• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Aug 1986; 83(16): 6020–6024.
PMCID: PMC386429

Early postimplantation embryo lethality due to DNA rearrangements in a transgenic mouse strain.

Abstract

Insertional mutagenesis in a transgenic mouse strain (HUGH/3) was caused by integration of plasmid DNA containing the human growth hormone gene and pBR322 plasmid sequences. From this study, which includes another instance of mutagenesis, and from other reports, it is apparent that insertional mutagenesis occurs fairly frequently during DNA integration in the mouse egg and that it is not specific for the exogenous DNA employed. The mutation in HUGH/3 is recessive and results in death of embryos homozygous for the donor sequences shortly after implantation, at the egg cylinder stage on days 4-5 of gestation. Restriction mapping of the insert and of the flanking DNA regions indicates that integration must have involved a series of complex events. Approximately five copies of plasmid sequences are arrayed in tandem but are interrupted at least twice by mouse cellular sequences. In addition, the mouse flanking DNA shows extensive rearrangements, probably including a deletion of at least 10 kilobases. The rearrangements may reflect an initially unstable DNA structure followed by attainment of a more stable conformation.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lebkowski JS, DuBridge RB, Antell EA, Greisen KS, Calos MP. Transfected DNA is mutated in monkey, mouse, and human cells. Mol Cell Biol. 1984 Oct;4(10):1951–1960. [PMC free article] [PubMed]
  • Mounts P, Kelly TJ., Jr Rearrangements of host and viral DNA in mouse cells transformed by simian virus 40. J Mol Biol. 1984 Aug 15;177(3):431–460. [PubMed]
  • Brinster RL, Chen HY, Trumbauer M, Senear AW, Warren R, Palmiter RD. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell. 1981 Nov;27(1 Pt 2):223–231. [PubMed]
  • Wagner EF, Stewart TA, Mintz B. The human beta-globin gene and a functional viral thymidine kinase gene in developing mice. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5016–5020. [PMC free article] [PubMed]
  • Fiddes JC, Seeburg PH, DeNoto FM, Hallewell RA, Baxter JD, Goodman HM. Structure of genes for human growth hormone and chorionic somatomammotropin. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4294–4298. [PMC free article] [PubMed]
  • Wagner EF, Covarrubias L, Stewart TA, Mintz B. Prenatal lethalities in mice homozygous for human growth hormone gene sequences integrated in the germ line. Cell. 1983 Dec;35(3 Pt 2):647–655. [PubMed]
  • Grosschedl R, Weaver D, Baltimore D, Costantini F. Introduction of a mu immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody. Cell. 1984 Oct;38(3):647–658. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Wahl GM, Stern M, Stark GR. Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization by using dextran sulfate. Proc Natl Acad Sci U S A. 1979 Aug;76(8):3683–3687. [PMC free article] [PubMed]
  • Steinmetz M, Höchtl J, Schnell H, Gebhard W, Zachau HG. Cloning of V region fragments from mouse liver DNA and localization of repetitive DNA sequences in the vicinity of immunoglobulin gene segments. Nucleic Acids Res. 1980 Apr 25;8(8):1721–1729. [PMC free article] [PubMed]
  • Krayev AS, Markusheva TV, Kramerov DA, Ryskov AP, Skryabin KG, Bayev AA, Georgiev GP. Ubiquitous transposon-like repeats B1 and B2 of the mouse genome: B2 sequencing. Nucleic Acids Res. 1982 Dec 11;10(23):7461–7475. [PMC free article] [PubMed]
  • Covarrubias L, Nishida Y, Mintz B. Early developmental mutations due to DNA rearrangements in transgenic mouse embryos. Cold Spring Harb Symp Quant Biol. 1985;50:447–452. [PubMed]
  • Overbeek PA, Lai SP, Van Quill KR, Westphal H. Tissue-specific expression in transgenic mice of a fused gene containing RSV terminal sequences. Science. 1986 Mar 28;231(4745):1574–1577. [PubMed]
  • Palmiter RD, Wilkie TM, Chen HY, Brinster RL. Transmission distortion and mosaicism in an unusual transgenic mouse pedigree. Cell. 1984 Apr;36(4):869–877. [PubMed]
  • Mark WH, Signorelli K, Lacy E. An insertional mutation in a transgenic mouse line results in developmental arrest at day 5 of gestation. Cold Spring Harb Symp Quant Biol. 1985;50:453–463. [PubMed]
  • Woychik RP, Stewart TA, Davis LG, D'Eustachio P, Leder P. An inherited limb deformity created by insertional mutagenesis in a transgenic mouse. Nature. 1985 Nov 7;318(6041):36–40. [PubMed]
  • Schnieke A, Harbers K, Jaenisch R. Embryonic lethal mutation in mice induced by retrovirus insertion into the alpha 1(I) collagen gene. Nature. 304(5924):315–320. [PubMed]
  • Hutchison KW, Copeland NG, Jenkins NA. Dilute-coat-color locus of mice: nucleotide sequence analysis of the d+2J and d+Ha revertant alleles. Mol Cell Biol. 1984 Dec;4(12):2899–2904. [PMC free article] [PubMed]
  • Copeland NG, Jenkins NA, Lee BK. Association of the lethal yellow (Ay) coat color mutation with an ecotropic murine leukemia virus genome. Proc Natl Acad Sci U S A. 1983 Jan;80(1):247–249. [PMC free article] [PubMed]
  • Varmus HE, Quintrell N, Ortiz S. Retroviruses as mutagens: insertion and excision of a nontransforming provirus alter expression of a resident transforming provirus. Cell. 1981 Jul;25(1):23–36. [PubMed]
  • Hawley RG, Shulman MJ, Murialdo H, Gibson DM, Hozumi N. Mutant immunoglobulin genes have repetitive DNA elements inserted into their intervening sequences. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7425–7429. [PMC free article] [PubMed]
  • King W, Patel MD, Lobel LI, Goff SP, Nguyen-Huu MC. Insertion mutagenesis of embryonal carcinoma cells by retroviruses. Science. 1985 May 3;228(4699):554–558. [PubMed]
  • Folger KR, Wong EA, Wahl G, Capecchi MR. Patterns of integration of DNA microinjected into cultured mammalian cells: evidence for homologous recombination between injected plasmid DNA molecules. Mol Cell Biol. 1982 Nov;2(11):1372–1387. [PMC free article] [PubMed]
  • Roberts JM, Buck LB, Axel R. A structure for amplified DNA. Cell. 1983 May;33(1):53–63. [PubMed]
  • Wahl GM, Robert de Saint Vincent B, DeRose ML. Effect of chromosomal position on amplification of transfected genes in animal cells. Nature. 1984 Feb 9;307(5951):516–520. [PubMed]
  • Yunis JJ, Soreng AL. Constitutive fragile sites and cancer. Science. 1984 Dec 7;226(4679):1199–1204. [PubMed]
  • Artzt K, Shin HS, Bennett D. Gene mapping within the T/t complex of the mouse. II. Anomalous position of the H-2 complex in t haplotypes. Cell. 1982 Mar;28(3):471–476. [PubMed]
  • Herrmann B, Bućan M, Mains PE, Frischauf AM, Silver LM, Lehrach H. Genetic analysis of the proximal portion of the mouse t complex: evidence for a second inversion within t haplotypes. Cell. 1986 Feb 14;44(3):469–476. [PubMed]
  • Gluecksohn-Waelsch S. Genetic control of morphogenetic and biochemical differentiation: lethal albino deletions in the mouse. Cell. 1979 Feb;16(2):225–237. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links