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Production of Transgenic Mice with Yeast Artificial Chromosomes

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Developmental Biology Protocols: Volume II

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 136))

Abstract

The stable introduction of recombinant DNA into the germline of mammals is one of the major technological advances in biology and has greatly facilitated the study of gene function in development and disease,as well as the development of biotherapeutics. Landmark experiments conducted in the early 1980s established the feasibility and reproducibility of stably introducing DNA by microinjection into the male pronucleus of single-cell mouse embryos (15).The utilization of transgenic mice now represents a major strategy for the examination of genetic and biologic questions in vivo,both in basic research and industry.

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References

  1. Wagner, T. E., Hoppe, P. C., Jollick, J. D., Scholl, D. R., Hodinka, R. L., and Gault, J. B. (1981) Microinjection of a rabbit ββglobin gene into zygotes and its subsequent expression in adult mice and their offspring. Proc. Natl. Acad. Sci. USA 78, 6376–6380.

    Article  PubMed  CAS  Google Scholar 

  2. Wagner, E. F., Stewart, T. A., and Mintz, B. (1981) The human ββglobin gene and a functional thymidine kinase in developing mice. Proc. Natl. Acad. Sci. USA 78, 5016–5020.

    Article  PubMed  CAS  Google Scholar 

  3. Harbers, K., Jahner, D., and Jaenisch, R. (1981) Microinjection of cloned retroviral genomes into mouse zygotes: integration and expression in the animal. Nature 293, 540–542.

    Article  PubMed  CAS  Google Scholar 

  4. Gordon, J. W., Scangos, G. A., Plotkin, D. J., Barbosa, J. A., and Ruddle, F. H. (1980) Genetic transformation of mouse embryos by microinjection of purified DNA. Proc. Natl. Acad. Sci. USA 77, 7380–7384.

    Article  PubMed  CAS  Google Scholar 

  5. Brinster, R. L., Chen, Y., Trumbauer, E., Senera, A. W., Warren, R., and Palmiter, R. D. (1981) Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 27, 223–231.

    Article  PubMed  CAS  Google Scholar 

  6. Jaenisch, R. (1988) Transgenic animals. Science 240, 1468–1474.

    Article  PubMed  CAS  Google Scholar 

  7. Gordon, J. W. (1993) Production of transgenic mice, in Guide to Techniques in Mouse Development Vol. 225, (Wassarman, P. M. and DePamphilis, M. L., eds.), Academic Press, San Diego, CA, pp. 747–771.

    Chapter  Google Scholar 

  8. Brinster, R. L., Allen, J. M., Behringer, R. R., Gelinas, R. E., and Palmiter, R. D. (1988) Introns increase transcriptional efficiency in transgenic mice. Proc. Natl. Acad. Sci. USA 85, 836–840.

    Article  PubMed  CAS  Google Scholar 

  9. Choi, T., Huang, C., Gorman, C., and Jaenisch, R. (1991) A generic intron increases gene expression in transgenic mice. Mol. Cell. Biol. 11, 3070–3074.

    PubMed  CAS  Google Scholar 

  10. Burke, D., Carle, G., and Olson, M. (1987) Cloning of large segments of exogenous DNA into yeast artificial chromosomes. Science 236, 806–812.

    Article  PubMed  CAS  Google Scholar 

  11. Spencer, F., Ketner, G., Connelley, C., and Hieter, P. (1993) Targeted recombination based cloning and manipulation of large DNA segments in yeast. Methods 5, 161–175.

    Article  CAS  Google Scholar 

  12. Hieter, P., Connelly, C., Shero, J., McCormick, M. K., Antonarakis, S., Pavan, W., and Reeves, R. (1990) Yeast artificial chromosomes: promises kept and pending, in Genome Analysis Volume I: Genetic and Physical Mapping (Davies, K. E., and Tilghman, S., eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 83–

    Google Scholar 

  13. Mendez, M. J., Green, L. L., Corvalan, J. R. F., Jia, X.-C., Maynard-Currie, C. E., Yang, X.-D., et al. (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nature Genet. 15, 146–156.

    Article  PubMed  CAS  Google Scholar 

  14. Lamb, B. T. and Gearhart, J. D. (1995) YAC transgenics and the study of genetics and human disease. Curr. Opin. Genet. Dev. 5, 342–348.

    Article  PubMed  CAS  Google Scholar 

  15. Peterson, K. R., Clegg, C. H., Li, Q., and Stamatoyannopoulos, G. (1997) Production of transgenic mice with yeast artificial chromosomes. Trends Genet. 13, 61–66.

    Article  PubMed  CAS  Google Scholar 

  16. Jakobovits, A. (1994) Humanizing the mouse genome. Curr. Biol. 4, 761–763.

    Article  PubMed  CAS  Google Scholar 

  17. Jakobovits, A., Moore, A. L., Green, L. L., Vergara, G. J., Maynard-Currie, C. E., Austin, H. A., and Klapholz, S. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 362, 255–258.

    Article  PubMed  CAS  Google Scholar 

  18. Mendez, M. J., Abderrahim, H., Noguchi, M., David, N. E., Hardy, M. C., Green, L. L., et al. (1995) Analysis of the structural integrity of YACs comprimising human immunoglobulin genes in yeast and in embryonic stem cells. Genomics 26, 294–307.

    Article  PubMed  CAS  Google Scholar 

  19. Green, L. L., Hardy, M. C., Maynard-Currie, C. E., Tsuda, H., Louie, D. M., Mendez, M. J., et al. (1994) Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nature Genet. 7, 13–21.

    Article  PubMed  CAS  Google Scholar 

  20. 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) Creation of mice expressing human antibody light chains by introduction of a yeast artificial chromosome containing the core region of the human immunoglobulin k locus. Biotechnology 11, 911–914.

    Article  PubMed  CAS  Google Scholar 

  21. Zweigerdt, R., Braun, T., and Arnold, H.-H. (1997) Faithful expression of the Myf-5 gene during mouse myogenesis requires distant control regions: A transgene approach using yeast artificial chromosomes. Devlop. Biol. 192, 172–180.

    Article  CAS  Google Scholar 

  22. Guthrie, C., and Fink, G. R. (1991) Guide to Yeast Genetics and Molecular Biology. Academic, San Diego, CA.

    Google Scholar 

  23. Lamb, B. T., Sisodia, S. S., Lawler, A. M., Slunt, H. H., Kitt, C. A., Kearns, W. G., Pearson, P. L., Price, D. L., and Gearhart, J. D. (1993) Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice. Nature Genet. 5, 22–30.

    Article  PubMed  CAS  Google Scholar 

  24. Tsuda, H., Maynard-Currie, C. E., Reid, L. H., Yoshida, T., Edamura, K., Maeda, N., Smithies, O., and Jakobovits, A. (1997) Inactivation of the mouse HPRT locus by a 203-bp retroposon insertion and a 55-kb gene-targeted deletion: Establishment of new HPRT-deficient mouse embryonic stem cell lines. Genomics 42, 413–421.

    Article  PubMed  CAS  Google Scholar 

  25. Ramirez-Solis, R., Cavis, A. C., and Bradley, A. (1993) Gene targeting in embryonic stem cells. Methods Enzymol. 225, 855–878.

    Article  PubMed  CAS  Google Scholar 

  26. Stewart, C. L. (1993) Production of chimeras between embryonic stem cells and embryos, in Guides to Techniques in Mouse Development Vol. 225, (Wassarman, P. M. and DePamphilis, M. L., eds.), Academic, San Diego, CA, pp. 823–855.

    Chapter  Google Scholar 

  27. Abbondanzo, S. J., Gadi, I., and Stewart, C. L. (1993) Derivation of embryonic stem cell lines, in Guides to Techniques in Mouse Development Vol. 225, (Wassarman, P. M. and DePamphilis, M. L., eds.), Academic, San Diego, CA, pp. 803–823.

    Chapter  Google Scholar 

  28. Lee, J. T., Strauss, W. M., Dausman, J. A., and Jaenisch, R. (1996) A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell 86, 83–94.

    Article  PubMed  CAS  Google Scholar 

  29. Lee, J. T., and Jaenisch, R. (1996) A method for high efficiency YAC lipofection into murine embryonic stem cells. Nucleic Acids Res. 24, 5054–5055.

    Article  PubMed  CAS  Google Scholar 

  30. Strauss, W. M., Dausman, J., Beard, C., Johnson, C., Lawrence, J. B., and Jaenisch, R. (1993) Germ-line transmission of a yeast artificial chromosome spanning the murine Col1A1 ( a1(I)Collagen) locus. Science 259, 1904–1907.

    Article  PubMed  CAS  Google Scholar 

  31. Lamb, B. T., Call, L. M., Slunt, H. H., Bardel, K. A., Lawler, A. M., Eckman, C. B., Younkin, S. G., Holtz, G., Wagner, S. L., Price, D. L., Sisodia, S. S., and Gearhart, J. D. (1997) Altered metabolism of familial Alzheimer’s disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice. Hum. Mol. Genet. 6, 1535–1541.

    Article  PubMed  CAS  Google Scholar 

  32. Pearson, B. E., and Choi, T. K. (1993) Expression of the human b-amyloid precursor protein gene from a yeast artificial chromosome in transgenic mice. Proc. Natl. Acad. Sci. USA 90, 10578–10582.

    Article  PubMed  CAS  Google Scholar 

  33. Choi, T. K., Hollenbach, P. W., Pearson, B. E., Ueda, R. M., Weddel, G. N., Kurahara, C. G., Woodhouse, C. S., Kay, R. M., and Loring, J. F. (1993) Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome. Nature Genet. 4, 117–123.

    Article  PubMed  CAS  Google Scholar 

  34. Schedl, A., Larin, Z., Montoliu, L., Thies, E., Kelsey, G., Lehrach, H., and Schütz, G. (1993) A method for the generation of YAC transgenic mice by pronuclear microinjection. Nucleic Acids Res. 21, 4783–4787.

    Article  PubMed  CAS  Google Scholar 

  35. Peterson, K. R., Clegg, C. H., Huxley, C., Josephson, B. M., Haugen, H. S., Furukawa, T., and Stamatoyannopoulos, G. (1993) Transgenic mice containing a 248-kb yeast artificial chromosome carrying the human β-globin locus display proper developmental control of human globin genes. Proc. Natl. Acad. Sci. USA 90, 7593–7597.

    Article  PubMed  CAS  Google Scholar 

  36. Gaensler, K. M. L., Kitamura, M., and Kan, Y. W. (1993) Germ-line transmission and developmental regulation of a 150-kb yeast artificial chromosome containing the human β-globin locus in transgenic mice. Proc. Natl. Acad. Sci. USA 90, 11381–11385.

    Article  PubMed  CAS  Google Scholar 

  37. Antoch, M. P., Song, E.-J., Chang, A.-M., Vitaterna, M. H., Zhao, Y., Wilsbacher, L. D., Sangoram, A. M., King, D. P., Pinto, L. H., and Takahashi, J. S. (1997) Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667.

    Article  PubMed  CAS  Google Scholar 

  38. Bungert, J., Dave, U., Lim, K.-C., Lieuw, K. H., Shavit, J. A., Liu, Q., and Engel, J. D. (1995) Synergistic regulation of human β-globin gene switching by locus control region elements HS3 and HS4. Genes Dev. 9, 3083–3096.

    Article  PubMed  CAS  Google Scholar 

  39. Frazer, K. A., Narla, G., Zhang, J. L., and Rubin, E. M. (1995) The apolipoprotein(a) gene is regulated by sex hormones and acute-phase inducers in YAC transgenic mice. Nature Genet. 9, 424–431.

    Article  PubMed  CAS  Google Scholar 

  40. Frazer, K. A., Ueda, Y., Zhu, Y., Gifford, V. R., Garofalo, M. R., Mohandas, N., et al. (1997) Computational and biological analysis of 680 kb of DNA from the human 5q31 cytokine gene cluster region. Genome Res. 7, 495–512.

    PubMed  CAS  Google Scholar 

  41. Hamilton, B. A., Smith, D. J., Mueller, K. L., Kerrebrock, A. W., Bronson, R. T., Berkel, V. V., et al. (1997) The vibrator mutation causes neurodegeneration via reduced expression of PITPa: positional complementation cloning and extragenic suppression. Neuron 18, 711–722.

    Article  PubMed  CAS  Google Scholar 

  42. Heard, E., Kress, C., Mongelard, F., Courtier, B., Rougeulle, C., Ashworth, A., et al. (1996) Transgenic mice carrying an Xist-containing YAC. Hum. Mol. Genet. 5, 441–450.

    Article  PubMed  CAS  Google Scholar 

  43. Hiemisch, H., Schutz, G., and Kaestner, K. H. (1997) Transcriptional regulation in endoderm development: characterization of an enhancer controlling Hnf3g expression by transgenesis and targeted mutagenesis. EMBO J. 16, 3995–4006.

    Article  PubMed  CAS  Google Scholar 

  44. Hodgson, J. G., Smith, D. J., McCutcheon, K., Koide, H. B., Nishiyama, K., Dinulos, et al. (1996) Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Hum. Mol. Genet. 5, 1875–1885.

    Article  PubMed  CAS  Google Scholar 

  45. Huxley, C., Passage, E., Manson, A., Putzu, G., Figarella-Branger, D., Pellissier, J. F., and Fontes, M. (1996) Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. Hum. Mol. Genet. 5, 563–569.

    Article  PubMed  CAS  Google Scholar 

  46. Liu, Q., Bungert, J., and Engel, J. D. (1997) Mutation of gene-proximal regulatory elements disrupts human ε-γ-, and β-globin expression in yeast artificial chromsome transgenic mice. Proc. Natl. Acad. Sci. USA 94, 169–174.

    Article  PubMed  CAS  Google Scholar 

  47. Manson, A. L., Trezise, A. E., MacVinish, L. J., Kasschau, K. D., Birchall, N., Episkopou, V., Vassaux, G., Evans, M. J., Colledge, W. H., Cuthbert, A. W., and Huxley, C. (1997) Complementation of null CF mice with a human CFTR YAC transgene. EMBO J. 16, 4238–4249.

    Article  PubMed  CAS  Google Scholar 

  48. Matsuura, S., Episkopou, V., Hamvas, R., and Brown, S. D. M. (1996) Xist expression from an Xist YAC transgene carried on the mouse Y chromosome. Hum. Molec. Genet. 5, 451–459.

    Article  PubMed  CAS  Google Scholar 

  49. McCormick, S. P. A., Ng, J. K., Taylor, S., Flynn, L. M., Hammer, R. E., and Young, S. G. (1995) Mutagenesis of the human apolipoprotein B gene in a yeast artificial chromosome reveals the site of attachment for apolipoprotein(a) Proc. Natl. Acad. Sci. USA 92, 10,147–10,151.

    Article  PubMed  CAS  Google Scholar 

  50. McCormick, S. P., Ng, J. K., Cham, C. M., Taylor, S., Marcovina, S. M., Segrest, J. P., Hammer, R. E., and Young, S. G. (1997) Transgenic mice expressing human ApoB95 and ApoB97. Evidence that sequences within the carboxyl-terminal portion of human apoB100 are important for the assembly of lipoprotein. J. Biol. Chem. 272, 23616–23622.

    Article  PubMed  CAS  Google Scholar 

  51. Montoliu, L., Schedl, A., Kelsey, G., Zentgraf, H., Lichter, P., and Schutz, G. (1994) Germ line transmission of yeast artificial chromosomes in transgenic mice. Reprod. Fertil. Dev. 6, 577–584.

    Article  PubMed  CAS  Google Scholar 

  52. Peterson, K. R., Li, Q. L., Clegg, C. H., Furukawa, T., Navas, P. A., Norton, E. J., Kimbrough, T. G., and Stamatoyannopoulos. (1995) Use of yeast artificial chromosomes (YACs) in studies of mammalian development: Production of β-globin locus YAC mice carrying human globin developmental mutants. Proc. Natl. Acad. Sci. USA 92, 5655–5659.

    Article  PubMed  CAS  Google Scholar 

  53. Schedl, A., Beermann, F., Thies, E., Montoliu, L., Kelsey, G., and Schütz, G. (1992) Transgenic mice generated by pronuclear injection of a yeast artificial chromosome. Nucleic Acids Res. 20, 3073–3077.

    Article  PubMed  CAS  Google Scholar 

  54. Schedl, A., Montoliu, L., Kelsey, G., and Schütz, G. (1993) A yeast artificial chromosome covering the tyrosinase gene confers copy number-dependent expression in transgenic mice. Nature 362, 258–261.

    Article  PubMed  CAS  Google Scholar 

  55. Schedl, A., Ross, A., Lee, M., Engelkamp, D., Rashbass, P., Heyningen, V. V., and Hastie, N. D. (1996) Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell 86, 71–82.

    Article  PubMed  CAS  Google Scholar 

  56. Smith, D. J., Zhu, Y., Zhang, J., Cheng, J.-F., and Rubin, E. M. (1995) Construction of a panel of transgenic mice containing a contiguous 2-Mb set of YAC/P1 clones from human chromosome 21q22.2. Genomics 27, 425–434.

    Article  PubMed  CAS  Google Scholar 

  57. Ainscough, J. F.-X., Koide, T., Tada, M., Barton, S., and Surani, M. A. (1997) Imprinting of Igf2 and H19 from a 130 kb YAC transgene. Development 124, 3621–3632.

    PubMed  CAS  Google Scholar 

  58. Yang, W. Y., Model, P., and Heintz, N. (1997) Homologous recombination based modification in Esherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nature Biotech. 15, 859–865.

    Article  CAS  Google Scholar 

  59. Mullins, L. J., Kotelevtseva, N., Boyd, A. C., and Mullins, J. J. (1997) Efficient Cre-lox linearisation of BACs: applications to physical mapping and generation of transgenic animals. Nucleic Acids Res. 25, 2539–2540.

    Article  PubMed  CAS  Google Scholar 

  60. Nielsen, L. B., McCormick, S. P. A., Pierotti, V., Tam, C., Gunn, M. D., Shizuya, H., and Young, S. G. (1997) Human apolipoprotein B transgenic mice generated with 207-and 145-kilobase pair bacterial artificial chromosomes. J. Biol. Chem. 272, 29752–29758.

    Article  PubMed  CAS  Google Scholar 

  61. Wutz, A., Smrzka, O. W., Schweifer, N., Schellander, K., Wagner, E. F., and Barlow, D. P. (1997) Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389, 745–749.

    Article  PubMed  CAS  Google Scholar 

  62. Gnirke, A., Huxley, C., Peterson, K., and Olson, M. V. (1993) Microinjection of intact 200-to 500-kb fragments of YAC DNA into mammalian cells. Genomics 15, 659–667.

    Article  PubMed  CAS  Google Scholar 

  63. Maule, J. C., Porteous, D. J., and Brookes, A. J. (1994) An improved method for recovering intact pulsed field gel purified DNA of at least 1.6 megabases. Nucleic Acids Res. 22, 3245–3246.

    Article  PubMed  CAS  Google Scholar 

  64. Brinster, R. L., Chen, H. Y., Trumbauer, M. E., Yagle, M. K., and Palmiter, R. D. (1985) Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc. Natl. Acad. Sci. USA 82, 4438–4442.

    Article  PubMed  CAS  Google Scholar 

  65. Peterson, K. R. (1997) Production and analysis of transgenic mice containing yeast artificial chromosomes, in Genetic Engineering (Setlow, J. K., ed.), Plenum Press, New York, pp. 235–

    Google Scholar 

  66. Fairhead, C., Heard, E., Arnaud, D., Avner, P., and Dujon, B. (1995) Insertion of unique sites into YAC arms for rapid physical analysis following YAC transfer into mammalian cells. Nucleic Acids Res. 23, 4011–4012.

    Article  PubMed  CAS  Google Scholar 

  67. Ferrin, L. J. and Camerini-Otero, R. D. (1991) Selective cleavage of human DNA: RecA-assisted restriction endonuclease (RARE) cleavage. Science 254, 1494–1497.

    Article  PubMed  CAS  Google Scholar 

  68. Rosenberg, C., Voltz, A. K., Lawler, A. L., Lamb, B. T., Stetten, G., and Gearhart, J. D. (1996) Alterations of yeast artificial chromosome transgenic sequences in stretched embyronic stem-cell chromatin visualized by fluorescence in situ hybridization. Cyotogenet. Cell. Genet. 75, 67–70.

    Article  CAS  Google Scholar 

  69. Kovacic, R. T., Comai, L., and Bendich, A. J. (1995) Protection of megabase DNA from shearing. Nucl. Acids Res. 23, 3999–4000.

    Article  PubMed  CAS  Google Scholar 

  70. Couto, L. B., Spangler, E. A., and Rubin, E. M. (1989) A method for the preparative isolation and concentration of intact yeast artificial chromosomes. Nucleic Acids Res. 17, 8010.

    Article  PubMed  CAS  Google Scholar 

  71. Lamb, B. T., Bardel, K. A., Kulame, L. S., Anderson, J. J., Holtz, G., Wagner, S. L., Sisodia, S. S., and Hoeger, E. J. (1999) Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice. Nature Neurosci. 2, 695–697.

    Article  PubMed  CAS  Google Scholar 

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Jakobovits, A., Lamb, B.T., Peterson, K.R. (2000). Production of Transgenic Mice with Yeast Artificial Chromosomes. In: Tuan, R.S., Lo, C.W. (eds) Developmental Biology Protocols: Volume II. Methods in Molecular Biology™, vol 136. Humana Press. https://doi.org/10.1385/1-59259-065-9:435

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  • DOI: https://doi.org/10.1385/1-59259-065-9:435

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