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 (1–5).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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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.
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.
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.
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.
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.
Jaenisch, R. (1988) Transgenic animals. Science 240, 1468–1474.
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.
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.
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.
Burke, D., Carle, G., and Olson, M. (1987) Cloning of large segments of exogenous DNA into yeast artificial chromosomes. Science 236, 806–812.
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.
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–
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.
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.
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.
Jakobovits, A. (1994) Humanizing the mouse genome. Curr. Biol. 4, 761–763.
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.
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.
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.
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.
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.
Guthrie, C., and Fink, G. R. (1991) Guide to Yeast Genetics and Molecular Biology. Academic, San Diego, CA.
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.
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.
Ramirez-Solis, R., Cavis, A. C., and Bradley, A. (1993) Gene targeting in embryonic stem cells. Methods Enzymol. 225, 855–878.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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–
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.
Ferrin, L. J. and Camerini-Otero, R. D. (1991) Selective cleavage of human DNA: RecA-assisted restriction endonuclease (RARE) cleavage. Science 254, 1494–1497.
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.
Kovacic, R. T., Comai, L., and Bendich, A. J. (1995) Protection of megabase DNA from shearing. Nucl. Acids Res. 23, 3999–4000.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Humana Press Inc.
About this protocol
Cite this protocol
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
Download citation
DOI: https://doi.org/10.1385/1-59259-065-9:435
Publisher Name: Humana Press
Print ISBN: 978-0-89603-853-0
Online ISBN: 978-1-59259-065-0
eBook Packages: Springer Protocols