Skip to main content

Advertisement

SpringerLink
Log in

Artificial chromosome-based transgenes in the study of genome function

  • Review
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

The transfer of large DNA fragments to the mouse genome in the form of bacterial, yeast or phage artificial chromosomes is an important process in the definition of transcription units, the modeling of inherited disease states, the dissection of candidate regions identified by linkage analysis and the construction of in vivo reporter genes. However, as with small recombinant transgenes, the transferred sequences are usually integrated randomly often with accompanying genomic alterations and variable expression of the introduced genes due to the site of integration and/or copy number. Therefore, alternative methods of integrating large genomic transgenes into the genome have been developed to avoid the variables associated with random integration. This review encourages the reader to imagine the large variety of applications where artificial chromosome transgenes can facilitate in vivo and ex vivo studies in the mouse and provides a context for making the necessary decisions regarding the specifics of experimental design.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  • Alami R, Greally JM, Tanimoto K, Hwang S, Feng YQ, et al. (2000) Beta-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice. Hum Mol Genet 9, 631–636

    Article  PubMed  CAS  Google Scholar 

  • Antoch MP, Song EJ, Chang AM, Vitaterna MH, Zhao Y, et al. (1997) Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667

    Article  PubMed  CAS  Google Scholar 

  • Asahi M, Otsu K, Nakayama H, Hikoso S, Takeda T, et al. (2004) Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc Natl Acad Sci USA 101 9199–9204

    Article  PubMed  CAS  Google Scholar 

  • Behringer RR, Ryan TM, Palmiter RD, Brinster RL, Townes TM (1990) Human gamma- to beta-globin gene switching in transgenic mice. Genes Dev 4(3), 380–390

    PubMed  CAS  Google Scholar 

  • Bronson SK, Pei J, Taillon-Miller P, Chorney MJ, Geraghty DE, et al. (1991) Isolation and characterization of yeast artificial chromosome clones linking the HLA-B and HLA-C loci. Proc Natl Acad Sci USA 88, 1676–1680

    Article  PubMed  CAS  Google Scholar 

  • Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, et al. (1996) Single-copy transgenic mice with chosen-site integration. Proc Natl Acad Sci USA 93, 9067–9072

    Article  PubMed  CAS  Google Scholar 

  • Bungert J, Dave U, Lim KC, Lieuw KH, Shavit JA, et al. (1995) Synergistic regulation of human beta-globin gene switching by locus control region elements HS3 and HS4. Genes Dev 9(24), 3083–3096

    PubMed  CAS  Google Scholar 

  • Burke DT, Carle GF, Olson MV (1987) Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors. Science 236, 806–812

    PubMed  CAS  Google Scholar 

  • Call LM, Moore CS, Stetten G, Gearhart JD (2000) A cre-lox recombination system for the targeted integration of circular yeast artificial chromosomes into embryonic stem cells. Hum Mol Genet 9, 1745–1751

    Article  PubMed  CAS  Google Scholar 

  • Campbell C, Gulati R, Nandi AK, Floy K, Hieter P, et al. (1991) Generation of a nested series of interstitial deletions in yeast artificial chromosomes carrying human DNA. Proc Natl Acad Sci USA 88, 5744–5748

    Article  PubMed  CAS  Google Scholar 

  • Caron K, James JR, Kim H, Morham SG, Lopez M, et al. (2002) A genetically clamped renin transgene for the induction of hypertension. Proc Natl Acad Sci USA 99(12), 8248–8252

    Article  PubMed  CAS  Google Scholar 

  • Carvajal JJ, Cox D, Summerbell D, Rigby PW (2001) A BAC transgenic analysis of the Mrf4/Myf5 locus reveals interdigitated elements that control activation and maintenance of gene expression during muscle development. Development 128, 1857–1868

    PubMed  CAS  Google Scholar 

  • Caskey CT, Kruh GD (1979) The HPRT locus. Cell 16, 1–9

    Article  PubMed  CAS  Google Scholar 

  • Chada K, Magram J, Raphael K, Radice G, Lacy E, et al. (1985) Specific expression of a foreign beta-globin gene in erythroid cells of transgenic mice. Nature 314, 377–380

    Article  PubMed  CAS  Google Scholar 

  • Chiocco MJ, Kulnane LS, Younkin L, Younkin S, Evin G, et al. (2004) Altered amyloid-beta metabolism and deposition in genomic-based beta-secretase transgenic mice. J Biol Chem 279, 52535–52542

    Article  PubMed  CAS  Google Scholar 

  • Choi TK, Hollenbach PW, Pearson BE, Ueda RM, Weddell GN, et al. (1993) Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome. Nat Genet 4, 117–123

    Article  PubMed  CAS  Google Scholar 

  • Cocchia M, Kouprina N, Kim SJ, Larionov V, Schlessinger D, et al. (2000) Recovery and potential utility of YACs as circular YACs/BACs. Nucleic Acids Res 28, E81

    Article  PubMed  CAS  Google Scholar 

  • Costantini F, Lacy E (1981) Introduction of a rabbit beta-globin gene into the mouse germ line. Nature 294, 92–94

    Article  PubMed  CAS  Google Scholar 

  • Cvetkovic B, Keen HL, Zhang X, Davis D, Yang B, et al. (2002) Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse. Physiol Genomics 11(3), 253–262

    PubMed  CAS  Google Scholar 

  • Cvetkovic B, Yang B, Williamson RA, Sigmund CD (2000) Appropriate tissue- and cell-specific expression of a single copy human angiotensinogen transgene specifically targeted upstream of the HPRT locus by homologous recombination. J Biol Chem 275, 1073–1078

    Article  PubMed  CAS  Google Scholar 

  • Dillon N, Festenstein R (2002) Unravelling heterochromatin: competition between positive and negative factors regulates accessibility. Trends Genet 18(5), 252–258

    Article  PubMed  CAS  Google Scholar 

  • Doetschman T, Gregg RG, Maeda N, Hooper ML, Melton DW, et al. (1987) Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 330, 576–578

    Article  PubMed  CAS  Google Scholar 

  • Evans V, Hatzopoulos A, Aird WC, Rayburn HB, Rosenberg RD, et al. (2000) Targeting the Hprt locus in mice reveals differential regulation of Tie2 gene expression in the endothelium. Physiol Genomics 2, 67–75

    PubMed  CAS  Google Scholar 

  • Farhadi HF, Lepage P, Forghani R, Friedman H, Orfali W, et al. (2003) A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J Neurosci 23(32), 10164–10173

    Google Scholar 

  • Feng YQ, Lorincz MC, Fiering S, Greally JM, Bouhassira EE (2001) Position effects are influenced by the orientation of a transgene with respect to flanking chromatin. Mol Cell Biol 21, 298–309

    Article  PubMed  CAS  Google Scholar 

  • Feng YQ, Seibler J, Alami R, Eisen A, Westerman KA, et al. (1999) Site-specific chromosomal integration in mammalian cells: highly efficient CRE recombinase-mediated cassette exchange. J Mol Biol 292, 779–785

    Article  PubMed  CAS  Google Scholar 

  • Festenstein R, Tolaini M, Corbella P, Mamalaki C, Parrington J, et al. (1996) Locus control region function and heterochromatin-induced position effect variegation. Science 271, 1123–1125

    PubMed  CAS  Google Scholar 

  • Forrester WC, Takegawa S, Papayannopoulou T, Stamatoyannopoulos G, Groudine M (1987) Evidence for a locus activation region: the formation of developmentally stable hypersensitive sites in globin-expressing hybrids. Nucleic Acids Res 15, 10159–10177

    PubMed  CAS  Google Scholar 

  • Fournier RE, Ruddle FH (1977) Microcell-mediated transfer of murine chromosomes into mouse, Chinese hamster, and human somatic cells. Proc Natl Acad Sci USA 74, 319–323

    Article  PubMed  CAS  Google Scholar 

  • Frengen E, Weichenhan D, Zhao B, Osoegawa K, van Geel M, et al. (1999) A modular, positive selection bacterial artificial chromosome vector with multiple cloning sites. Genomics 58, 250–253

    Article  PubMed  CAS  Google Scholar 

  • Frengen E, Zhao B, Howe S, Weichenhan D, Osoegawa K, et al. (2000) Modular bacterial artificial chromosome vectors for transfer of large inserts into mammalian cells. Genomics 68, 118–126

    Article  PubMed  CAS  Google Scholar 

  • 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, 7905–7909

    Article  PubMed  CAS  Google Scholar 

  • Galli-Taliadoros LA, Sedgwick JD, Wood SA, Korner H (1995) Gene knock-out technology: a methodological overview for the interested novice. J Immunol Methods 181, 1–15

    Article  PubMed  CAS  Google Scholar 

  • Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373, 523–527

    Article  PubMed  CAS  Google Scholar 

  • Garrick D, Fiering S, Martin DI, Whitelaw E (1998) Repeat-induced gene silencing in mammals. Nat Genet 18, 56–59

    Article  PubMed  CAS  Google Scholar 

  • Gerasimova TI, Corces VG (2001) Chromatin insulators and boundaries: effects on transcription and nuclear organization. Annu Rev Genet 35, 193–208

    Article  PubMed  CAS  Google Scholar 

  • Giraldo P, Montoliu L (2001) Size matters: use of YACs, BACs and PACs in transgenic animals. Transgenic Res 10, 83–103

    Article  PubMed  CAS  Google Scholar 

  • Glover DM, Hames (1995) DNA cloning: A practical approach, 2nd ed. (New York: IRL Press)

  • Gong S, Yang XW, Li C, Heintz N (2002) Highly efficient modification of bacterial artificial chromosomes (BACs) using novel shuttle vectors containing the R6Kgamma origin of replication. Genome Res 12, 1992–1998

    Article  PubMed  CAS  Google Scholar 

  • Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, et al. (2003) A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925

    Article  PubMed  CAS  Google Scholar 

  • Guillot PV, Liu L, Kuivenhoven JA, Guan J, Rosenberg RD, et al. (2000) Targeting of human eNOS promoter to the Hprt locus of mice leads to tissue-restricted transgene expression. Physiol Genomics 2, 77–83

    PubMed  CAS  Google Scholar 

  • Guy LG, Kothary R, DeRepentigny Y, Delvoye N, Ellis J, et al. (1996) The beta-globin locus control region enhances transcription of but does not confer position-independent expression onto the lacZ gene in transgenic mice. EMBO J 15, 3713–3721

    PubMed  CAS  Google Scholar 

  • Guy LG, Kothary R, Wall L (1997) Position effects in mice carrying a lacZ transgene in cis with the beta-globin LCR can be explained by a graded model. Nucleic Acids Res 25(21), 4400–4407

    Article  PubMed  CAS  Google Scholar 

  • Habets PE, Clout DE, Deprez RH, van Roon MA, Moorman AF, et al. (2003) Cardiac expression of Gal4 causes cardiomyopathy in a dose-dependent manner. J Muscle Res Cell Motil 24, 205–209

    Article  PubMed  CAS  Google Scholar 

  • Hatada S, Kuziel W, Smithies O, Maeda N (1999) The influence of chromosomal location on the expression of two transgenes in mice. J Biol Chem 274, 948–955

    Article  PubMed  CAS  Google Scholar 

  • Heaney JD, Rettew AN, Bronson SK (2004) Tissue-specific expression of a BAC transgene targeted to the Hprt locus in mouse embryonic stem cells. Genomics 83, 1072–1082

    Article  PubMed  CAS  Google Scholar 

  • Henikoff S (1998) Conspiracy of silence among repeated transgenes. Bioessays 20, 532–535

    Article  PubMed  CAS  Google Scholar 

  • Hernandez D, Mee PJ, Martin JE, Tybulewicz VL, Fisher EM (1999) Transchromosomal mouse embryonic stem cell lines and chimeric mice that contain freely segregating segments of human chromosome 21. Hum Mol Genet 8, 923–933

    Article  PubMed  CAS  Google Scholar 

  • Hodgson JG, Smith DJ, McCutcheon K, Koide HB, Nishiyama K, 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 

  • Hoess RH, Ziese M, Sternberg N (1982) P1 site-specific recombination: nucleotide sequence of the recombining sites. Proc Natl Acad Sci USA 79, 3398–3402

    Article  PubMed  CAS  Google Scholar 

  • Hooper M, Hardy K, Handyside A, Hunter S, Monk M (1987) HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–295

    Article  PubMed  CAS  Google Scholar 

  • Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102

    Article  PubMed  CAS  Google Scholar 

  • Imai T, Olson MV (1990) Second-generation approach to the construction of yeast artificial-chromosome libraries. Genomics 8, 297–303

    Article  PubMed  CAS  Google Scholar 

  • Ioannou PA, Amemiya CT, Garnes J, Kroisel PM, Shizuya H, et al. (1994) A new bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nat Genet 6, 84–89

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Jakobovits A, Moore AL, Green LL, Vergara GJ, Maynard-Currie CE, et al. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature 362, 255–258

    Article  PubMed  CAS  Google Scholar 

  • Kammesheidt A, Boyce FM, Spanoyannis AF, Cummings BJ, Ortegon M, et al. (1992) Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci USA 89, 10857–10861

    Article  PubMed  CAS  Google Scholar 

  • Karpen GH (1994) Position-effect variegation and the new biology of heterochromatin. Curr Opin Genet Dev 4, 281–291

    Article  PubMed  CAS  Google Scholar 

  • Kaufman RM, Pham CT, Ley TJ (1999) Transgenic analysis of a 100-kb human beta-globin cluster-containing DNA fragment propagated as a bacterial artificial chromosome. Blood 94, 3178–3184

    PubMed  CAS  Google Scholar 

  • Kawabata S, Higgins GA, Gordon JW (1991) Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein. Nature 354, 476–478

    Article  PubMed  CAS  Google Scholar 

  • Kim SH, Moores JC, David D, Respess JG, Jolly DJ, et al. (1986) The organization of the human HPRT gene. Nucleic Acids Res 14, 3103–3118

    PubMed  CAS  Google Scholar 

  • Kim UJ, Birren BW, Slepak T, Mancino V, Boysen C, et al. (1996) Construction and characterization of a human bacterial artificial chromosome library. Genomics 34, 213–218

    Article  PubMed  CAS  Google Scholar 

  • Kim UJ, Shizuya H, de Jong PJ, Birren B, Simon MI (1992) Stable propagation of cosmid sized human DNA inserts in an F factor based vector. Nucleic Acids Res 20, 1083–1085

    PubMed  CAS  Google Scholar 

  • Kouprina N, Eldarov M, Moyzis R, Resnick M, Larionov V (1994) A model system to assess the integrity of mammalian YACs during transformation and propagation in yeast. Genomics 21, 7–17

    Article  PubMed  CAS  Google Scholar 

  • Krulewski TF, Neumann PE, Gordon JW (1989) Insertional mutation in a transgenic mouse allelic with Purkinje cell degeneration. Proc Natl Acad Sci USA 86, 3709–3712

    Article  PubMed  CAS  Google Scholar 

  • Kucherlapati RS, Eves EM, Song KY, Morse BS, Smithies O (1984) Homologous recombination between plasmids in mammalian cells can be enhanced by treatment of input DNA. Proc Natl Acad Sci USA 81, 3153–3157

    Article  PubMed  CAS  Google Scholar 

  • Kuehn MR, Bradley A, Robertson EJ, Evans MJ (1987) A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326, 295–298

    Article  PubMed  CAS  Google Scholar 

  • Kyba M, Perlingeiro RC, Daley GQ (2002) HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK, Kas E, Poljak L, Adachi Y (1992) Scaffold-associated regions: cis-acting determinants of chromatin structural loops and functional domains. Curr Opin Genet Dev 2, 275–285

    Article  PubMed  CAS  Google Scholar 

  • Lamb BT, Call LM, Slunt HH, Bardel KA, Lawler AM, et al. (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 

  • Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, et al. (1993) Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]. Nat Genet 5, 22–30

    Article  PubMed  CAS  Google Scholar 

  • Lang G, Wotton D, Owen MJ, Sewell WA, Brown MH, et al. (1988) The structure of the human CD2 gene and its expression in transgenic mice. EMBO J 7, 1675–1682

    PubMed  CAS  Google Scholar 

  • Larionov V, Kouprina N, Nikolaishvili N, Resnick MA (1994) Recombination during transformation as a source of chimeric mammalian artificial chromosomes in yeast (YACs). Nucleic Acids Res 22, 4154–4162

    PubMed  CAS  Google Scholar 

  • Lawrance SK, Smith CL, Srivastava R, Cantor CR, Weissman SM (1987) Megabase-scale mapping of the HLA gene complex by pulsed field gel electrophoresis. Science 235, 1387–1390

    PubMed  CAS  Google Scholar 

  • Le TH, Oliverio MI, Kim HS, Salzler H, Dash RC, et al. (2004) A gammaGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice. Physiol Genomics 18, 290–298

    Article  PubMed  CAS  Google Scholar 

  • Le Y, Gagneten S, Larson T, Santha E, Dobi A, et al. (2003) Far-upstream elements are dispensable for tissue-specific proenkephalin expression using a Cre-mediated knock-in strategy. J Neurochem 84, 689–697

    Article  PubMed  CAS  Google Scholar 

  • Lee EC, Yu D,d’ Martinez V, Tessarollo L, Swing DA, et al. (2001) A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 73, 56–65

    Article  PubMed  CAS  Google Scholar 

  • Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3, 662–673

    Article  PubMed  CAS  Google Scholar 

  • Li J, Baker MD (2000) Mechanisms involved in targeted gene replacement in mammalian cells. Genetics 156, 809–821

    PubMed  CAS  Google Scholar 

  • Li S, Hammer RE, George-Raizen JB, Meyers KC, Garrard WT (2000) High-level rearrangement and transcription of yeast artificial chromosome-based mouse Ig kappa transgenes containing distal regions of the contig. J Immunol 164, 812–824

    PubMed  CAS  Google Scholar 

  • Lin FL, Sperle K, Sternberg N (1985) Recombination in mouse L cells between DNA introduced into cells and homologous chromosomal sequences. Proc Natl Acad Sci USA 82, 1391–1395

    Article  PubMed  CAS  Google Scholar 

  • Magin TM, McWhir J, Melton DW (1992) A new mouse embryonic stem cell line with good germ line contribution and gene targeting frequency. Nucleic Acids Res 20, 3795–3796

    PubMed  CAS  Google Scholar 

  • Magness ST, Jijon H, Van Houten FN, Sharpless NE, Brenner DA, et al. (2004) In vivo pattern of lipopolysaccharide and anti-CD3-induced NF-kappa B activation using a novel gene-targeted enhanced GFP reporter gene mouse. J Immunol 173, 1561–1570

    PubMed  CAS  Google Scholar 

  • Magness ST, Tugores A, Brenner DA (2000) Analysis of ferrochelatase expression during hematopoietic development of embryonic stem cells. Blood 95, 3568–3577

    PubMed  CAS  Google Scholar 

  • McCormick SP, Ng JK, Veniant M, Boren J, Pierotti V, et al. (1996) Transgenic mice that overexpress mouse apolipoprotein B. Evidence that the DNA sequences controlling intestinal expression of the apolipoprotein B gene are distant from the structural gene. J Biol Chem 271, 11963–11970

    Article  PubMed  CAS  Google Scholar 

  • Mendez MJ, Abderrahim H, Noguchi M, David NE, Hardy MC, et al. (1995) Analysis of the structural integrity of YACs comprising human immunoglobulin genes in yeast and in embryonic stem cells. Genomics 26, 294–307

    Article  PubMed  CAS  Google Scholar 

  • Mendez MJ, Green LL, Corvalan JR, Jia XC, Maynard-Currie CE, et al. (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 15, 146–156

    Article  PubMed  CAS  Google Scholar 

  • Miao GG, Smeyne RJ, D’Arcangelo G, Copeland NG, Jenkins NA, et al. (1994) Isolation of an allele of reeler by insertional mutagenesis. Proc Natl Acad Sci USA 91, 11050–11054

    Article  PubMed  CAS  Google Scholar 

  • Milot E, Strouboulis J, Trimborn T, Wijgerde M, de Boer E, et al. (1996) Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell 87(1), 105–114

    Article  PubMed  CAS  Google Scholar 

  • Minami T, Donovan DJ, Tsai JC, Rosenberg RD, Aird WC (2002) Differential regulation of the von Willebrand factor and Flt-1 promoters in the endothelium of hypoxanthine phosphoribosyltransferase- targeted mice. Blood 100, 4019–4025

    Article  PubMed  CAS  Google Scholar 

  • Minami T, Kuivenhoven JA, Evans V, Kodama T, Rosenberg RD, et al. (2003) Ets Motifs Are Necessary for Endothelial Cell-Specific Expression of a 723-bp Tie-2 Promoter/Enhancer in Hprt Targeted Transgenic Mice. Arterioscler Thromb Vasc Biol 23, 2041–2047

    Article  PubMed  CAS  Google Scholar 

  • Misra RP, Bronson SK, Xiao Q, Garrison W, Li J, et al. (2001) Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation. BMC Biotechnol 1, p12

    Article  PubMed  CAS  Google Scholar 

  • Mori H, Kondo A, Ohshima A, Ogura T, Hiraga S (1986) Structure and function of the F plasmid genes essential for partitioning. J Mol Biol 192, 1–15

    Article  PubMed  CAS  Google Scholar 

  • Morimoto S, Cassell MD, Sigmund CD (2002) The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene. Circ Res 90, 80–86

    Article  PubMed  CAS  Google Scholar 

  • Muller H(1930) Types of visible variations induced by X-rays in Drosophila. J Genet 22, 299–334

    Article  Google Scholar 

  • Muller K, Heller H, Doerfler W (2001) Foreign DNA integration. Genome-wide perturbations of methylation and transcription in the recipient genomes. J Biol Chem 276, 14271–14278

    Article  PubMed  CAS  Google Scholar 

  • Muyrers JP, Zhang Y, Testa G, Stewart AF (1999) Rapid modification of bacterial artificial chromosomes by ET- recombination. Nucleic Acids Res 27, 1555–1557

    Article  PubMed  CAS  Google Scholar 

  • Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Goncalves O, et al. (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387, 500–505

    Article  PubMed  CAS  Google Scholar 

  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, et al. (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389

    Article  PubMed  CAS  Google Scholar 

  • Neil DL, Villasante A, Fisher RB, Vetrie D, Cox B, et al. (1990) Structural instability of human tandemly repeated DNA sequences cloned in yeast artificial chromosome vectors. Nucleic Acids Res 18, 1421–1428

    PubMed  CAS  Google Scholar 

  • Nelson TJ, Duncan SA, Misra RP (2004) Conserved enhancer in the serum response factor promoter controls expression during early coronary vasculogenesis. Circ Res 94, 1059–1066

    Article  PubMed  CAS  Google Scholar 

  • Oberdoerffer P, Kanellopoulou C, Heissmeyer V, Paeper C, Borowski C, et al. (2005) Efficiency of RNA Interference in the Mouse Hematopoietic System Varies between Cell Types and Developmental Stages. Mol Cell Biol 25, 3896–3905

    Article  PubMed  CAS  Google Scholar 

  • Patel PI, Framson PE, Caskey CT, Chinault AC (1986) Fine structure of the human hypoxanthine phosphoribosyltransferase gene. Mol Cell Biol 6(2), 393–403

    PubMed  CAS  Google Scholar 

  • Peterson KR, Navas PA, Li Q, Stamatoyannopoulos G (1998) LCR-dependent gene expression in beta-globin YAC transgenics: detailed structural studies validate functional analysis even in the presence of fragmented YACs. Hum Mol Genet 7, 2079–2088

    Article  PubMed  CAS  Google Scholar 

  • Porcu S, Kitamura M, Witkowska E, Zhang Z, Mutero A, et al. (1997) The human beta globin locus introduced by YAC transfer exhibits a specific and reproducible pattern of developmental regulation in transgenic mice. Blood 90, 4602–4609

    PubMed  CAS  Google Scholar 

  • Quon D, Wang Y, Catalano R, Scardina JM, Murakami K, et al. (1991) Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature 352, 239–241

    Article  PubMed  CAS  Google Scholar 

  • Rachel RA, Wellington SJ, Warburton D, Mason CA, Beermann F (2002) A new allele of Gli3 and a new mutation, circletail (Crc), resulting from a single transgenic experiment. genesis 33, 55–61

    Article  PubMed  CAS  Google Scholar 

  • Radomska HS, Gonzalez DA, Okuno Y, Iwasaki H, Nagy A, et al. (2002) Transgenic targeting with regulatory elements of the human CD34 gene. Blood 100, 4410–4419

    Article  PubMed  CAS  Google Scholar 

  • Reeves RH, Pavan WJ, Hieter P (1990) Modification and manipulation of mammalian DNA cloned as YACs. Genet Anal Tech Appl 7, 107–113

    Article  PubMed  CAS  Google Scholar 

  • Robertson G, Garrick D, Wu W, Kearns M, Martin D, et al. (1995) Position-dependent variegation of globin transgene expression in mice. Proc Natl Acad Sci USA 92, 5371–5375

    Article  PubMed  CAS  Google Scholar 

  • Ross AJ, Waymire KG, Moss JE, Parlow AF, Skinner MK, et al. (1998) Testicular degeneration in Bclw-deficient mice. Nat Genet 18(3), 251–256

    Article  PubMed  CAS  Google Scholar 

  • Rubnitz J, Subramani S (1986) Extrachromosomal and chromosomal gene conversion in mammalian cells. Mol Cell Biol 6, 1608–1614

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Schedl A, Larin Z, Montoliu L, Thies E, Kelsey G, et al. (1993a) A method for the generation of YAC transgenic mice by pronuclear microinjection. Nucleic Acids Res 21, 4783–4787

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Scheerer JB, Adair GM (1994) Homology dependence of targeted recombination at the Chinese hamster APRT locus. Mol Cell Biol 14, 6663–6673

    PubMed  CAS  Google Scholar 

  • Selkoe DJ(1994) Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer’s disease. Annu Rev Cell Biol 10, 373–403

    Article  PubMed  CAS  Google Scholar 

  • Shizuya H, Birren B, Kim UJ, Mancino V, Slepak T, et al. (1992) Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector. Proc Natl Acad Sci USA 89, 8794–8797

    Article  PubMed  CAS  Google Scholar 

  • Silverman GA, Jockel JI, Domer PH, Mohr RM, Taillon-Miller P, et al. (1991) Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9, 219–228

    Article  PubMed  CAS  Google Scholar 

  • Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, et al. (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat Genet 16, 28–36

    Article  PubMed  CAS  Google Scholar 

  • Smith DJ, Zhu Y, Zhang J, Cheng JF, Rubin EM (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 

  • Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS (1985) Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature 317, 230–234

    Article  PubMed  CAS  Google Scholar 

  • Snow JW, Abraham N, Ma MC, Bronson SK, Goldsmith MA (2003) Transgenic bcl-2 is not sufficient to rescue all hematolymphoid defects in STAT5A/5B-deficient mice. Exp Hematol 31, 1253–1258

    Article  PubMed  CAS  Google Scholar 

  • Song KY, Schwartz F, Maeda N, Smithies O, Kucherlapati R (1987) Accurate modification of a chromosomal plasmid by homologous recombination in human cells. Proc Natl Acad Sci USA 84, 6820–6824

    Article  PubMed  CAS  Google Scholar 

  • Soukharev S, Miller JL, Sauer B (1999) Segmental genomic replacement in embryonic stem cells by double lox targeting. Nucleic Acids Res 27, E21

    Article  PubMed  CAS  Google Scholar 

  • Sternberg N (1990) Bacteriophage P1 cloning system for the isolation, amplification, and recovery of DNA fragments as large as 100 kilobase pairs. Proc Natl Acad Sci USA 87, 103–107

    Article  PubMed  CAS  Google Scholar 

  • Stief A, Winter DM, Stratling WH, Sippel AE (1989) A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature 341, 343–345

    Article  PubMed  CAS  Google Scholar 

  • Strauss WM, Dausman J, Beard C, Johnson C, Lawrence JB, et al. (1993) Germ line transmission of a yeast artificial chromosome spanning the murine alpha 1(I) collagen locus. Science 259, 1904–1907

    PubMed  CAS  Google Scholar 

  • Tanimoto K, Liu Q, Bungert J, Engel JD (1999) Effects of altered gene order or orientation of the locus control region on human beta-globin gene expression in mice. Nature 398, 344–348

    Article  PubMed  CAS  Google Scholar 

  • Testa G, Zhang Y, Vintersten K, Benes V, Pijnappel WW, et al. (2003) Engineering the mouse genome with bacterial artificial chromosomes to create multipurpose alleles. Nat Biotechnol 21, 443–447

    Article  PubMed  CAS  Google Scholar 

  • Thomas KR, Folger KR, Capecchi MR (1986) High frequency targeting of genes to specific sites in the mammalian genome. Cell 44, 419–428

    Article  PubMed  CAS  Google Scholar 

  • Tomizuka K, Shinohara T, Yoshida H, Uejima H, Ohguma A, et al. (2000) Double trans-chromosomic mice: maintenance of two individual human chromosome fragments containing Ig heavy and kappa loci and expression of fully human antibodies. Proc Natl Acad Sci USA 97, 722–727

    Article  PubMed  CAS  Google Scholar 

  • Tomizuka K, Yoshida H, Uejima H, Kugoh H, Sato K, et al. (1997) Functional expression and germline transmission of a human chromosome fragment in chimaeric mice. Nat Genet 16, 133–143

    Article  PubMed  CAS  Google Scholar 

  • Tsuda H, Maynard-Currie CE, Reid LH, Yoshida T, Edamura K, et al. (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 

  • Tuan D, Solomon W, Li Q, London IM (1985) The “beta-like-globin” gene domain in human erythroid cells. Proc Natl Acad Sci USA 82, 6384–6388

    Article  PubMed  CAS  Google Scholar 

  • Valenzuela DM, Murphy AJ, Frendewey D, Gale NW, Economides AN, et al. (2003) High-throughput engineering of the mouse genome coupled with high- resolution expression analysis. Nat Biotechnol 21, 652–659

    Article  PubMed  CAS  Google Scholar 

  • Wirak DO, Bayney R, Ramabhadran TV, Fracasso RP, Hart JT, et al. (1991) Deposits of amyloid beta protein in the central nervous system of transgenic mice. Science 253, 323–325

    PubMed  CAS  Google Scholar 

  • Wu CL, Melton DW (1993) Production of a model for Lesch-Nyhan syndrome in hypoxanthine phosphoribosyltransferase-deficient mice. Nat Genet 3, 235–240

    Article  PubMed  CAS  Google Scholar 

  • Wutz A, Rasmussen TP, Jaenisch R (2002) Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nat Genet 30, 167–174

    Article  PubMed  CAS  Google Scholar 

  • Yang XW, Model P, Heintz N (1997) Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nat Biotechnol 15, 859–865

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Seed B (2003) Site-specific gene targeting in mouse embryonic stem cells with intact bacterial artificial chromosomes. Nat Biotechnol 21, 447–451

    Article  PubMed  CAS  Google Scholar 

  • Zeng C, Kouprina N, Zhu B, Cairo A, Hoek M, et al. (2001) Large-insert BAC/YAC libraries for selective re-isolation of genomic regions by homologous recombination in yeast. Genomics 77, 27–34

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA, 17033-0850, USA

    Jason D. Heaney & Sarah K. Bronson

Authors
  1. Jason D. Heaney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah K. Bronson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarah K. Bronson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heaney, J.D., Bronson, S.K. Artificial chromosome-based transgenes in the study of genome function. Mamm Genome 17, 791–807 (2006). https://doi.org/10.1007/s00335-006-0023-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-006-0023-9

Keywords

Search

Navigation