC, Hollis RP, Calos MP (2001) Phage R4 integrase mediates site-specific integration in human cells. Gene 278(1–2):167–176

    CAS  PubMed  Google Scholar 

  183. Stoll SM, Ginsburg DS, Calos MP (2002) Phage TP901-1 site-specific integrase functions in human cells. J Bacteriol 184(13):3657–3663

    PubMed Central  CAS  PubMed  Google Scholar 

  184. Keravala A, Groth AC, Jarrahian S, Thyagarajan B, Hoyt JJ, Kirby PJ, Calos MP (2006) A diversity of serine phage integrases mediate site-specific recombination in mammalian cells. Mol Genet Genomics 276(2):135–146. doi:10.1007/s00438-006-0129-5

    CAS  PubMed  Google Scholar 

  185. Russell JP, Chang DW, Tretiakova A, Padidam M (2006) Phage Bxb1 integrase mediates highly efficient site-specific recombination in mammalian cells. Biotechniques 40(4):462

    Google Scholar 

  186. Hauschild J, Petersen B, Santiago Y, Queisser AL, Carnwath JW, Lucas-Hahn A, Zhang L, Meng X, Gregory PD, Schwinzer R, Cost GJ, Niemann H (2011) Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. Proc Natl Acad Sci USA 108(29):12013–12017. doi:10.1073/pnas.1106422108

    PubMed Central  CAS  PubMed  Google Scholar 

  187. Carlson DF, Tan W, Lillico SG, Stverakova D, Proudfoot C, Christian M, Voytas DF, Long CR, Whitelaw CB, Fahrenkrug SC (2012) Efficient TALEN-mediated gene knockout in livestock. Proc Natl Acad Sci USA 109(43):17382–17387. doi:10.1073/pnas.1211446109

    PubMed Central  CAS  PubMed  Google Scholar 

  188. Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, Bogdanove AJ, Voytas DF (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186(2):757–761. doi:10.1534/genetics.110.120717

    PubMed Central  CAS  PubMed  Google Scholar 

  189. Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188(4):773–782. doi:10.1534/genetics.111.131433

    PubMed Central  CAS  PubMed  Google Scholar 

  190. Carlson DF, Fahrenkrug SC, Hackett PB (2012) Targeting DNA with fingers and TALENs. Mol Ther Nucleic Acids 1:e3. doi:10.1038/mtna.2011.5

    PubMed Central  PubMed  Google Scholar 

  191. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J (2013) RNA-programmed genome editing in human cells. Elife (Cambridge) 2:e00471. doi:10.7554/eLife.00471

    Google Scholar 

  192. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821. doi:10.1126/science.1225829

    CAS  PubMed  Google Scholar 

  193. Sun N, Abil Z, Zhao H (2012) Recent advances in targeted genome engineering in mammalian systems. Biotechnol J 7(9):1074–1087. doi:10.1002/biot.201200038

    CAS  PubMed  Google Scholar 

  194. Dai Y, Vaught TD, Boone J, Chen SH, Phelps CJ, Ball S, Monahan JA, Jobst PM, McCreath KJ, Lamborn AE, Cowell-Lucero JL, Wells KD, Colman A, Polejaeva IA, Ayares DL (2002) Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 20(3):251–255

    CAS  PubMed  Google Scholar 

  195. McCreath KJ, Howcroft J, Campbell KH, Colman A, Schnieke AE, Kind AJ (2000) Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. Nature 405(6790):1066–1069

    CAS  PubMed  Google Scholar 

  196. Yu G, Chen J, Yu H, Liu S, Xu X, Sha H, Zhang X, Wu G, Xu S, Cheng G (2006) Functional disruption of the prion protein gene in cloned goats. J Gen Virol 87(Pt 4):1019–1027. doi:10.1099/vir.0.81384-0

    CAS  PubMed  Google Scholar 

  197. Zhu C, Li B, Yu G, Chen J, Yu H, Xu X, Wu Y, Zhang A, Cheng G (2009) Production of Prnp−/− goats by gene targeting in adult fibroblasts. Transgenic Res 18(2):163–171. doi:10.1007/s11248-008-9220-5

    CAS  PubMed  Google Scholar 

  198. Denning C, Burl S, Ainslie A, Bracken J, Dinnyes A, Fletcher J, King T, Ritchie M, Ritchie WA, Rollo M, de Sousa P, Travers A, Wilmut I, Clark AJ (2001) Deletion of the alpha(1,3)galactosyl transferase (GGTA1) gene and the prion protein (PrP) gene in sheep. Nat Biotechnol 19(6):559–562

    CAS  PubMed  Google Scholar 

  199. Zhou ZR, Zhong BS, Jia RX, Wan YJ, Zhang YL, Fan YX, Wang LZ, You JH, Wang ZY, Wang F (2013) Production of myostatin-targeted goat by nuclear transfer from cultured adult somatic cells. Theriogenology 79(2):225–233. doi:10.1016/j.theriogenology.2012.08.006

    CAS  PubMed  Google Scholar 

  200. Thomas KR, Capecchi MR (1987) Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51(3):503–512

    CAS  PubMed  Google Scholar 

  201. Porter AC, Itzhaki JE (1993) Gene targeting in human somatic cells. Complete inactivation of an interferon-inducible gene. Eur J Biochem 218(2):273–281

    CAS  PubMed  Google Scholar 

  202. Brown JP, Wei W, Sedivy JM (1997) Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277(5327):831–834

    CAS  PubMed  Google Scholar 

  203. Smith LC, Suzuki J, Goff AK, Filion F, Therrien J, Murphy BD, Kohan-Ghadr HR, Lefebvre R, Brisville AC, Buczinski S, Fecteau G, Perecin F, Meirelles FV (2012) Developmental and epigenetic anomalies in cloned cattle. Reprod Domest Anim 47(Suppl 4):107–114. doi:10.1111/j.1439-0531.2012.02063.x

    PubMed  Google Scholar 

  204. Smih F, Rouet P, Romanienko PJ, Jasin M (1995) Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells. Nucleic Acids Res 23(24):5012–5019

    PubMed Central  CAS  PubMed  Google Scholar 

  205. Rouet P, Smih F, Jasin M (1994) Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol Cell Biol 14(12):8096–8106

    PubMed Central  CAS  PubMed  Google Scholar 

  206. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, Cost GJ, Zhang L, Santiago Y, Miller JC, Zeitler B, Cherone JM, Meng X, Hinkley SJ, Rebar EJ, Gregory PD, Urnov FD, Jaenisch R (2011) Genetic engineering of human pluripotent cells using TALE nucleases. Nat Biotechnol 29(8):731–734. doi:10.1038/nbt.1927

    PubMed Central  CAS  PubMed  Google Scholar 

  207. Lombardo A, Cesana D, Genovese P, Di Stefano B, Provasi E, Colombo DF, Neri M, Magnani Z, Cantore A, Lo Riso P, Damo M, Pello OM, Holmes MC, Gregory PD, Gritti A, Broccoli V, Bonini C, Naldini L (2011) Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nat Methods 8(10):861–869. doi:10.1038/nmeth.1674

    CAS  PubMed  Google Scholar 

  208. Santiago Y, Chan E, Liu PQ, Orlando S, Zhang L, Urnov FD, Holmes MC, Guschin D, Waite A, Miller JC, Rebar EJ, Gregory PD, Klug A, Collingwood TN (2008) Targeted gene knockout in mammalian cells by using engineered zinc-finger nucleases. Proc Natl Acad Sci USA 105(15):5809–5814. doi:10.1073/pnas.0800940105

    PubMed Central  CAS  PubMed  Google Scholar 

  209. Whyte JJ, Zhao J, Wells KD, Samuel MS, Whitworth KM, Walters EM, Laughlin MH, Prather RS (2011) Gene targeting with zinc finger nucleases to produce cloned eGFP knockout pigs. Mol Reprod Dev 78(1):2. doi:10.1002/mrd.21271

    CAS  PubMed  Google Scholar 

  210. Yang D, Yang H, Li W, Zhao B, Ouyang Z, Liu Z, Zhao Y, Fan N, Song J, Tian J, Li F, Zhang J, Chang L, Pei D, Chen YE, Lai L (2011) Generation of PPARγ mono-allelic knockout pigs via zinc-finger nucleases and nuclear transfer cloning. Cell Res 21(6):979–982. doi:10.1038/cr.2011.70

    PubMed Central  CAS  PubMed  Google Scholar 

  211. Yu S, Luo J, Song Z, Ding F, Dai Y, Li N (2011) Highly efficient modification of beta-lactoglobulin (BLG) gene via zinc-finger nucleases in cattle. Cell Res 21(11):1638–1640. doi:10.1038/cr.2011.153

    PubMed Central  CAS  PubMed  Google Scholar 

  212. Bogdanove AJ, Voytas DF (2011) TAL effectors: customizable proteins for DNA targeting. Science 333(6051):1843–1846. doi:10.1126/science.1204094

    CAS  PubMed  Google Scholar 

  213. Seruggia D, Montoliu L (2014) The new CRISPR-Cas system: RNA-guided genome engineering to efficiently produce any desired genetic alteration in animals. Transgenic Res 23(5):707–716. doi:10.1007/s11248-014-9823-y

    CAS  PubMed  Google Scholar 

  214. Kim YG, Cha J, Chandrasegaran S (1996) Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci USA 93(3):1156–1160

    PubMed Central  CAS  PubMed  Google Scholar 

  215. Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, Beausejour CM, Waite AJ, Wang NS, Kim KA, Gregory PD, Pabo CO, Rebar EJ (2007) An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25(7):778–785. doi:10.1038/nbt1319

    CAS  PubMed  Google Scholar 

  216. Szczepek M, Brondani V, Büchel J, Serrano L, Segal DJ, Cathomen T (2007) Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat Biotechnol 25(7):786–793. doi:10.1038/nbt1317

    CAS  PubMed  Google Scholar 

  217. Watanabe M, Umeyama K, Matsunari H, Takayanagi S, Haruyama E, Nakano K, Fujiwara T, Ikezawa Y, Nakauchi H, Nagashima H (2010) Knockout of exogenous EGFP gene in porcine somatic cells using zinc-finger nucleases. Biochem Biophys Res Commun 402(1):14–18. doi:10.1016/j.bbrc.2010.09.092

    CAS  PubMed  Google Scholar 

  218. Whyte JJ, Prather RS (2011) Genetic modifications of pigs for medicine and agriculture. Mol Reprod Dev 78(10–11):879–891. doi:10.1002/mrd.21333

    PubMed Central  CAS  PubMed  Google Scholar 

  219. Bao L, Chen H, Jong U, Rim C, Li W, Lin X, Zhang D, Luo Q, Cui C, Huang H, Zhang Y, Xiao L, Fu Z (2014) Generation of GGTA1 biallelic knockout pigs via zinc-finger nucleases and somatic cell nuclear transfer. Sci China Life Sci 57(2):263–268. doi:10.1007/s11427-013-4601-2

    CAS  PubMed  Google Scholar 

  220. Kim E, Kim S, Kim DH, Choi BS, Choi IY, Kim JS (2012) Precision genome engineering with programmable DNA-nicking enzymes. Genome Res 22(7):1327–1333. doi:10.1101/gr.138792.112

    PubMed Central  CAS  PubMed  Google Scholar 

  221. Ramirez CL, Certo MT, Mussolino C, Goodwin MJ, Cradick TJ, McCaffrey AP, Cathomen T, Scharenberg AM, Joung JK (2012) Engineered zinc finger nickases induce homology-directed repair with reduced mutagenic effects. Nucleic Acids Res 40(12):5560–5568. doi:10.1093/nar/gks179

    PubMed Central  CAS  PubMed  Google Scholar 

  222. Wang J, Friedman G, Doyon Y, Wang NS, Li CJ, Miller JC, Hua KL, Yan JJ, Babiarz JE, Gregory PD, Holmes MC (2012) Targeted gene addition to a predetermined site in the human genome using a ZFN-based nicking enzyme. Genome Res 22(7):1316–1326. doi:10.1101/gr.122879.111

    PubMed Central  PubMed  Google Scholar 

  223. Liu X, Wang Y, Guo W, Chang B, Liu J, Guo Z, Quan F, Zhang Y (2013) Zinc-finger nickase-mediated insertion of the lysostaphin gene into the beta-casein locus in cloned cows. Nat Commun 4:2565. doi:10.1038/ncomms3565

    PubMed Central  PubMed  Google Scholar 

  224. Camenisch TD, Brilliant MH, Segal DJ (2008) Critical parameters for genome editing using zinc finger nucleases. Mini Rev Med Chem 8(7):669–676

    CAS  PubMed  Google Scholar 

  225. Deng D, Yan C, Pan X, Mahfouz M, Wang J, Zhu JK, Shi Y, Yan N (2012) Structural basis for sequence-specific recognition of DNA by TAL effectors. Science 335(6069):720–723. doi:10.1126/science.1215670

    PubMed Central  CAS  PubMed  Google Scholar 

  226. Mak AN, Bradley P, Cernadas RA, Bogdanove AJ, Stoddard BL (2012) The crystal structure of TAL effector PthXo1 bound to its DNA target. Science 335(6069):716–719. doi:10.1126/science.1216211

    PubMed Central  CAS  PubMed  Google Scholar 

  227. Tesson L, Usal C, Ménoret S, Leung E, Niles BJ, Remy S, Santiago Y, Vincent AI, Meng X, Zhang L, Gregory PD, Anegon I, Cost GJ (2011) Knockout rats generated by embryo microinjection of TALENs. Nat Biotechnol 29(8):695–696. doi:10.1038/nbt.1940

    CAS  PubMed  Google Scholar 

  228. Mussolino C, Cathomen T (2011) On target? Tracing zinc-finger-nuclease specificity. Nat Methods 8(9):725–726. doi:10.1038/nmeth.1680

    CAS  PubMed  Google Scholar 

  229. Cade L, Reyon D, Hwang WY, Tsai SQ, Patel S, Khayter C, Joung JK, Sander JD, Peterson RT, Yeh JR (2012) Highly efficient generation of heritable zebrafish gene mutations using homo- and heterodimeric TALENs. Nucleic Acids Res 40(16):8001–8010. doi:10.1093/nar/gks518

    PubMed Central  CAS  PubMed  Google Scholar 

  230. Tan WS, Carlson DF, Walton MW, Fahrenkrug SC, Hackett PB (2012) Precision editing of large animal genomes. Adv Genet 80:37–97. doi:10.1016/B978-0-12-404742-6.00002-8

    CAS  PubMed  Google Scholar 

  231. Kambadur R, Sharma M, Smith TP, Bass JJ (1997) Mutations in myostatin (GDF8) in double-muscled belgian blue and piedmontese cattle. Genome Res 7(9):910–916

    CAS  PubMed  Google Scholar 

  232. Grobet L, Martin LJ, Poncelet D, Pirottin D, Brouwers B, Riquet J, Schoeberlein A, Dunner S, Ménissier F, Massabanda J, Fries R, Hanset R, Georges M (1997) A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 17(1):71–74. doi:10.1038/ng0997-71

    CAS  PubMed  Google Scholar 

  233. Proudfoot C, Carlson DF, Huddart R, Long CR, Pryor JH, King TJ, Lillico SG, Mileham AJ, McLaren DG, Whitelaw CB, Fahrenkrug SC (2014) Genome edited sheep and cattle. Transgenic Res. doi:10.1007/s11248-014-9832-x

    PubMed Central  PubMed  Google Scholar 

  234. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823. doi:10.1126/science.1231143

    PubMed Central  CAS  PubMed  Google Scholar 

  235. Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, Peterson RT, Yeh JR, Joung JK (2013) Efficient genome editing in zebrafish using a CRISPR-Cas system. Nat Biotechnol 31(3):227–229. doi:10.1038/nbt.2501

    PubMed Central  CAS  PubMed  Google Scholar 

  236. Makarova KS, Grishin NV, Shabalina SA, Wolf YI, Koonin EV (2006) A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action. Biol Direct 1:7. doi:10.1186/1745-6150-1-7

    PubMed Central  PubMed  Google Scholar 

  237. Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819):1709–1712. doi:10.1126/science.1138140

    CAS  PubMed  Google Scholar 

  238. Yan Q, Zhang Q, Yang H, Zou Q, Tang C, Fan N, Lai L (2014) Generation of multi-gene knockout rabbits using the Cas9/gRNA system. Cell Regen (Lond) 3(1):12. doi:10.1186/2045-9769-3-12

    PubMed Central  Google Scholar 

  239. Huang J, Guo X, Fan N, Song J, Zhao B, Ouyang Z, Liu Z, Zhao Y, Yan Q, Yi X, Schambach A, Frampton J, Esteban MA, Yang D, Yang H, Lai L (2014) RAG1/2 knockout pigs with severe combined immunodeficiency. J Immunol 193(3):1496–1503. doi:10.4049/jimmunol.1400915

    CAS  PubMed  Google Scholar 

  240. Reyes LM, Estrada JL, Wang ZY, Blosser RJ, Smith RF, Sidner RA, Paris LL, Blankenship RL, Ray CN, Miner AC, Tector M, Tector AJ (2014) Creating class I MHC-null pigs using guide RNA and the Cas9 endonuclease. J Immunol 193(11):5751–5757. doi:10.4049/jimmunol.1402059

    CAS  PubMed  Google Scholar 

  241. Boulanger L, Pannetier M, Gall L, Allais-Bonnet A, Elzaiat M, Le Bourhis D, Daniel N, Richard C, Cotinot C, Ghyselinck NB, Pailhoux E (2014) FOXL2 is a female sex-determining gene in the goat. Curr Biol 24(4):404–408. doi:10.1016/j.cub.2013.12.039

    CAS  PubMed  Google Scholar 

  242. Chen Y, Cui Y, Shen B, Niu Y, Zhao X, Wang L, Wang J, Li W, Zhou Q, Ji W, Sha J, Huang X (2014) Germline acquisition of Cas9/RNA-mediated gene modifications in monkeys. Cell Res. doi:10.1038/cr.2014.167

    Google Scholar 

  243. Wan H, Feng C, Teng F, Yang S, Hu B, Niu Y, Xiang AP, Fang W, Ji W, Li W, Zhao X, Zhou Q (2014) One-step generation of p53 gene biallelic mutant Cynomolgus monkey via the CRISPR/Cas system. Cell Res. doi:10.1038/cr.2014.158

    Google Scholar 

  244. Zhou X, Xin J, Fan N, Zou Q, Huang J, Ouyang Z, Zhao Y, Zhao B, Liu Z, Lai S, Yi X, Guo L, Esteban MA, Zeng Y, Yang H, Lai L (2014) Generation of CRISPR/Cas9-mediated gene-targeted pigs via somatic cell nuclear transfer. Cell Mol Life Sci. doi:10.1007/s00018-014-1744-7

    Google Scholar 

  245. Li P, Estrada JL, Burlak C, Montgomery J, Butler JR, Santos RM, Wang ZY, Paris LL, Blankenship RL, Downey SM, Tector M, Tector AJ (2014) Efficient generation of genetically distinct pigs in a single pregnancy using multiplexed single-guide RNA and carbohydrate selection. Xenotransplantation. doi:10.1111/xen.12131

    Google Scholar 

  246. Whitworth KM, Lee K, Benne JA, Beaton BP, Spate LD, Murphy SL, Samuel MS, Mao J, O’Gorman C, Walters EM, Murphy CN, Driver J, Mileham A, McLaren D, Wells KD, Prather RS (2014) Use of the CRISPR/Cas9 system to produce genetically engineered pigs from in vitro-derived oocytes and embryos. Biol Reprod 91(3):78. doi:10.1095/biolreprod.114.121723

    PubMed  Google Scholar 

  247. Ni W, Qiao J, Hu S, Zhao X, Regouski M, Yang M, Polejaeva IA, Chen C (2014) Efficient gene knockout in goats using CRISPR/Cas9 system. PLoS ONE 9(9):e106718. doi:10.1371/journal.pone.0106718

    PubMed Central  PubMed  Google Scholar 

  248. Hai T, Teng F, Guo R, Li W, Zhou Q (2014) One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Res 24(3):372–375. doi:10.1038/cr.2014.11

    PubMed Central  CAS  PubMed  Google Scholar 

  249. Ma Y, Ma J, Zhang X, Chen W, Yu L, Lu Y, Bai L, Shen B, Huang X, Zhang L (2014) Generation of eGFP and Cre knockin rats by CRISPR/Cas9. FEBS J 281(17):3779–3790. doi:10.1111/febs.12935

    CAS  PubMed  Google Scholar 

  250. Sung YH, Baek IJ, Kim DH, Jeon J, Lee J, Lee K, Jeong D, Kim JS, Lee HW (2013) Knockout mice created by TALEN-mediated gene targeting. Nat Biotechnol 31(1):23–24. doi:10.1038/nbt.2477

    CAS  PubMed  Google Scholar 

  251. Hsu PD, Scott DA, Weinstein JA, Ran FA, Konermann S, Agarwala V, Li Y, Fine EJ, Wu X, Shalem O, Cradick TJ, Marraffini LA, Bao G, Zhang F (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31(9):827–832. doi:10.1038/nbt.2647

    PubMed Central  CAS  PubMed  Google Scholar 

  252. Mali P, Aach J, Stranges PB, Esvelt KM, Moosburner M, Kosuri S, Yang L, Church GM (2013) CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol 31(9):833–838. doi:10.1038/nbt.2675

    CAS  PubMed  Google Scholar 

  253. Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, Sander JD (2013) High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31(9):822–826. doi:10.1038/nbt.2623

    PubMed Central  CAS  PubMed  Google Scholar 

  254. Gasiunas G, Barrangou R, Horvath P, Siksnys V (2012) Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci USA 109(39):E2579–E2586. doi:10.1073/pnas.1208507109

    PubMed Central  CAS  PubMed  Google Scholar 

  255. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, Zhang F (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154(6):1380–1389. doi:10.1016/j.cell.2013.08.021

    CAS  PubMed  Google Scholar 

  256. Hickman AB, Dyda F (2014) CRISPR-Cas immunity and mobile DNA: a new superfamily of DNA transposons encoding a Cas1 endonuclease. Mob DNA 5:23. doi:10.1186/1759-8753-5-23

    PubMed Central  PubMed  Google Scholar 

  257. Krupovic M, Makarova KS, Forterre P, Prangishvili D, Koonin EV (2014) Casposons: a new superfamily of self-synthesizing DNA transposons at the origin of prokaryotic CRISPR-Cas immunity. BMC Biol 12:36. doi:10.1186/1741-7007-12-36

    PubMed Central  PubMed  Google Scholar 

  258. Katter K, Geurts AM, Hoffmann O, Mates L, Landa V, Hiripi L, Moreno C, Lazar J, Bashir S, Zidek V, Popova E, Jerchow B, Becker K, Devaraj A, Walter I, Grzybowksi M, Corbett M, Filho AR, Hodges MR, Bader M, Ivics Z, Jacob HJ, Pravenec M, Bosze Z, Rulicke T, Izsvak Z (2013) Transposon-mediated transgenesis, transgenic rescue, and tissue-specific gene expression in rodents and rabbits. Faseb J 27(3):930–941. doi:10.1096/fj.12-205526

    PubMed Central  CAS  PubMed  Google Scholar 

  259. Staunstrup NH, Madsen J, Primo MN, Li J, Liu Y, Kragh PM, Li R, Schmidt M, Purup S, Dagnaes-Hansen F, Svensson L, Petersen TK, Callesen H, Bolund L, Mikkelsen JG (2012) Development of transgenic cloned pig models of skin inflammation by DNA transposon-directed ectopic expression of human beta1 and alpha2 integrin. PLoS ONE 7(5):e36658. doi:10.1371/journal.pone.0036658

    PubMed Central  CAS  PubMed  Google Scholar 

  260. Al-Mashhadi RH, Sorensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF (2013) Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci Transl Med 5(166):166. doi:10.1126/scitranslmed.3004853

    Google Scholar 

  261. Macdonald J, Taylor L, Sherman A, Kawakami K, Takahashi Y, Sang HM, McGrew MJ (2012) Efficient genetic modification and germ-line transmission of primordial germ cells using piggyBac and Tol2 transposons. Proc Natl Acad Sci USA 109(23):E1466–E1472. doi:10.1073/pnas.1118715109

    PubMed Central  CAS  PubMed  Google Scholar 

  262. Park TS, Han JY (2012) piggyBac transposition into primordial germ cells is an efficient tool for transgenesis in chickens. Proc Natl Acad Sci USA 109(24):9337–9341. doi:10.1073/pnas.1203823109

    PubMed Central  CAS  PubMed  Google Scholar 

  263. Liu X, Li N, Hu X, Zhang R, Li Q, Cao D, Liu T, Zhang Y (2013) Efficient production of transgenic chickens based on piggyBac. Transgenic Res 22(2):417–423. doi:10.1007/s11248-012-9642-y

    CAS  PubMed  Google Scholar 

  264. Tyack SG, Jenkins KA, O’Neil TE, Wise TG, Morris KR, Bruce MP, McLeod S, Wade AJ, McKay J, Moore RJ, Schat KA, Lowenthal JW, Doran TJ (2013) A new method for producing transgenic birds via direct in vivo transfection of primordial germ cells. Transgenic Res 22(6):1257–1264. doi:10.1007/s11248-013-9727-2

    CAS  PubMed  Google Scholar 

  265. Flisikowska T, Thorey IS, Offner S, Ros F, Lifke V, Zeitler B, Rottmann O, Vincent A, Zhang L, Jenkins S, Niersbach H, Kind AJ, Gregory PD, Schnieke AE, Platzer J (2011) Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases. PLoS ONE 6(6):e21045. doi:10.1371/journal.pone.0021045

    PubMed Central  CAS  PubMed  Google Scholar 

  266. Li P, Estrada JL, Burlak C, Tector AJ (2013) Biallelic knockout of the alpha-1,3 galactosyltransferase gene in porcine liver-derived cells using zinc finger nucleases. J Surg Res 181(1):e39–e45. doi:10.1016/j.jss.2012.06.035

    CAS  PubMed  Google Scholar 

  267. Lutz AJ, Li P, Estrada JL, Sidner RA, Chihara RK, Downey SM, Burlak C, Wang ZY, Reyes LM, Ivary B, Yin F, Blankenship RL, Paris LL, Tector AJ (2013) Double knockout pigs deficient in N-glycolylneuraminic acid and galactose alpha-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 20(1):27–35. doi:10.1111/xen.12019

    PubMed  Google Scholar 

  268. Kwon DN, Lee K, Kang MJ, Choi YJ, Park C, Whyte JJ, Brown AN, Kim JH, Samuel M, Mao J, Park KW, Murphy CN, Prather RS (2013) Production of biallelic CMP-Neu5Ac hydroxylase knock-out pigs. Sci Rep 3:1981. doi:10.1038/srep01981

    PubMed Central  PubMed  Google Scholar 

  269. Lillico SG, Proudfoot C, Carlson DF, Stverakova D, Neil C, Blain C, King TJ, Ritchie WA, Tan W, Mileham AJ, McLaren DG, Fahrenkrug SC, Whitelaw CB (2013) Live pigs produced from genome edited zygotes. Sci Rep 3:2847. doi:10.1038/srep02847

    PubMed  Google Scholar 

  270. Watanabe M, Nakano K, Matsunari H, Matsuda T, Maehara M, Kanai T, Kobayashi M, Matsumura Y, Sakai R, Kuramoto M, Hayashida G, Asano Y, Takayanagi S, Arai Y, Umeyama K, Nagaya M, Hanazono Y, Nagashima H (2013) Generation of interleukin-2 receptor gamma gene knockout pigs from somatic cells genetically modified by zinc finger nuclease-encoding mRNA. PLoS ONE 8(10):e76478. doi:10.1371/journal.pone.0076478

    PubMed Central  CAS  PubMed  Google Scholar 

  271. Ji D, Zhao G, Songstad A, Cui X, Weinstein EJ (2014) Efficient creation of an APOE knockout rabbit. Transgenic Res. doi:10.1007/s11248-014-9834-8

    PubMed  Google Scholar 

  272. Xin J, Yang H, Fan N, Zhao B, Ouyang Z, Liu Z, Zhao Y, Li X, Song J, Yang Y, Zou Q, Yan Q, Zeng Y, Lai L (2013) Highly efficient generation of GGTA1 biallelic knockout inbred mini-pigs with TALENs. PLoS ONE 8(12):e84250. doi:10.1371/journal.pone.0084250

    PubMed Central  PubMed  Google Scholar 

  273. Liu H, Chen Y, Niu Y, Zhang K, Kang Y, Ge W, Liu X, Zhao E, Wang C, Lin S, Jing B, Si C, Lin Q, Chen X, Lin H, Pu X, Wang Y, Qin B, Wang F, Wang H, Si W, Zhou J, Tan T, Li T, Ji S, Xue Z, Luo Y, Cheng L, Zhou Q, Li S, Sun YE, Ji W (2014) TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. Cell Stem Cell 14(3):323–328. doi:10.1016/j.stem.2014.01.018

    PubMed Central  CAS  PubMed  Google Scholar 

  274. Park TS, Lee HJ, Kim KH, Kim JS, Han JY (2014) Targeted gene knockout in chickens mediated by TALENs. Proc Natl Acad Sci USA 111(35):12716–12721. doi:10.1073/pnas.1410555111

    PubMed Central  CAS  PubMed  Google Scholar 

  275. Niu Y, Shen B, Cui Y, Chen Y, Wang J, Wang L, Kang Y, Zhao X, Si W, Li W, Xiang AP, Zhou J, Guo X, Bi Y, Si C, Hu B, Dong G, Wang H, Zhou Z, Li T, Tan T, Pu X, Wang F, Ji S, Zhou Q, Huang X, Ji W, Sha J (2014) Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156(4):836–843. doi:10.1016/j.cell.2014.01.027

    CAS  PubMed  Google Scholar 

  276. Honda A, Hirose M, Sankai T, Yasmin L, Yuzawa K, Honsho K, Izu H, Iguchi A, Ikawa M, Ogura A (2014) Single-step generation of rabbits carrying a targeted allele of the tyrosinase gene using CRISPR/Cas9. Exp Anim. doi:10.1538/expanim.14-0034

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Authors acknowledge the financial support from CONICET, FONCyT, UNRC (Republica Argentina), ICAR (India), as well as from DAAD and DFG (Germany).

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Authors and Affiliations

  1. Departamento de Biología Molecular, Facultad de Ciencias Exactas, Fco-Qcas y Naturales, Universidad Nacional de Río Cuarto, Río Cuarto, Córdoba, Republic of Argentina

    Pablo Bosch, Diego O. Forcato, Fabrisio E. Alustiza, Ana P. Alessio, Alejandro E. Fili, María F. Olmos Nicotra, Ana C. Liaudat & Nancy Rodríguez

  2. Friedrich-Loeffler-Institute, Institute of Farm Animal Genetics, Biotechnology, 31535, Neustadt, Germany

    Thirumala R. Talluri & Wilfried A. Kues

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  1. Pablo Bosch
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  2. Diego O. Forcato
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  3. Fabrisio E. Alustiza
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  4. Ana P. Alessio
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  5. Alejandro E. Fili
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  6. María F. Olmos Nicotra
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  7. Ana C. Liaudat
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  8. Nancy Rodríguez
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  9. Thirumala R. Talluri
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  10. Wilfried A. Kues
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Correspondence to Wilfried A. Kues.

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Bosch, P., Forcato, D.O., Alustiza, F.E. et al. Exogenous enzymes upgrade transgenesis and genetic engineering of farm animals. Cell. Mol. Life Sci. 72, 1907–1929 (2015). https://doi.org/10.1007/s00018-015-1842-1

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  • DOI: https://doi.org/10.1007/s00018-015-1842-1

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