Ecological geneticsEcological geneticsЭкологическая генетика1811-09322411-9202Eco-Vector248010.17816/ecogen13258-76ArticlesСтатьиResearch ArticleTransgenic farm animals: status of the current researches and the futureТрансгенные сельскохозяйственные животные: современное состояние исследований и перспективыZinovievaNatalia AnatolyevnaЗиновьеваНаталия Анатольевна

doctor of biology science, academician, director

д. б. н., академик, директор. Всероссийский научно-исследовательский институт животноводства им. Л. К. Эрнста

n_zinovieva@mail.ruVolkovaNatalya AleksandrovnaВолковаНаталья Александровна

doctor of biology science, head of the laboratory of cellular engineering

д. б. н., заведующая, лаборатория клеточной инженерии

natavolkova@inbox.ruBagirovVugar AliniyazovichБагировВугар Алиниязович

doctor of biology science, head of the laboratory of a reproductive cryobiology

д. б. н., зав. лаборатории репродуктивной криобиологии

vugarbagirov@mail.ruBremGottfriedБремГоттфрид

ординариус

gottfried.brem@agrobiogen.deThe All-Russian research institute of animal husbandry of L. K. ErnstВсероссийский научно-исследовательский институт животноводства им. Л. К. ЭрнстаUniversity of Veterinary MedicineИнститут животноводства и генетики, ветеринарно-медицинский университет15062015132VOL 13, NO2 (2015)ТОМ 13, №2 (2015)587630032016Copyright ©; 2015, Zinovieva N.A., Volkova N.A., Bagirov V.A., Brem G.Copyright ©; 2015, Зиновьева Н.А., Волкова Н.А., Багиров В.А., Брем Г.2015Zinovieva N.A., Volkova N.A., Bagirov V.A., Brem G.Зиновьева Н.А., Волкова Н.А., Багиров В.А., Брем Г.http://creativecommons.org/licenses/by/4.0https://journals.eco-vector.com/ecolgenet/article/view/2480

The production of transgenic farm animals is of great interest of modern basic and applied researches. This article reviews methods for production of transgenic farm animals including pronuclear microinjection, nuclear transfer of genetically transformed somatic cells, retrovirus and lentivirusmediated gene transfer, the application of spermatogonia as a target for gene transfer. Using site-specific endonucleases (ZNF, TALEN, CRISPR/Cas9) as modern techniques allowing significantly to improve the gene transfer efficiency in farm animals are briefly described. The particular attention is focused on method for genetic modifications of chicken. The advances in various areas of genetic engineering domestic animals are discussed including creating animals with altered metabolism status to improve the quality and efficiency of production, which are genetically resistant to infectious diseases, producers of biologically active recombinant proteins, donors of organs for human transplantation(xenotransplantation) and animals-modelsfor translation biomedical researches. The innovative immune therapy assay as an example of practical application of transgenic animals-bioreactor technology is characterized.

Создание трансгенных сельскохозяйственных животных представляет огромный интерес для решения ряда фундаментальных и прикладных задач современной науки. В статье рассматриваются методы создания трансгенных сельскохозяйственных животных, дискутируются их преимущества и недостатки. Описаны современные достижения в различных направлениях генетической инженерии домашних животных: создании животных с измененных обменом веществ для повышения качества и эффективности производства продукции, генетически устойчивых к инфекционным заболеваниям, являющихся продуцентами биологически активных рекомбинантных белков, доноров внутренних органов для пересадки человеку (ксенотрансплантация) и животных-моделей.

recombinant DNAtransgenesisgenetically modified farm animalsanimals-bioreactorsрекомбинантная ДНКтрансгенезгенетические модифицированные сельскохозяйственные животныеживотные-биореакторыВолкова Н. А., Волкова Л. А., Фомин И. К. с соавт. (2013) Интеграция и экспрессия маркерных генов в эмбрионах кур при использовании ретровирусныхэкспрессирующихся векторов. Сельскохозяйственная биология. № 2: С. 58-61.Волкова Н. А., Волкова Л. А., Фомин И. К. с соавт. (2012) Оптимизация условий введения рекомбинантной ДНК в сперматогенные клетки семенников петухов in vivo. Сельскохозяйственная биология. № 6: С. 56-61.Зиновьева Н. А., Мелерзанов А. В., Петерсен Е. В. с соавт. (2014) Использование трансгенных GAL-KO свиней в ксенотрансплантации: проблемы и перспективы. Сельскохозяйственная биология. № 2: С. 42-49.Зиновьева Н. А., Эрнст Л. К. (2006) Проблемы биотехнологии и селекции сельскохозяйственных животных. Изд. 2-ое, дополненное. Дубровицы: ВИЖ.Немудрый А. А., Валетдинова К. Р., Медведев С. П. с соавт. (2014) Системы редактирования геномов TALEN и CRISPR/Cas - инструменты открытий. Acta Naturae. Т. 6. № 3 (22): С. 20-42.Савченкова И. П., Зиновьева Н. А., Булла Й., Брем Г. (1996) Эмбриональные стволовые клетки, их генетическое изменение путем гомологичной рекомбинации и использование в получении трансгенных животных. Успехи современной биологии. Т. 116 (1): С. 78-91.Серов О. Л. (2013) Трансгенные животные: фундаментальные и прикладные аспекты. Вавиловский журнал генетики и селекции. 2013. Т. 17. № 4/2: C. 1055-1064.Сингина Г. Н., Волкова Н. А., Багиров В. А., Зиновьева Н. А. (2014) Криобанки соматических клеток как перспективный способ сохранения генетических ресурсов животных. Сельскохозяйственная биология. № 6: С. 3-14.Сингина Г. Н., Лопухов А. В., Зиновьева Н. А. с соавт. (2013) Оптимизация параметров энуклеации и слияния ооцита с соматической клеткой при получении клонированных эмбрионов млекопитающих. Сельскохозяйственная биология. № 2: С. 46-51.Шумаков В., Тоневицкий А. (1999) Ксенотрансплантация: научные и этические проблемы. Журнал «Человек». № 6. Дата обращения: 14.04.2015. URL: http://vivovoco.astronet.ru/VV/PAPERS/MEN/TRANSPLANT. HTM.Эрнст Л. К., Волкова Н. А., Зиновьева Н. А. (2008) Фенотипический эффект экспрессии рекомбинантных генов в организме трансгенных животных разных видов. М.: РАСХН. 251 с.Эрнст Л. К., Зиновьева Н. А. (2008) Биологические проблемы животноводства в XXI веке // М.: РАСХН. 501 с.Bagle T. R., Kunkulol R. R., BaigM. S., MoreS. Y. (2013) Transgenic animals and their application in medicine. Int. J. Med. Res. Health Sci. V. 2 (1): P. 107-116.Bosch P., Forcato D. O., Alustiza F. E. et al. (2015) Exogenous enzymes upgrade transgenesis and genetic engineering of farm animals. Cell. Mol. Life Sci. V. 72: P. 1907-1929. DOI 10.1007/s00018-015-1842-1.Brackett B. G., Baranska W., Sawikki W., Korpowski H. (1971) Uptake of heterologous genome by mammalian spermatozoa and itstransfer to ova through fertilization. Proc. Natl. Acad. Sсi. V. 68: P. 353-357.Brem G., Brenig B., Goodman H. M. et al. (1985) Production of transgenic mice, rabbits and pig by microinjection into pronuclei. Zuchtkunde. V. 20: P. 251-252.Brinster R., Nagano M. (1998) Spermatogonial stem cell transplantation, cryopreservation and culture.Semin. Cell. Dev. Biol. V. 9 (4): P. 401-409.Byun S. J., Kim S. W., Kim K. W. et al. (2011)Oviduct-specific enhanced green fluorescent protein expression in transgenic chickens.Biosci. Biotechnol. Biochem. V. 75 (4): P. 646-9.Campbell K. H., McWhir J., Ritchie W. A., Wilmut I. (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature. V. 380: P. 64-66.Carlson D. F., Tan W., Lillico S. G. et al. (2012)Efficient TALEN-mediated gene knockout in livestock.PNAS. V. 109 (43): P. 17382-17387. Cited 10.04.2015. Access for registered users. DOI:10.1073/pnas.1211446109.Chan A., Homan E., Ballou L. et al. (1998) Transgenic cattle produced by reverse-transcribed gene transfer in oocytes. PNAS USA. V. 95: P. 14 028-14 033.Chang K., Qian J., Jiang M. et al. (2002) Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer. BMC Biotechnol. V. 2: P. 5. DOI doi:10.1186/1472-6750-2-5.Chapman S. C., Lawson A., Macarthur W. C. et al. (2005) Ubiquitous GFP expression in transgenic chickens using a lentivira vector. Development. V. 132: P. 935-940.Cibelli J. B., Campbell K. H., Seidel G. E. et al. (2002) The health profile of cloned animals. Nat Biotechnol. V. 20: P. 13-14.Clark K. J., Carlson D. F., Fahrenkrug S. C. (2007). Pigs taking wings with transposons and recombinases. Genome Biol. V. 8, Suppl 1: S13.Cong, L., Ran FA, Cox D. et al. (2013) Multiplex genome engineering using CRISPR/Cas system. Science. V. 339 (6121): P. 819-823.d’Apice A. J., Cowan P. J. (2009) Xenotransplantation: The next generation of engineered animals. TransplImmunol. V. 21: P. 111-115.Dai Y., Vaught T. D., Boone J. et al. (2002) Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nature Biotechnology. V. 20: P. 251-255.de Koning D. J., Archibald A., Haley C. S. (2007) Livestock genomics: bridging the gap between mice and men. Trends Biotechnol. V. 25: P. 483-489Delacote F., Perez C., Guyot V. et al. (2013) High frequency targeted mutagenesis using engineered endonucleases and DNA-end processing enzymes. PloS one. V. 8 (1): e53217.Dougherty D. C., Sanders M. M. (2005) Estrogen action: revitalization of the chick oviduct model. Trends EndocrinolMetab. V. 16: P. 414-419.Dyck M. K., Lacroix D., Pothier F., Sirard M. A. (2003) Making recombinant proteins in animals - different systems, different applications. Trends in Biotechnology. V. 21 (9): P. 394- 409.Ebert K. M., Low M. J., Overstrom E. W.et al. (1988)Moloney MLV-rat somatotropin fusion gene produces biologically active somatotropin in a transgenic pig. MolEndocrinol. V. 2 (3): P. 277-83.Furlan-Magaril M., Rebollar E., Guerrero G. et al. (2011) An insulator embedded in the chicken β-globin locus regulates chromatin domain configuration and differential gene expression. Nucleic Acids Res. V. 39 (1): P. 89-103.Gandolfi F., Lavitrano M., Camaioni A. et al. (1989) The use of sperm-mediated gene transfer for the generation of transgenic pigs. J. Reprod. Fert. V. 81: P. 23-28.Gandolfi. F. (1998) Spermatozoa, DNA binding and transgenic animals. Trans. Res. V. 7: P. 147-155.Garrels W., Mates L., Holler S. et al. (2010). Generation of transgenic pigs by the Sleeping Beauty transposition in zygotes. Reprod. Dom. Anim. V. 45: P. 65Ghazizadeh S., Harington R., Taichmann L. (1999)In vivo transduction of mouse epidermis with recombinant retroviral vectors: implications for cutaneous gene therapy. Gene Ther. V. 7: P. 1267-1275.Gordon, J. W., Scangos, D. J., Plotkin, J. A. et al. (1980) Genetic transformation ofmouse embryos by microinjection of purified DNA (1980) Proc. Natl. Acad. Sci. USA. V. 77: P. 7380-7384.Grosse-Hovest L., Hartlapp I., Marwan W. et al. (2003) A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killing. Eur J Immunol. V. 33 (5): P. 1334-1340.Grosse-Hovest L., Müller S., Minoia R. et al. (2004) Cloned transgenic farm animals produce a bispecific antibody for T cell-mediated tumor cell killing. Proc Natl Acad Sci. V. 101 (18): P. 6858-6863.Grosse-Hovest L., Wick W., Minoia R. et al. (2005) Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo. Int J Cancer. V. 117 (6): P. 1060-1064.Hai T., Teng F., Guo R. et al. (2014) One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Res. V. 24: P. 372-375. Cited 10.04.2015. Access for registered users. DOI:10.1038/cr.2014.11.Hammer R., Pursel V., Rexroad J. et al. (1985) Production of trans-genie rabbits, sheep and pigs by microinjection. Nature. V. 315: P. 680-683.Harrison M. M., Jenkins B. V., O’Connor-Giles K. M., Wildonger J. A (2014) CRISPR view of development. Genes & Dev. V. 28: P. 1859-1872. Cited 10.04.2015. Access for registered users. DOI: 10.1101/gad.248252.114.Harvey A. J., Speksnijder, Baugh L. R. et al. (2002) Expression of exogenous protein in G. the egg white of transgenic chickens. Nat. Biotechnol. V. 20: P. 396-399.Haskell R., Bowen R. (1995) Efficient production of transgenic cattle by retroviral infection of early embryos. Mol. Reprod. Dev. V. 40 (3): P. 386-390Hauschild J., Petersen B., Santiago Y., et al. (2011) Efficient generation of a biallelic knockout in pigs using zincfinger nucleases. Proc Natl Acad Sci. V. 108: P. 12 013-12 017.Heo Y., Quan X., Xu Y. et al. (2014) CRISPR/Cas9 nuclease-mediated gene knock-in in bovine pluripotent stem cells and embryos. Stem Cells Dev. Cited 10.04.2015. Access for registered users. DOI:10.1089/scd.2014.0278.Hofmann A., Kessler B., Ewerling S. et al. (2003) Efficienttransgenesis in farm animals by lentiviral vectors. EMBO Rep. V. 4 (11): P. 1054-1060. DOI: 10.1038/sj.embor.7400007.Hofmann A., Kessler B., Ewerling S. et al. (2006) Epigenetic regulation of lentiviral transgene vectors in a large animal model. MolTher. V. 13: P. 59-66.Hofmann A., Zakhartchenko V., Weppert M. et al. (2004) Generation of transgenic cattle by lentiviral gene transfer into oocytes. Biol. Reprod. V. 71 (2): P. 405-409.Horii T., Arai Y., Yamazaki M. et al. (2014) Validation of microinjection methods for generating knockout mice by CRISPR/Cas-mediated genome engineering. Scientific Rep. V.4: P.4513. Cited 10.04.2015. Access for registered users. DOI: 10.1038/srep04513.Houdebine L. (2009) Production of pharmaceutical proteins by transgenic animals. Comparative Immunology, Microbiology and Infectious Diseases. V. 32: P. 107-121.Iqbal K., Barg-Kues B., Broll S. et al. (2009). Cytoplasmic injection of circular plasmids allows targeted expression in mammalian embryos. BioTechniques. V. 47: P. 959-968.Ivarie R. (2003)Aviantransgenesis: progress towards the promise. Trends Biotechnol. V. 21: P. 14-19Ivics Z, Hackett P. B., Plasterk R. H., Izsvák Z. (1997) Molecular reconstruction of Sleeping Beauty, a Tc1-616 like transposon from fish, and its transposition in human cells. Cell. V. 91: P. 501-510.Jacobsen J. C., Bawden C. S., Rudiger S. R. et al. (2010) An ovine transgenic Huntington's disease model. Hum Mol Genet. V. 19: P. 1873-1882.Jahner D., Jaenisch R. (1985) Retorvirus-induced de novo methylation of flanking host sequences correlates with gene inactivity. Nature. V. 315: P. 594-597.Jim K. (2009) First US approval for a transgenic animal drug. Nature Biotechnology. V. 27 (4): P. 302-304.Kamihira M., Ono K., Esaka K. et al. (2005) High-Level Expression of Single-Chain Fv-Fc Fusion Protein in Serum and Egg White of Genetically Manipulated Chickens by Using a Retroviral Vector. J. Virol. V. 79 (17): P. 10 864-10 874.Kues W. A., Garrels W., Mates L. et al. (2010) Production of transgenic pigs by the Sleeping Beauty transposon system. Transgenic Research. V. 19: P. 336.Kues W. A., Niemann H. (2011) Advances in farm animal transgenesis. Prev Vet Med. V. 102: P. 146-156. doi: 10.1016/j.prevetmed.2011.04.009.Klymiuk N., Böcker W., Schönitzer V. et al. (2012) First inducible transgene expression in porcine large animal models. The FASEB Journal. V. 26 (3). P. 1086-1099.Kodama D., Nishimiya D., Nishijima K. et al. (2012) Chicken oviduct-specific expression of transgene by a hybrid ovalbumin enhancer and the Tet expression system. J Biosci Bioeng. V. 113 (2): P. 146-53.Kolber-Simonds D., Lai L., Watt S. R. et al. (2004) Production of alpha-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. Proceedings of the National Academy of Sciences of the United States of America. V. 101 (19): P. 7335-7340.Kuroiwa Y., Kasinathan P., Choi Y. J. et al. (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat Biotechnol. V. 20: P. 889-894.Kwon M. S., Koo B. C., Choi B. R. et al. (2008) Generation of transgenic chickens that produce bioactive human granulocyte-colony stimulating factor. Molecular Reproduction and Development. V. 75: P. 1120-1126.Kwon S. C., Choi J. W., Jang H. J. et al. (2010) Production of biofunctional recombinant human interleukin 1 receptor antagonist (rhIL1RN) from transgenic quail egg white. Biology of Reproduction. V. 82: P. 1057-1064.Lai L., Kolber-Simonds D., Park K. W. et al. (2002). Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning.Science. V. 295 (5557): P. 1089-1092.Lassnig C., Mueller M. (2013) Disease-Resistant Transgenic Animals. In: Christou P. et al. (eds.), Sustainable Food Production, Springer Science+Business Media New York. P. 747-760. Cited 10.04.2015. Access for registered users. DOI 10.1007/978-1-4614-5797-8.Lee S, Park H, Kong I, Wang Z (2013) 30 a transcription activatorlike effector nuclease (Talen)-mediated universal gene knock-in strategy for mammary glands-specific expression of recombinant proteins in dairy cattle. ReprodFertil Dev. V. 26: P. 129-129Lillico S. G., A. Sherman M. J. McGrew C. D. et al. (2007) Oviduct-specific expression of two therapeutic proteins in transgenic hens. PNAS. V. 104 (6): P. 1771-1776.Luo Y., Lin L., Bolund L., Jensen T. G., Sørensen C. B. Genetically modified pigs for biomedical research // J Inherit Metab Dis., 2012, 35 (4), p. 695-713.Maione B., Lavitrano M., Spadatora C., Kiessling A. A. (1998) Sperm-mediated gene transfer in mice. Mol. Reprod. Dev. V. 50: P. 406-409.Mali P., Yang L., Esvelt K. M. et al. (2013) RNA-guided human genome engineering via Cas9. Science. V. 339: P. 823-826.McCreath K. J., Howcroft J., Campbell K. H. et al. (2000) Production of genetargeted sheep by nuclear transfer from cultured somatic cells. Nature. V. 405: P. 1066-1069.McGrew M. J., Sherman A., Ellard F. M. et al. (2004)Efficient production of germline transgenic chickens using lentiviral vectors. EMBO Rep. V. 5: P. 728-733.Melo E. O., Canavessi A. M., Franco M. M., Rumpf R. (2007) Animal transgenesis: state of the art and applications. J. Appl. Genet. V. 48 (1). P. 47-61.Miller J. C., Tan S, Qiao G. et al. (2011) A TALE nuclease architecture for efficient genome editing. Nat Biotechnol. V. 29 (2): P. 143-148.Miyahara D., Mori T., Makino R. et al. (2014) Culture Conditions for Maintain Propagation, Long-term Survival and Germline Transmission of Chicken Primordial Germ Cell-Like Cells J. Poult. Sci. V. 51: P. 87-95Moghaddassi S., Eyestone W., Bishop C. E. (2014) TALENmediated modification of the bovine genome for large-scale production of human serum albumin. PLoS One. V. 9 (2): e89631.Mozdziak P. E., Borwornpinyo S., McCoy D. W., Petitte J. N. (2003) Development of transgenic chickens expressing bacterial betagalactosidase. Dev. Dyn. V. 226: P. 439-445.Mozdziak P. E., Petitte J. N. (2004) Status of transgenic chicken models for developmental biology. Dev. Dyn. V. 229: P. 414-421.Muramatsu T., Mizutani Y., Ohmori Y., Okumura J. (1997) Comparison of three nonviral transfection methods for foreign gene expression in early chicken embryos in ovo. Biochem. Biophys. Res. Commun. V. 230: P. 376-380.Nakamura Y. Kagami H., Tagami T. (2013) Development, differentiation and manipulation of chickengerm cells Develop. Growth Differ. V. 55: P. 20-40.Ni W., Qiao J., Hu S. et al. (2014) Efficient Gene Knockout in Goats Using CRISPR/Cas9 System.PLoS ONE. V. 9 (9): e106718. Cited 10.04.2015. Access for registered users. DOI:10.1371/journal.pone.0106718.Palmiter R. D., Brinster R. L., Hammer R. E. et al. (1982) Dramatic growth of mice that develop from eggs micro-injected with metallothionein-growth hormone fusion gene. Nature. V. 300: P. 611-615.Palmiter R., Sandgren E., Avarbock M. et al. (1991) Heterologous introns can enhance expression of transgenes in mice. PNAS USA. V. 88: P. 478-482.Phelps C. J., Koike C, Vaught T. D. et al. (2003) Production of alpha 1,3-galactosyltransferase-deficient pigs. Science. V. 299 (5605): P. 411-414.Perry A. C. F., Wakayama T., Kishikawa H. et al. (1999) Mammalian transgenesis by intracytoplasmic sperm injection. Science. V. 284: P. 1180-1183Perry A. C., Rothman A., de las Heras J. I. et al. (2001) Efficient metaphase II transgenesis with different transgene archetypes. Nat Biotechnol. V. 19: P. 1071-1073.Porteus M. H., Carroll D. (2005) Gene targeting using zinc finger nucleases. Nat Biotech. V. 23: P. 967-973.Pursel V. G., Hammer R. E., Bolt D. J. et al. (1990)Integration, expression and germ-line transmission of growth-related genes in pigs.J Reprod Fertil Suppl. V. 41: P. 77-87.Raju T. S., Briggs J. B., Borge S. M., Jones A. J. (2000) Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology. V. 10: P. 477-486.Rapp J. C., Harvey A. J., Speksnijder G. L. et al. (2003) Biologically active human interferon a-2b produced in the egg white of transgenic hens. Transgenic Res. V. 12: P. 569-575.Renner S., Fehlings C., Herbach N. et al. (2010) Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes. V. 59. P. 1228-1238.RexroadC. E.Jr., Hammer R. E., Behringer R. R. et al. (1990) Insertion, expression and physiology of growth-regulating genes in ruminants. J Reprod Fertil Suppl. V. 41: P. 119-124.RexroadC. E.Jr., Hammer R. E., Bolt D. J. et al. (1989)Production of transgenic sheep with growth-regulating genes. Mol Reprod Dev. V. 1 (3): 164-169.RichtJ. A., Kasinathan P., Hamir A. N. et al. (2007) Production of cattle lacking prion protein. Nature Biotechnology. V. 25: P. 132-138.Ritchie W. A., King T., Neil C. et al. (2009) Transgenic sheep designed for transplantation studies. Mol. Reprod. Dev. V. 76: P. 61-64.Rogers C. S., Stoltz D. A., Meyerholz D. K. et al. (2008) Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science. V. 321. P. 1837-1841.Schelander K., Peli J., Small F., Brem G. (1995) Artificial insemination in cattle with DNA-treated sperm. Anim. Biotechnol. V. 6: P. 41-50Schnieke A., Kind A., Ritchie W. et al. (1997) Human factor IX transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts. Science. V. 278: P. 2130-2133Scott B. B., Lois C. (2005) Generation of tissue-specific transgenic birds with lentiviral vectors. PNAS. V. 102 (45): P. 16 443-16 447.Scott B. B., Velho T. A., Sim S., Lois C. (2010) Applications of avian transgenesis. ILAR J. V. 51 (4): P. 353-61.Shimizu M., Losos J. K., Gibbins A. M. (2005) Analysis of an approach to oviduct-specific expression of modified chicken lysozyme genes. Biochem Cell Biol. V. 83 (1): P. 49-60.Simons J., Wilmut I., Clark A. et al. (1988) Gene transfer into sheep. Bio/Technol. V. 6: P. 179-183.Smith C. A., Roeszler K. N., Sinclair A. H. (2009) Robust and ubiquitous GFP expression in a single generation of chicken embryos using the avian retroviral vector, RCASBP. Differentiation. V. 77 (5): P. 473-82.Sommer J. R., Estrada J. L., Collins E. B. et al. (2011) Production of ELOVL4 transgenic pigs: a large animal model for Stargardt-like macular degeneration. Br J Ophthalmol. V. 95 (12). P. 1749-1754. doi: 10.1136/bjophthalmol-2011-300417.Sperandio S., Lulli V., Bacci M. et al. (1996) Sperm mediated DNA transfer in bovine and swine species. Anim. Biotechnol. V. 7: P. 59-77.Tan W., Carlson D. F., Lancto C. A. et al. (2013) Efficient nonmeiotic allele introgression in livestock using custom endonucleases. PNAS. V. 110 (41): P. 16526-16531 Cited 10.04.2015. Access for registered users. DOI:10.1073/pnas.1310478110/-/DCSupplemental.Tyack S. G., Jenkins K. A., O’Neil T. E. et al. (2013) A new method for producing transgenic birds via direct in vivo transfection of primordial germ cells. Transgenic Reserch. V. 22: P. 1257-1264Wang S., Sun X., Ding F. et al. (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. V. 72: P. 535-541.Wang Y., Zhao S., Bai L. et al. (2013) Expression Systems and Species Used for Transgenic Animal Bioreactors.BioMed Research International. V. 2013, Article ID 580463, 9 pages. URL: http: // dx.doi.org/10.1155/2013/580463.Ward K. A., Nancarrow C. D., Murray J. D. et al. (1989)The physiological consequences of growth hormone fusion gene expression in transgenic sheep. J. Cell Biochem. V. 13: P. 164Weiss E. H., Lilienfeld B. G., Muller S. et al. (2009) HLA-E/human beta2-microglobulin transgenic pigs: Protection against xenogeneic human anti-pig natural killer cell cytotoxicity. Transplantation. V. 87: P. 35-43.Whitelaw C. B., Radcliffe P. A., Ritchie W. A. et al. (2004) Efficient generation of transgenic pigs using equine infectious anaemia virus (EIAV) derived vector. FEBS Lett. V. 571: P. 233-236.Whitworth K. M., Lee K., Benne J. A. et al. (2014) Use of the CRISPR/Cas9 System to Produce Genetically Engineered Pigs from In Vitro-Derived Oocytes and Embryos. Biology of Reproduction. V. 91 (3): P. 78-90.Wiedenheft B., Sternberg S. H., Doudna J. A. (2012) RNA-guided genetic silencing systems in bacteria and archaea. Nature. V. 482: P. 331-338.Wieghart M., Hoover J. L., McGrane M. M.et al. (1990) Production of transgenic pigs harbouring a rat phosphoenolpyruvate carboxykinase-bovine growth hormone fusion gene. J ReprodFertil Suppl. V. 41: P. 89-96.Wine J. J. (2010) The development of lung disease in cystic fibrosis pigs. Sci. Transl. Med. V. 2, 29ps20.Xin J., Yang H., Fan N. et al. (2013)Highly efficient generation of GGTA1 biallelic knockout inbred mini-pigs with TALENs.PLoS One8 (12): e84250.