Abstract
Until the advent of transgenic mouse technology, studies of mammalian gene expression and regulation were largely limited to cell lines transfected with constructs containing limited genetic information. Developmental studies were not possible since cell lines are generally locked into one ontogenic stage. Transgenic mice provided two improvements and facilitated the study of gene function in development and disease. First, transgene expression in mice allowed assessment of phenotypes. Second, gene expression could be studied throughout development and tissue-specific regulatory elements could be analyzed. However, expression of transgenes was erratic due to position effects and copy number-independent expression. In many instances these problems were due to the nature of the transgene constructs, which typically were limited in their size due to constraints on how large a DNA fragment could be isolated without degradation and introduced into the mouse. Thus, deletion of cis sequences was necessary during the design of transgenes to be injected. Many large genes with exons spanning several hundred kilobases or multigenic loci could not be used as transgenes. cDNAs were substituted for large genes or individual genes from a multigene cluster were utilized in place of an entire locus. However, expression from these constructs was subject to the effects of surrounding chromatin into which they were integrated. Some improvement resulted when other cis-acting elements, such as enhancers, introns or polyadenylation signals were included. These additional sequences assisted studies in which the main goal was to express the transgene, but these truncated constructs lacked their natural regulatory elements and thus developmental studies were not necessarily indicative of how the native gene might be regulated. Ideally, a system in which large genes or loci could be successfully used in the generation of transgenic mice might improve the utility of transgenic studies. Inclusion of distal regulatory elements within the native locus might validate developmental studies and insulate the construct from position effects. With this in mind several lab groups successfully implemented the use of large DNA constructs, in particular yeast artificial chromosomes (YACs), as transgenes (1–21).
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Choi, T.K., Hollenbach, P.W., Pearson, B.E., Ueda, R.M., Weddell, G.N., Kurahara, C.G., Woodhouse, C.S., Kay, R.M. and Loring, J.F. (1993) Nature Genet. 4, 117–123.
Davies, N.P., Rosewell, I.R., Richardson, J.C., Cook, G.P., Neuberger, M.S., Brownstein, B.H., Norris, M.L. and Brüggemann, M. (1993) Biotechnology 11, 911–914.
Gaensler, K.M.L., Kitamura, M. and Kan, Y.W. (1993) Proc. Nat. Acad. Sci. U.S.A. 90, 11381–11385.
Jakobovits, A., Moore, A.L., Green, L.L., Vergara, G.J., Maynard-Carrie, C.E., Austin, H.A. and Klapholz, S. (1993) Nature 362, 255–258.
Lamb, B.T., Sisodia, S.S., Lawler, A.M., Slunt, H.H., Kitt, CA., Kearns, W.G., Pearson, P.L., Price, D.L. and Gearhart, J.D. (1993) Nature Genet. 5, 22–30.
Pearson, B.E. and Choi, T.K. (1993) Proc. Nat. Acad. Sci. U.S.A. 90, 10578–10582.
Peterson, K.R., Clegg, C.H., Huxley, C., Josephson, B.M., Haugen, H.S., Furukawa, T. and Stamatoyannopoulos, G. (1993) Proc. Nat. Acad. Sci. U.S.A. 90, 7593–7597.
Schedl, A., Montoliu, L., Kelsey, G. and Schutz, G. (1993) Nature 362, 258–261.
Strauss, W.M., Dausman, J., Beard, C., Johnson, C., Lawrence, J.B. and Jaenisch, R. (1993) Science 259, 1904–1907.
Green, L.L., Hardy, M.C., Maynard-Currie, C.E., Tsuda, H., Louie, D.M., Mcndez, M.J., Abderrahim, H., Noguchi, M., Smith, D.H., Zeng, David, N.E., Sasai, H., Garza, D., Brenner, D.G., Hales, J.F., McGuinness, R.P., Capon, D. J., Klapholz, S. and Jakobovits, A. (1994) Nature Genet. 7, 13–21.
Bungert, J., Dave, U., Lim, K.-C, Lieuw, K.H., Shavit, J.A., Liu, Q. and Engel, J.D. (1995) Genes Dev. 9, 3083–3096.
Frazer, K.A., Narla, G., Zhang, J.L. and Rubin E.M. (1995) Nature Genet. 9, 424–431.
McCormick, S.P.A., Ng, J.K., Taylor, S., Flynn, L.M., Hammer, R.E. and Young, S.G. (1995) Proc. Nat. Acad. Sci. U.S.A. 92, 10147–10151.
Peterson, K.R., Li, Q., Clegg, C.H., Furukawa, T., Navas, P.A., Norton, E.J., Kimbrough, T.G. and Stamatoyannopoulos, G. (1995) Proc. Nat. Acad. Sci. U.S.A. 92, 5655–5659.
Smith, D.J., Zhu, Y., Zhang, J., Cheng, J.-F. and Rubin, E.M. (1995) Genomics 27, 425–434.
Heard, E., Kress, C., Mongelard, F., Courtier, B., Rougeulle, C., Ashworth, A., Vourc’h, C., Babinet, C. and Avner, P. (1996) Human Mol. Genet. 5, 441–450.
Huxley, C., Passage, E., Manson, A., Putzu, G., Figarella-Branger, D., Pellissier, J.F. and Fontés, M. (1996) Human Mol. Genet. 5, 563–569.
Lee, J.T., Strauss, W.M., Dausman, J.A. and Jaenisch, R. (1996) Cell 83, 83–94.
Matsuura, S., Episkopou, V., Hamvas, R. and Brown, S.D.M. (1996) Human Mol. Genet. 5, 451–459.
Peterson, K.R., Clegg, C.H., Navas, P.A., Norton, E.J., Kimbrough, T.G. and Stamatoyannopoulos, G. (1996) Proc. Nat. Acad. Sci. U.S.A. 93, 6605–6609.
Schedl, A., Ross, A., Lee, M., Engelkamp, D., Rashbass, P., Van Heyningen, V. and Hastie, N.D. (1996) Cell 86, 71–82.
Steinberg, N. (1990) Proc. Nat. Acad. Sci. U.S.A. 87, 103–107.
Ioannou, P.A., Amemiya, C.T., Garnes, J., Kroisel, P.M., Shizuyu, H., Chen, C., Batzer, M.A. and de Jong, P.J. (1994) Nature Genet. 6, 84–89.
Kim, U.-J., Shizuyu, H., de Jong, P.J., Birren, B. and Simon, M.I. (1992) Nucl. Acids Res. 20, 1083–1085.
Shizuyu, H., Birren, B., Kim, U.-J., Mancino, V., Slepak, T., Tachiiri, Y. and Simon, M. (1992) Proc. Nat. Acad. Sci. U.S.A. 89, 8794–8797.
Burke, D.T., Carle, G.F. and Olson, M.V. (1987) Science 236, 806–812.
Rothstein, R. (1995) in Guide to Yeast Genetics and Molecular Biology (Guthrie, C.and Fink, G.R., eds.), pp. 281–301, Academic Press, San Diego, CA.
Duff, K. and Huxley, C. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 187–198, Humana Press, Totowa, NJ.
Huxley, C. and Gnirke, A. (1994) in YAC Libraries, A User’s Guide (Nelson, D.L. and Brownstein, B.H., eds.), pp. 143–163, W. H. Freeman and Co., Salt Lake City, UT.
Huxley, C. (1994) in Genetic Engineering, Vol. 16 (Setlow, J.K., ed.), pp. 65–91, Plenum Press, New York, NY.
Lamb, B.T. and Gearhart, J.D. (1995) Curr. Opin. Genet. Dev. 5, 342–348.
Davies, N.P. and Huxley, C. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 281–292, Humana Press, Totowa, NJ.
Schedl, A., Grimes, B. and Montoliu, L. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 293–306, Humana Press, Totowa, NJ.
Strauss, W.M. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 307–327, Humana Press, Totowa, NJ.
Smith, D.R. (1994) in YAC Libraries, A User’s Guide (Nelson, D.L. and Brownstein, B.H., eds.), pp. 1–31, W. H. Freeman and Co.
Ling, L.L., Smith, D.R. and Moir, D.T. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 231–237, Humana Press, Totowa, NJ.
McKee-Johnson, J.W. and Reeves, R.H. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 167–186, Humana Press, Totowa, NJ.
Fairhead, C., Heard, E., Arnaud, D., Avner, P. and Dujon, B. (1995) Nucl. Acids Res. 23, 4011–4012.
Barton, M.C., Hoekstra, M.F. and Emerson, B.M. (1990) Nucleic Acids Res. 18, 7349–7355.
Duff, K., McGuigan, A., Huxley, C., Schulz, F. and Hardy, J. (1994) Gene Therapy 1, 70–75.
McCormick, S.P.A., Peterson, K.R., Hammer, R.E., Clegg, C.H. and Young, S.G. (1996) Trends Cardiovasc. Med. 6, 16–24.
Peterson, K.R., Clegg, C.H., Li, Q., Navas, P.A., Norton, E.J., Leppig, K.A. and Stamatoyannopoulos, G.(1995) in Hemoglobin Switching, (Stamatoyannopoulos, G., ed.), pp. 45–58, Intercept, Ltd., Andover, UK.
Ausubet, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A. and Struhl, K., eds. (1996) in Current Protocols in Molecular Biology, pp. 13.2.4–13.2.12, Greene Publishing Associates and John Wiley and Sons, New York, NY.
Hugerat, Y., Spencer, F., Zenvirth, D. and Simchen, G. (1994) Genomics 22, 108–117.
Spencer, F., Hugerat, Y., Simchen, G., Hurko, O., Connelly, C. and Hieter, P. (1994) Genomics 22, 118–126.
Spencer, F. and Simchen, G. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 239–252, Humana Press, Totowa, NJ.
Hamer, L., Johnston, M. and Green, E.D. (1995) Proc. Nat. Acad. Sci. U.S.A. 92, 11706–11710.
Gnirke, A., Huxley, C., Peterson, K. and Olson, M.V. (1993) Genomics 15, 659–667.
Couto, L.B., Spangler, E.A. and Rubin, E.M. (1989) Nucl. Acids Res. 17, 8010.
Schedl, A., Larin, Z., Montoliu, L., Thies, E., Kelsey, G., Lehrach, H. and Schütz, G. (1993) Nucl. Acids Res. 21, 4783–4787.
Montoliu, L., Schedl, A., Kelsey, G., Lichter, P., Larin, Z., Lehrach, H. and Schütz, G. (1993) Cold Spring Harbor Symp. Quant. Biol. 58, 55–62.
Maule, J.C., Porteous, D.J. and Brookes, A.J. (1994) Nucl. Acids Res. 22, 3245–3246.
Nishio, H., Takeshima, Y., Narita, N., Yanagawa, H., Suzuki, Y., Ishikawa, Y., Minami, R., Nakamura, H. and Matsuo, M. (1994) J. Clin. Invest. 94, 1037–1042.
Nobile, C., Galvagni, F., Marchi, J., Roberts, R. and Vitiello, L. (1995) Genomics 28, 97–100.
Gaensler, K.M.L., Burmeister, M., Brownstein, B.H., Taillon-Miller, P. and Myers, R.M. (1991) Genomics 10, 976–984.
Ferrin, L.J. and Camerini-Otero, R.D. (1991) Science 254, 1494–1497.
Iadonato, S.P. and Gnirke, A. (1996) in Methods in Molecular Biology, Vol. 54: YAC Protocols (Markie, D., ed.), pp. 75–85, Humana Press, Totowa, NJ.
Schedl, A., Beermann, F., Thies, E., Montoliu, L., Kelsey, G. and Schütz, G. (1992) Nucl. Acids Res. 20, 3073–3077.
Beermann, F., Ruppert, S., Hummler, E., Bosch, F.X., Müller, G., Rüther, U. and Schütz, G. (1990) EMBO J. 9, 2819–2826.
Tuan, D., Solomon, W., Li, Q. and London, I. (1985) Proc. Nat. Acad. Sci. U.S.A. 82, 6384–6388.
Forrester, W.C., Thompson, C., Elder, J.T. and Groudine, M. (1986) Proc. Nat. Acad. Sci. U.S.A. 83, 1359–1363.
Grosveld, F., Blom Van Assendelft, G., Greaves, D. and Kollias, G. (1987) Cell 51, 975–985.
Forrester, W.C., Takegawa, S., Papayannopoulou, T., Stamatoyannopoulos, G. and Groudine, M. (1987) Nucl. Acids Res. 15, 10159–10177.
Stamatoyannopoulos, G. and Nienhuis, A.W. (1994) in Molecular Basis of Blood Diseases, 2nd ed. (Stamatoyannopoulos, G., Nienhuis, A.W., Majerus P., Varmus H, eds.), pp. 107–155, W.B. Saunders. Chicago, IL.
Fishwild, D.M., O’Donnell, S.L., Bengoechea, T., Hudson, D.V., Harding, F., Bernhard, S.L., Jones, D., Kay, R.M., Higgins, K.M., Schramm, S.R. and Lonberg, N. (1996) Nature Biotech. 14, 845–851.
Chance, P.F. and Fischbeck, K.H. (1994) Hum. Mol. Genet. 3, 1503–1507.
Glaser, T., Walton, D.S. and Maas, R.L. (1992) Nature Genet. 2, 232–239.
Jordan, T., Hanson, I., Zaletayev, D., Hodgson, S., Presser, J., Seawright, A., Hastie, N. and Van Heyningen, V. (1992) Nature Genet. 1, 328–332.
Noll, M. (1993) Curr. Opin. Genet. Dev. 3, 595–605.
Hill, R.E., Favor, J., Hogan, B.L., Ton, C.C., Saunders, G.F., Hanson, I.M., Presser, J., Jordan, T., Hastie, N.D. and Van Heyningen, V. (1991) Nature 354, 522–525.
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Peterson, K.R. (1997). Production and Analysis of Transgenic Mice Containing Yeast Artificial Chromosomes. In: Setlow, J.K. (eds) Genetic Engineering. Genetic Engineering, vol 19. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5925-2_13
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