Abstract
Cytologically detectable instability of centromeric satellite DNA may cause hereditary disorders in human. To study the mechanisms of such instability, two transgenic mouse lines and 11 clones of transfected F9 mouse embryonic teratocarcinoma cells were obtained with the 3.8-kb repetitive unit (Sat) of Bos taurus satellite DNA IV. Intergeneration and somatic instability of exogenous satellite DNA (satDNA) was observed in transgenic mice and transfected cells as a change in nucleotide sequence of an internal Sat region approximately 1000 bp in size. Since Sat was in the hemizygous state in both cases by the experimental protocol, the instability was attributed to intra-allelic processes. Intergeneration instability probably took place in the premeiotic period of gametogenesis or in early embryo development and led to prenatal death of transgenic embryos after at least one generation. No direct or inverse correlation was observed between methylation and instability of Sat. The results testify that submicroscopic changes in highly repetitive noncoding DNA sequences may already affect the genome function in higher eukaryotes.
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REFERENCES
Amarger, V., Gauguier, D., Verle, M., et al., Analysis of Distribution in the Human, Pig and Rat Genomes Points toward a General Subtelomeric Origin of Minisatellite Structures, Genomics, 1998, vol. 52, pp. 62–71.
Bois, P.R.J., Hypermutable Minisatellites, a Human Affair?, Genomics, 2003, vol. 81, pp. 349–355.
McMurray, C.T., DNA Secondary Structure: A Common and Causative Factor for Expansion in Human Disease, Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 1823–1825.
Vergnaud, J. and Denoeud, T., Minisatellites: Mutability and Genome Architecture, Genome Res., 2000, vol. 10, pp. 899–907.
Buard, J., Collick, A., Brown, J., and Jeffreys, A.J., Somatic Versus Germ Line Mutation Processes at Minisatellite CEB1 (D2S90) in Human and Transgenic Mice, Genomics, 2000, vol. 65, pp. 95–103.
Stead, J.D. and Jeffreys, A.J., Allele Diversity and Germ Line Mutation at the Insulin Minisatellite, Hum. Mol. Genet., 2000, vol. 9, pp. 713–723.
Kelly, R., Bulfield, G., Collick, A., et al., Characterization of Highly Unstable Mouse Minisatellite Locus: Evidence for Somatic Mutation during Early Development, Genomics, 1989, vol. 5, pp. 844–856.
Gibbs, M., Collick, A., Kelly, R.G., and Jeffreys, A.J., A Tetranucleotide Repeat Mouse Minisatellite Displaying Substantial Somatic Instability during Early Preimplantation Development, Genomics, 1993, vol. 17, pp. 121–128.
Gaitskhoki, V.S. and Patkin, E.L., Satellite DNAs and Diseases-Possible Mechanisms: Trinucleotide Repeats, Russ. J. Genet., 2000, vol. 36, no. 7, pp. 713–728.
Bennett, S.T., Lucassen, A.M., Gough, S.C.L., et al., Susceptibility to Human Type 1 Diabetes at IDDM2 Is Determined by Tandem Repeat Variation at the Insulin Gene Minisatellite Locus, Nat. Genet., 1995, vol. 9, pp. 284–292.
Virtaneva, K., Amato, E.D., Miao, J., et al., Unstable Minisatellite Expansion Causing Recessively Inherited Myoklonus Epilepsy, EPM1, Nat. Genet., 1997, vol. 15, pp. 393–396.
Patkin, E.L. and Gaitskhoki, V.S., Satellite DNAs and Diseases-Possible Mechanisms: Minisatellite Instability, Russ. J. Genet., 2000, vol. 36, no. 9, pp. 989–993.
Ji, W., Hernandez, R., Zhang, X.-Y., et al., DNA Demethylation and Pericentromeric Rearrangements of Chromosome 1, Mutat. Res., 1997, vol. 379, pp. 33–41.
Xu, G.-L., Bestor, T.H., Bourc'his, D., et al., Chromosome Instability and Immunodeficiency Syndrome Caused by Mutations in a DNA Methyltransferase Gene, Nature, 1999, vol. 402, pp. 187–191.
Barbasa, A.C.C., Otto, P.A., and Wianna-Morgante, A.M., Replication Timing of Homologous a-Satellite DNA in Roberts Syndrome, Chromosome Res., 2000, vol. 8, pp. 645–650.
Jeanpierre, M., Turleau, C., Aurias, A., et al., An Embryonic-like Methylation Pattern of Classical Satellite DNA Is Observed in ICF Syndrome, Hum. Mol. Genet., 1993, vol. 2, pp. 731–735.
Gisselsson, D., Hoglund, M., Mertens, F., and Mandahal, N., Variable Stability of Chromosomes Containing Amplified a-Satellite Sequences in Human Mesenchymal Tumors, Chromosoma, 1999, vol. 108, pp. 271–277.
Nijman, I.J. and Lenstra, J.A., Mutation and Recombination in Cattle Satellite DNA: A Feedback Model for the Evolution of Satellite DNA Repeats, J. Mol. Evol., 2001, vol. 51, pp. 361–371.
Smirnov, A.F., Pavlova, V.A., Sleptsov, M.K., and Steklenev, E.P., The Variability of Satellite DNA II and IV in Cattle and Some Representatives of Subfamily Bovinae and Their Hybrids, Russ. J. Genet., 1996, vol. 32, no. 9, pp. 1096–1101.
Harrington, J.J., Van Bokkelen, G., Mays, R.W., et al., Formation of De Novo Centromeres and Construction of First-Generation Human Artificial Microchromosomes, Nat. Genet., 1997, vol. 15, pp. 345–355.
Gurney, M.E., What Transgenic Mice Tell Us about Neurodegenerative Disease, BioEssay, 2000, vol. 22, pp. 297–304.
Baskaran, S., Datta, S., Mandal, A., et al., Instability of CGG Repeats in Transgenic Mice, Russ. J. Genet., 2002, vol. 80, pp. 930–935.
Popov, A.V., Smirnov, A.F., Suchkova, I.O., et al., Formation of Heterochromatin Regions in Transgenic Mice, Genetika (Moscow), 2000, vol. 36, no. 8, pp. 1119–1125.
Skowronski, J., Plucienniczak, A., Bednarek, A., and Jaworski, J., Bovine 1.709 Satellite: Recombination Hotspots and Dispersed Repeated Sequences, J. Mol. Biol., 1984, vol. 177, pp. 399–416.
Sambrook, J., Fritsch, E.F., and Maniatis, T., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York: Cold Spring Harbor Lab., 1989, vol. 1, pp. 182–184.
Promega Protocols and Applications Guide, Medison: Promega, 1990, pp. 40–41.
Vaisman, B.P. and Golinskii, G.F., A Technique of Microinjecting Cloned DNA Fragments (Foreign Genes) in the Nucleus of Mouse Fertilized Eggs, Obshchie zakonomernosti i kontroliruyushchie mekhanizmy rannego embriogeneza mlekopitayushchikh v norme i patologii. Sbornik nauchnykh trudov (General Regularities and Control Mechanisms of Mammalian Early Embryo Development in Norm and Pathology: A Collection of Works), Dyban, A.P., Ed., Leningrad: Meditsina, 1985, pp. 108–113.
Transcription and Translation: A Practical Approach, Hames, B.D. and Higgins, S.J., Eds., Oxford: IRL, 1984.
Maniatis, T., Fritsch, E.F., and Sambrook, J., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York: Cold Spring Harbor Lab., 1982.
Erlich, A.H., PCR Technology: Principles and Applications for DNA Amplification, New York: Stockton, 1989.
Saluz, H. and Jost, J.-P., Major Techniques to Study DNA Methylation, DNA Methylation: Molecular Biology and Biological Significance, Jost, J.P. and Saluz, H.P., Eds., Basel: Birkhauser, 1993, pp. 11–26.
Boan, F., Rodriguez, J.M., and Gomez-Marquez, J., A Non-Hypervariable Human Minisatellite Strongly Stimulates In Vitro Intramolecular Homologous Recombination, J. Mol. Biol., 1998, vol. 278, pp. 499–505.
Wahls, W.P. and Moore, P.D., Recombination Hotspot Activity of Hypervariable Minisatellite DNA Requires Minisatellite DNA-Binding Proteins, Som. Cell Mol. Genet., 1998, vol. 24, pp. 41–51.
Ohshima, K. and Wells, R.D., Hairpin Formation duringDNA Synthesis: Primer Realignment in Vitro in Triplet Repeats Sequences from Human Hereditary Disease Genes, Proc. Natl. Acad. Sci. USA, 1997, vol. 272, pp. 16798–16806.
Been, M.D., Burgess, R.R., and Champoux, J.J., Nucleotide Sequence Preference at Rat Liver and Wheat Germ Type I DNA Topoisomerase Breakage Sites in Duplex SV40 DNA, Nucleic Acids Res., 1984, vol. 12, pp. 3097–3114.
McFarlane, M. and Wilson, J.B., A Model for the Mechanism of Precise Integration of a Microinjected Transgene, Transgene Res., 1996, vol. 5, pp. 171–177.
Wells, R.D., Molecular Basis of Genetic Instability of Triplet Repeats, J. Biol. Chem., 1996, vol. 271, pp. 2875–2878.
Murti, J.R., Bumbulis, M., and Schimenti, J.C., Gene Conversion between Unlinked Sequences in the Germ Line of Mice, Genetics, 1994, vol. 137, pp. 837–843.
Kislyakova, T.V., Lyanguzova, M.S., Strunnikova, M.A., et al., Noninduced Single-Strand Breaks in DNA of F9 Mouse Tetatocarcinoma Cells, Tsitologiya, 2000, vol. 42, no. 11, pp. 1060–1068.
Jeffreys, A.J. and Neuman, R., Somatic Mutation Processes at a Human Minisatellite, Hum. Mol. Genet., 1997, vol. 6, pp. 129–136.
Bois, P., Stead, J.D.H., Bakshi, S., et al., Isolation and Characterization of Mouse Minisatellites, Genomics, 1998, vol. 50, pp. 317–330.
Lambert, S., Saintigny, Y., Delacote, F., et al., Analysis of Intrachromosomal Homologous Recombination in Mammalian Cells, Using Tandem Repeat Sequences, Mutat. Res., 1999, vol. 433, pp. 159–168.
Debrauwere, H., Buard, J., Tessier, J., et al., Meiotic Instability of Human Minisatellite CEB1 in Yeast Requires DNA Double-Strand Breaks, Nat. Genet., 1999, vol. 23, pp. 367–371.
Butner, K.A. and Lo, C.W., High Frequency DNA Rearrangements Associated with Mouse Centromeric Satellite DNA, J. Mol. Biol., 1986, vol. 187, pp. 547–556.
He, Q., Cederberg, H., Armour, J.A.L., et al., Cis-Regulation of Interallelic Exchanges in Mutation at Human Minisatellite MS205 in Yeast, Gene, 1999, vol. 232, pp. 143–153.
Imai, H., Nakagama, H., Komatsu, K., et al., Minisatellite Instability in Severe Combined Immunodeficiency Mouse Cells, Proc. Natl. Acad. Sci. USA, 1997, vol. 94, p. 10817.
Haber, J.E., Recombination: Frank View of Exchanges and Vice Versa, Curr. Opin. Cell Biol., 2000, vol. 12, pp. 286–292.
Hamada, T., Sasaki, H., Seki, R., and Sasaki, Y., Mechanism of Chromosomal Integration of Transgenes in Microinjected Mouse Eggs: Sequence Analysis of Genome-Transgene and Transgene-Transgene Junctions at Two Loci, Gene, 1993, vol. 128, pp. 197–202.
Yoder, J.A., Walsh, C.P., and Bestor, T.H., Cytosine Methylation and the Ecology of Intergenomic Parasites, Trends Genet., 1997, vol. 13, no. 8, pp. 335–340.
Hsieh, C.-L. and Lieber, M.R., CpG-Methylated Minichromosomes Become Inaccessible for V(D)J Recombination after Undergoing Replication, EMBO J., 1992, vol. 11, pp. 315–325.
Wu, J. and Issa, J.-P., Harman, J., et al., Expression of an Exogenous Eukaryotic DNA Methyltransferase Gene Induces Transformation of NIH 3T3 Cells, Proc. Natl. Acad. Sci. USA, 1993, vol. 90, pp. 8891–8895.
Zacharias, W., Methylation of Cytosine Influences the DNA Structure, DNA Methylation: Molecular Biology and Biological Significance, Jost, J.P. and Saluz, H.P., Basel: Birkhauser, 1993, pp. 27–38.
Noguiez, P., Jaulin, C., Plaz, F., et al., No Relationship between Genetic Instability in Bloom’s Syndrome and DNA Hypomethylation of Some Major Repetitive Sequences, Hum. Genet., 1993, vol. 92, pp. 57–60.
Chen, X., Marriapan, S.V.S., Catasti, P., et al., Hairpins Are Formed by the Single DNA Strands of the Fragile X Triplet Repeats: Structure and Biological Implications, Proc. Natl. Acad. Sci. USA, 1995, vol. 92, pp. 5199–5203.
Smith, S.S., Laayoun, A., Lingeman, R.G., et al., Hypermethylation of Telomere-like Foldbacks at Codon 12 of the Human c-Ha-ras Gene and the Trinucleotide Repeat of the FMR1 Gene of Fragile X, J. Mol. Biol., 1994, vol. 243, pp. 143–151.
Laayoun, A. and Smith, S.S., Methylation of Slipped Duplexes, Snapbacks and Cruciforms by Human DNA (Cytosine-5) Methyltransferase, Nucleic Acids Res., 1995, vol. 23, pp. 1584–1589.
Mitas, M., Trinucleotide Repeats Associated with Human Disease, Nucleic Acids Res., 1997, vol. 25, pp. 2245–2253.
Heller, H., Kammer, C., Wilgenbus, P., and Doerflier, W., Chromosomal Insertion of Foreign (Adenovirus Type 12, Plasmid, or Bacteriophage ?) DNA Is Associated with Enhanced Methylation of Cellular DNA Segments, Proc. Natl. Acad. Sci. USA, 1995, vol. 92, pp. 5515–5519.
Arnaud, P., Gaubely, C., Pelissier, T., and Deragon, J.-M., SINE Retroposons Can Be Used in Vivo as Nucleation Centers for De Novo Methylation, Mol. Cell. Biol., 2000, vol. 20, pp. 3434–3441.
Patkin, E.L., Epigenetic Mechanisms for Primary Differentiation in Mammalian Embryos, Int. Rev. Cytol., 2002, vol. 216, pp. 81–130.
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Suchkova, I.O., Slominska, N.A., Kustova, M.E. et al. Instability of Repetitive Units of Foreign Centromeric Satellite DNA in Transgenic Mice and Transfected Cells. Russian Journal of Genetics 40, 843–852 (2004). https://doi.org/10.1023/B:RUGE.0000039716.10439.81
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DOI: https://doi.org/10.1023/B:RUGE.0000039716.10439.81