1887

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Volume 70, Issue 4

Deviations from Expected Frequencies of CpG Dinucleotides in Herpesvirus DNAs May Be Diagnostic of Differences in the States of Their Latent Genomes Free

Abstract

SUMMARY

The DNA sequences of genomes from G + C-rich and A + T-rich lymphotropic herpesviruses [i.e. gammaherpesviruses; Epstein–Barr virus and herpesvirus saimiri (HVS)] are deficient in CpG dinucleotides and contain an excess of TpG and CpA dinucleotides relative to frequencies predicted from their mononucleotide compositions. In contrast, for sequences from genomes of G + C-rich and A + T-rich neurotropic herpesviruses (i.e. alphaherpesviruses; herpes simplex virus and varicella-zoster virus) and human cytomegalovirus (HCMV; a betaherpesvirus) the mean observed frequencies of these dinucleotides are close to those expected from their mononucleotide compositions. Comparisons between DNA sequences that encode proteins conserved in all these viruses also show that sequences of these lymphotropic viruses are CpG-deficient whereas the homologous genes from the neurotropic viruses and the HCMV are not. Analyses of local variations in dinucleotide frequencies reveal some occurrences of clustered CpG dinucleotides in generally deficient genomes (e.g. upstream of the thymidylate synthase gene of HVS) and locally CpG-deficient regions within some generally non-deficient genomes (e.g. the major immediate early genes of human, simian and murine CMVs). A relative deficiency in CpG and an excess of TpG and CpA dinucleotides is a diagnostic feature of higher eukaryotic DNA sequences that have been subjected to methylation of cytosine residues in CpG doublets with the resulting increase in mutations to give TpG (and thereby its complement, CpA). The available evidence implicates the latent genome as the site of methylation of these herpesviruses. We conclude that in the neurotropic herpesviruses the normal latent precursors to infectious progeny are not methylated whereas there is local methylation of the immediate early locus in the latent genomes of CMVs, and the latent genomes of these lymphotropic herpesviruses are extensively methylated.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): episomes , herpesvirus and methylation
© Society for General Microbiology 1989
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1989-04-01
2024-04-25
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References

  1. Allday M. J., Crawford D. H. 1988; Role of epithelium in EBV persistence and pathogenesis of B-cell tumours. Lancet i:855–857
     [Google Scholar]
  2. Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Parrell P. J., Gibson T. J., Hatfull G., Hudson G. S., Satchwell S. C., SÉguin C., Tuffell P. S., Barrell B. G. 1984; DNA sequence and expression of the B938 Epstein—Barr virus genome. Nature, London 310:207–211
     [Google Scholar]
  3. Bankier A. T., Dietrich W., Baer R., Barrell B., Colbere-Garapin F., Fleckenstein B., Bodemer W. 1985; Terminal repetitive sequences in herpesvirus saimiri virion DNA. Journal of Virology 55:133–139
     [Google Scholar]
  4. Bernardi G., Olofsson B., Filipski J., Zerial M., Salinas J., Cuny G., Meunier-Rotival M., Rodier F. 1985; The mosaic genome of warm-blooded vertebrates. Science 228:953–958
     [Google Scholar]
  5. Bird A. P. 1980; DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Research 8:1499–1504
     [Google Scholar]
  6. Bird A. P. 1986; CpG-rich islands and the function of DNA methylation. Nature, London 321:209–213
     [Google Scholar]
  7. Bodemer W., Niller H. H., Nitsche N., Scholz B., Fleckenstein B. 1986; Organization of the thymidylate synthase gene of herpesvirus saimiri. Journal of Virology 60:114–123
     [Google Scholar]
  8. Bolden A. H., Nalin C. M., Ward C. A., Poonian M. S., Mccomas W. W., Weissbach A. 1985; DNA methylation: sequences flanking C—G pairs modulate the specificity of the human DNA methylase. Nucleic Acids Research 13:3479–3494
     [Google Scholar]
  9. Buckmaster A. E., Scott S. D., Sanderson M. J., Boursnell M. E. G., Ross N. L. J., Binns M. M. 1988; Gene sequence and mapping data from Marek’s disease virus and herpesvirus of turkeys: implications for herpesvirus classification. Journal of General Virology 69:2033–2042
     [Google Scholar]
  10. Bzik D. J., Fox B. A., Deluca N. A., Person S. 1984; Nucleotide sequence specifying the glycoprotein gene, gB, of herpes simplex virus type 1. Virology 133:301–314
     [Google Scholar]
  11. Cameron K. R., Stemminger T., Craxton M., Bodemer W., Honess R. W., Fleckenstein B. 1987; The 160,000-Mr virion protein encoded at the right end of the herpesvirus saimiri genome is homologous to the 140,000-Mr membrane antigen encoded at the left end of the Epstein-Barr virus genome. Journal of Virology 61:2063–2070
     [Google Scholar]
  12. Clough D. W., Kunkbl L. M., Davidson R. L. 1982; 5-Azacytidine-induced reactivation of a herpes simplex thymidine kinase gene. Science 216:70–73
     [Google Scholar]
  13. Costa R. H., Draper K. G., Banks L., Powell K. L., Cohen G., Eisenbbrg R., Wagner E. K. 1983; High- resolution characterization of herpes simplex virus type l transcripts encoding alkaline exonuclease and a 50,000-dalton protein tentatively identified as a capsid protein. Journal of Virology 48:591–603
     [Google Scholar]
  14. Coulondre C., Miller J. H., Farabaugh P. J., Gilbert W. 1978; Molecular basis of base substitution hotspots in Escherichia coli. Nature, London 274:775–780
     [Google Scholar]
  15. Coussens P. M., Velicbr L. F. 1988; Structure and complete nucleotide sequence of the Marek’s disease herpesvirus gp5765 gene. Journal of Virology 62:2373–2379
     [Google Scholar]
  16. Cranage M. P., Kouzarides T., Bonnier A. T., Satchwell S., Weston K., Tomlinson P., Barrell B., Hart H., Bell S. E., Minson A. C., Smith G. L. 1986; Identification of the human cytomegalovirus glycoprotein B gene and induction of neutralizing antibodies via its expression in recombinant vaccinia virus. EMBO Journal 5:3057–3063
     [Google Scholar]
  17. Dalrymple M. A., Mcgeoch D. J., Davison A. I., Preston C. M. 1985; DNA sequence of the herpes simplex virus type l gene whose product is responsible for transcriptional activation of immediate-early promoters. Nucleic Acids Research 13:7865–7879
     [Google Scholar]
  18. Dambaugh T., Hennessy K., Fennewald S., Kieff E. 1986; The virus genome and its expression in latent infections. In The Epstein-Barr Virus: Recent Advances13–45 Epstein M., Achong B. London: Heinemann;
     [Google Scholar]
  19. Davis M. G., Huang E-S. 1985; Nucleotide sequence of a human cytomegalovirus DNA fragment encoding a 67-kilodalton phosphorylated viral protein. Journal of Virology 56:7–11
     [Google Scholar]
  20. Davison A. J., Scott J. E. 1986; The complete DNA sequence of varicella-zoster virus. Journal of General Virology 67:1759–1816
     [Google Scholar]
  21. Davison A. J., Taylor P. 1987; Genetic relations between varicella-zoster virus and Epstein—Barr virus. Journal of General Virology 68:1067–1079
     [Google Scholar]
  22. Deatly A. M., Spivack J. G., Lavi E., Fraser N. W. 1987; RNA from an immediate early region of the type l herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice. Proceedings of the National Academy of Sciences, U.S.A 84:3204 3208:
     [Google Scholar]
  23. Debroy C., Pedrrson N., Person S. 1985; Nucleotide sequence of a herpes simplex virus type 1 gene that causes cell fusion. Virology 145:36–48
     [Google Scholar]
  24. Desrosiers R. C. 1982; Specifically unmethylated cytidylic-guanylate sites in herpesvirus saimiri DNA in tumor cells. Journal of Virology 43:427–435
     [Google Scholar]
  25. Desrosiers R. C., Mulder C., Fleckenstein B. 1979; Methylation of herpesvirus saimiri DNA in lymphoid tumor cells. Proceedings of the National Academy of Sciences, U.S.A 76:3839–3843
     [Google Scholar]
  26. Draper K. G., Frine R. J., Wagner E. K. 1982; Detailed characterization of an apparently unspliced beta herpes simplex virus type l gene mapping in the interior of another. Journal of Virology 43:1123–1128
     [Google Scholar]
  27. Dressler G. R., Rock D. L., Fraser N. W. 1987; Latent herpes simplex virus type 1 DNA is not extensively methylated in vivo. Journal of General Virology 68:1761–1765
     [Google Scholar]
  28. Dyson P. J., Farrell P. J. 1985; Chromatin structure of Epstein—Barr virus. Journal of General Virolog y 66:1931–1940
     [Google Scholar]
  29. Farrell P. J. 1989; Epstein-Barr virus genome. In Advances in Viral Oncology 8103–132 Kleine G. New York: Raven Press;
     [Google Scholar]
  30. Fleckenstein B., Desrosiers R. C. 1982; Herpesvirus saimiri and herpesvirus ateles. In The Herpesviruses 1:253–332 Roizman B. New York & London: Plenum Press;
     [Google Scholar]
  31. Frink R. J., Eisenberg R., Cohen G., Wagner E. K. 1983; Detailed analysis of the portion of the herpes simplex virus type l genome encoding glycoprotein C. Journal of Virology 45:634–647
     [Google Scholar]
  32. Galloway D. A., Swain M. A. 1984; Organization of the left-hand end of the herpes simplex virus type 2 Bglll- N fragment. Journal of Virology 49:724–730
     [Google Scholar]
  33. Gompels U. A., Minson z. 1986; The properties and sequence of glycoprotein H of herpes simplex virus type 1. Virology 153:230–247
     [Google Scholar]
  34. Gompels U. A., Craxton M. A., Honess R. W. 1988; Conservation of gene organization in the lymphotropic herpesviruses, herpesvirus saimiri and Epstein-Barr virus. Journal of Virology 62:757–767
     [Google Scholar]
  35. Greenaway P. J., Wilkinson G. W. G. 1987; Nucleotide sequence of the most abundantly transcribed early gene of human cytomegalovirus strain AD169. Virus Research 7:17–31
     [Google Scholar]
  36. Hirai K., Ikuta K., Kitamoto N., Kato S. 1981; Latency of herpesvirus of turkey and Marek’s disease virus genomes in a chicken T-lymphoblastoid cell line. Journal of General Virology 53:133–143
     [Google Scholar]
  37. Honess R. W. 1984; Herpes simplex and ‘the herpes complex’ : diverse observations and a unifying hypothesis. Journal of General Virology 65:2077–2107
     [Google Scholar]
  38. Honess R. W., Watson D. H. 1977; Unity and diversity in the herpesviruses. Journal of General Virology 37:15–37
     [Google Scholar]
  39. Honess R. W., Bodemer W., Cameron K. R., Niller H.-H., Fleckenstein B., Randall R. E. 1986; The A + T- rich genome of herpesvirus saimiri contains a highly conserved gene for thymidylate synthase. Proceedings of the National Academy of Sciences, U.S.A 83:3604–3608
     [Google Scholar]
  40. Hutchinson N. I., Tocci M. J. 1986; Characterization of a major early gene from the human cytomegalovirus long inverted repeat: predicted amino acid sequence of a 30kDa protein encoded by the l.2kb mRNA. Virology 155:172–182
     [Google Scholar]
  41. Kanamori A., Ikuta K., Ueda S., Kato S., Hirai K. 1987; Methylation of Marek’s disease virus DNA in chicken T-lymphoblastoid cell lines. Journal of General Virology 68:1485–1490
     [Google Scholar]
  42. Kaschka-Dierich C., Nazerian K., Thomssen R. 1979; Intracellular state of Marek’s disease virus DNA in two tumour-derived chicken cell lines. Journal of General Virology 44:271–280
     [Google Scholar]
  43. Keil G. M., Ebeling-Keil A., Koszinowski U. H. 1987; Sequence and structural organization of murine cytomegalovirus immediate-early gene 1. Journal of Virology 61:1901–1908
     [Google Scholar]
  44. Kieff E., Dambaugh T., Hummel M., Heller M. 1983; Epstein-Barr virus transformation and replication. In Advances in Viral Oncology 3:133–182 Klein G. New York: Raven Press;
     [Google Scholar]
  45. Kintner C., Sugden B. 1981; Conservation and progressive methylation of Epstein-Barr virus DNA sequences in transformed cells. Journal of Virology 38:305–316
     [Google Scholar]
  46. Kouzarides T., Bankier A. T., Satchwell S. C., Weston K., Tomlinson P., Barrell B. G. 1987; Large-scale rearrangement of homologous regions in the genomes of HCMV and EBV. Virology 157:397–413
     [Google Scholar]
  47. Larocca D., Clough W. 1982; Hypomethylation of Epstein-Barr virus DNA in the nonproducer B-cell line EBR. Journnal Virology 43:1129–1131
     [Google Scholar]
  48. Mcgeoch D. J., Davison A. J. 1986; DNA sequence of the herpes simplex virus type 1 gene encoding glycoprotein gH, and identification of homologues in the genomes of varicella-zoster virus and Epstein—Barr virus. Nucleic Atids Research 14:4281–4292
     [Google Scholar]
  49. Mcgeoch D. I., Dolan A., Donald S., Rixon F. I. 1985; Sequence determination and genetic content of the short unique region in the genome of herpes simplex virus type 1. Journal of Molecular Biology 181:1–13
     [Google Scholar]
  50. Mcgeoch D. J., Dolan X., Donald S., Brauer H. K. 1986; Complete DNA sequence of the short repeat region in the genome of herpes simplex virus type 1. Nucleic Acids Research 14:1727–1745
     [Google Scholar]
  51. Mcgeoch D. J., Dalrymple M. A., Davison A. J., Dolan A., Frame M. C., Mcnab D., Perry L. J., Scott J. E., Taylor P. 1988; The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. Journal of General Virology 69:1531–1574
     [Google Scholar]
  52. Mcknight S. L. 1980; The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Research 8:5949–5964
     [Google Scholar]
  53. Mercer J. A., Wiley C. A., Spector D. H. 1988; Pathogenesis of murine cytomegalovirus infection : identification of infected cells in the spleen during acute and latent infections. Journal of Virology 62:987–997
     [Google Scholar]
  54. Nelson I. A., Fleckfinstein B., Jahn G., Galloway D. A., Mcdougall J. K. 1984; Structure of the transforming region of human cytomegalovirus AD169. Journal of Virology 49:109–115
     [Google Scholar]
  55. Nonoyama M. 1982; The molecular biology of Marek’s disease herpesvirus. In The Herpesviruses 1:333–346 Roizman B. New York & London: Plenum Press;
     [Google Scholar]
  56. Nussinov R. 1984; Doublet frequencies in evolutionary distinct groups. Nucleic Acids Research 12:1749–1763
     [Google Scholar]
  57. Payne L. N. 1982; Biology of Marek’s disease virus and the herpesvirus of turkeys. In The Herpesviruses 1:343–431 Roizman B. New York & London: Plenum Press;
     [Google Scholar]
  58. Pellett P. E., Mcknight J. L. C., Jenkins F. J., Roizman B. 1985; Nucleotide sequence and predicted amino acid sequence of a protein encoded in a small herpes simplex virus DNA fragment capable of trans-inducing alpha genes. Proceedings of the National Academy of Sciences, U.S.A 82:5870–5874
     [Google Scholar]
  59. Perry L. J., Mcgeoch D. J. 1988; The DNA sequences of the long repeat region and adjoining parts of the long unique region in the genome of herpes simplex virus type 1. Journal of General Virology 69:2831–2846
     [Google Scholar]
  60. Rawlins D., Milman G., Hayward S., Hayward G. 1985; Sequence specific DNA-binding of the Epstein-Barr virus nuclear antigen (EBNA-l) to clustered sites in the plasmid maintenance region. Cell 42:859–868
     [Google Scholar]
  61. Razin A., Cedar H., Riggs A. D. 1984; . DNA Methylation : Biochemistry and Biological Significance New York & Wien: Springer-Verlag;
     [Google Scholar]
  62. Rea T. J., Timmins J. G., Long G. W., Post L. E. 1985; Mapping and sequence of the gene for the pseudorabies virus glycoprotein which accumulates in the medium of infected cells. Journal of Virology 54:21–29
     [Google Scholar]
  63. Reisman D., Yates J., Sugden B. 1985; A putative origin of replication of plasmids derived from Epstein-Barr virus is composed of two cis-acting components. Molecular and Cell Biology 5:1822–1832
     [Google Scholar]
  64. Robbins A. K., Watson R. J., Whealy M. E., Hays W. W., Enquist L. W. 1986; Characterization of a pseudorabies virus glycoprotein gene with homology to herpes simplex virus type I and type 2 glycoprotein C. Journal of Virology 58:339–347
     [Google Scholar]
  65. Roizman B. 1982; The family Herpesviridae: general description, taxonomy, and classification. In The Herpesviruses 1:1–23 Roizman B. New York & London: Plenum Press.;
     [Google Scholar]
  66. Roizman B., Batterson B. 1984; The replication of herpesviruses. In General Virology497–526 Fields B. New York: Raven Press;
     [Google Scholar]
  67. Roizman B., Sears A. E. 1987; An inquiry into the mechanisms of herpes simplex virus latency. Annual Review of Microbiology 41:543–571
     [Google Scholar]
  68. Russell G. J., Subak-Sharpe J. H. 1977; Similarity of the general designs of protochordates and invertebrates. Nature, London 266:533–536
     [Google Scholar]
  69. Staden R. 1984; Graphic methods to determine the function of nucleic acid sequences. Nucleic Acids Research 12:521–538
     [Google Scholar]
  70. Staden R. 1986; The current status and portability of our sequence handling software. Nucleic Acids Research 14:217–231
     [Google Scholar]
  71. Stamminger T., Honess R. W., Young D. F., Bodbmer W., Blair E. D., Fleckfinstein B. 1987; Organization of terminal reiterations in the virion DNA of herpesvirus saimiri. Journal of General Virology 68:1049–1066
     [Google Scholar]
  72. Stenberg R. M., Thomsbn D. R., Stinski M. F. 1984; Structural analysis of the major immediate-early gene of human cytomegalovirus. Journal of Virology 49:190–199
     [Google Scholar]
  73. Stenberg R. M., Witte P. R., Stinski M. F. 1985; Multiple spliced and unspliced transcripts from human cytomegalovirus immediate-early region 2 and evidence for a common initiation site within immediate-early region 1. Journal of Virology 56:665–675
     [Google Scholar]
  74. Subak-Sharpe J. H. 1967; Base doublet frequency patterns in the nucleic acid and evolution of viruses. British Medical Bulletin 23:161–168
     [Google Scholar]
  75. Swain M. A., Galloway D. A. 1986; Herpes simplex virus specifies two subunits of ribonucleotide reductase encoded by 3′-coterminal transcripts. Journal of Virology 57:802–808
     [Google Scholar]
  76. Szyf M., Eliasson L., Mac V., Klein G., Razin A. 1985; Cellular and viral DNA hypomethylation associated with induction of Epstein-Barr virus lytic cycle. Proceedings of the National Academy of Sciences, U.S.A 82:8090–8094
     [Google Scholar]
  77. Watson R. J., Van De Woude G. 1982; DNA sequence of an immediate-early gene (IE mRNA-5) of herpes simplex virus type 1. Nucleic Acids Researth 10:979–991
     [Google Scholar]
  78. Weston K., Barrell B. G. 1986; Sequence of the short unique region, short repeats and part of the long repeats of human cytomegalovirus. Journal of Molecular Biology 192:177–208
     [Google Scholar]
  79. Wildy P., Field H. J., Nash A. X. 1982; Classical herpes latency revisited. In Virus Persistence, Symposium of the Society for General Microbiology no. 33133–167 Mahy B. W. J., Minson A. C., Darby G. K. Cambridge: Cambridge University Press;
     [Google Scholar]
  80. Wu C. A., Nelson N. J., Mcgeogh D. J., Challberg M. D. 1988; Identification of herpes simplex virus type 1 genes required for origin-dependent DNA synthesis. Journal of Virology 62:435–443
     [Google Scholar]
  81. Yates J., Warren N., Sugden B. 1985; Stable replication of plasmids derived from Epstein—Barr virus in various mammalian cells. Nature, London 313:812–815
     [Google Scholar]
  82. Youssoufian H., Hammer S. M., Hirsch M. S., Mulder C. 1982; Methylation of the viral genome in an in vitro model of herpes simplex virus latency. Proceedings of the National Academy of sciences, U.S.A 79:2207–2210
     [Google Scholar]
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Deviations from Expected Frequencies of CpG Dinucleotides in Herpesvirus DNAs May Be Diagnostic of Differences in the States of Their Latent Genomes
J. Gen. Virol. 70, 837 (1989); https://doi.org/10.1099/0022-1317-70-4-837
/content/journal/jgv/10.1099/0022-1317-70-4-837
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