1887

Abstract

The genetic content of wild-type human cytomegalovirus was investigated by sequencing the 235 645 bp genome of a low passage strain (Merlin). Substantial regions of the genome (genes RL1–UL11, UL105–UL112 and UL120–UL150) were also sequenced in several other strains, including two that had not been passaged in cell culture. Comparative analyses, which employed the published genome sequence of a high passage strain (AD169), indicated that Merlin accurately reflects the wild-type complement of 165 genes, containing no obvious mutations other than a single nucleotide substitution that truncates gene UL128. A sizeable subset of genes exhibits unusually high variation between strains, and comprises many, but not all, of those that encode proteins known or predicted to be secreted or membrane-associated. In contrast to unpassaged strains, all of the passaged strains analysed have visibly disabling mutations in one or both of two groups of genes that may influence cell tropism. One comprises UL128, UL130 and UL131A, which putatively encode secreted proteins, and the other contains RL5A, RL13 and UL9, which are members of the RL11 glycoprotein gene family. The case in support of a lack of protein-coding potential in the region between UL105 and UL111A was also strengthened.

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2004-05-01
2019-11-18
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References

  1. Akter, P., Cunningham, C., McSharry, B. & 8 other authors ( 2003; ). Two novel spliced genes in human cytomegalovirus. J Gen Virol 84, 1117–1122.[CrossRef]
    [Google Scholar]
  2. Arav-Boger, R., Willoughby, R. E., Pass, R. F., Zong, J. C., Jang, W. J., Alcendor, D. & Hayward, G. S. ( 2002; ). Polymorphisms of the cytomegalovirus (CMV)-encoded tumor necrosis factor-α and β-chemokine receptors in congenital CMV disease. J Infect Dis 186, 1057–1064.[CrossRef]
    [Google Scholar]
  3. Atalay, R., Zimmermann, A., Wagner, M., Borst, E., Benz, C., Messerle, M. & Hengel, H. ( 2002; ). Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcγ receptor homologs. J Virol 76, 8596–8608.[CrossRef]
    [Google Scholar]
  4. Bale, J. F., Jr, Petheram, S. J., Robertson, M., Murph, J. R. & Demmler, G. ( 2001; ). Human cytomegalovirus a sequence and UL144 variability in strains from infected children. J Med Virol 65, 90–96.[CrossRef]
    [Google Scholar]
  5. Bar, M., Shannon-Lowe, C. & Geballe, A. P. ( 2001; ). Differentiation of human cytomegalovirus genotypes in immunocompromised patients on the basis of UL4 gene polymorphisms. J Infect Dis 183, 218–225.[CrossRef]
    [Google Scholar]
  6. Bresnahan, W. A. & Shenk, T. ( 2000; ). A subset of viral transcripts packaged within human cytomegalovirus particles. Science 288, 2373–2376.[CrossRef]
    [Google Scholar]
  7. Cha, T. A., Tom, E., Kemble, G. W., Duke, G. M., Mocarski, E. S. & Spaete, R. R. ( 1996; ). Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol 70, 78–83.
    [Google Scholar]
  8. Chee, M. S., Bankier, A. T., Beck, S. & 12 other authors ( 1990; ). Analysis of the protein coding content of the sequence of human cytomegalovirus strain AD169. Curr Top Microbiol Immunol 154, 125–169.
    [Google Scholar]
  9. Dargan, D. J., Jamieson, F. E., Maclean, J., Dolan, A., Addison, C. & McGeoch, D. J. ( 1997; ). The published DNA sequence of the human cytomegalovirus strain AD169 lacks 929 base pairs affecting genes UL42 and UL43. J Virol 71, 9833–9836.
    [Google Scholar]
  10. Davison, A. J., Dolan, A., Akter, P., Addison, C., Dargan, D. J., Alcendor, D. J., McGeoch, D. J. & Hayward, G. S. ( 2003a; ). The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J Gen Virol 84, 17–28.[CrossRef]
    [Google Scholar]
  11. Davison, A. J., Akter, P., Cunningham, C. & 7 other authors ( 2003b; ). Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes. J Gen Virol 84, 657–663.[CrossRef]
    [Google Scholar]
  12. DeMarchi, J. M. ( 1983; ). Post-transcriptional control of human cytomegalovirus gene expression. Virology 124, 390–402.[CrossRef]
    [Google Scholar]
  13. Dunn, W., Chou, C., Li, H., Hai, R., Patterson, D., Stolc, V., Zhu, H. & Liu, F. ( 2003; ). Functional profiling of a human cytomegalovirus genome. Proc Natl Acad Sci U S A 100, 14223–14228.[CrossRef]
    [Google Scholar]
  14. Ewing, B. & Green, P. ( 1998; ). Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res 8, 186–194.
    [Google Scholar]
  15. Ewing, B., Hillier, L., Wendl, M. C. & Green, P. ( 1998; ). Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res 8, 175–185.[CrossRef]
    [Google Scholar]
  16. Felsenstein, J. ( 1989; ). phylip: phylogeny inference package (version 3.2). Cladistics 5, 164–166.
    [Google Scholar]
  17. Hitomi, S., Kozuka-Hata, H., Chen, Z., Sugano, S., Yamaguchi, N. & Watanabe, S. ( 1997; ). Human cytomegalovirus open reading frame UL11 encodes a highly polymorphic protein expressed on the infected cell surface. Arch Virol 142, 1407–1427.[CrossRef]
    [Google Scholar]
  18. Jahn, G., Knust, E., Schmolla, H., Sarre, T., Nelson, J. A., McDougall, J. K. & Fleckenstein, B. ( 1984; ). Predominant immediate-early transcripts of human cytomegalovirus AD 169. J Virol 49, 363–370.
    [Google Scholar]
  19. Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V. & Pestka, S. ( 2000; ). Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci U S A 97, 1695–1700.[CrossRef]
    [Google Scholar]
  20. Lilley, B. N., Ploegh, H. L. & Tirabassi, R. S. ( 2001; ). Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. J Virol 75, 11218–11221.[CrossRef]
    [Google Scholar]
  21. Lockridge, K. M., Zhou, S. S., Kravitz, R. H., Johnson, J. L., Sawai, E. T., Blewett, E. L. & Barry, P. A. ( 2000; ). Primate cytomegaloviruses encode and express an IL-10-like protein. Virology 268, 272–280.[CrossRef]
    [Google Scholar]
  22. Lurain, N. S., Kapell, K. S., Huang, D. D., Short, J. A., Paintsil, J., Winkfield, E., Benedict, C. A., Ware, C. F. & Bremer, J. W. ( 1999; ). Human cytomegalovirus UL144 open reading frame: sequence hypervariability in low-passage clinical isolates. J Virol 73, 10040–10050.
    [Google Scholar]
  23. Mocarski, E. S. & Tan Courcelle, C. ( 2001; ). Cytomegaloviruses and their replication. In Fields Virology, 4th edn, vol. 2, pp. 2629–2673. Edited by D. M. Knipe & P. M. Howley. Philadelphia: Lippincott Williams & Wilkins.
  24. Mocarski, E. S., Prichard, M. N., Tan, C. S. & Brown, J. M. ( 1997; ). Reassessing the organization of the UL42–UL43 region of the human cytomegalovirus strain AD169 genome. Virology 239, 169–175.[CrossRef]
    [Google Scholar]
  25. Murphy, E., Rigoutsos, I., Shibuya, T. & Shenk, T. E. ( 2003; ). Reevaluation of human cytomegalovirus coding potential. Proc Natl Acad Sci U S A 100, 13585–13590.[CrossRef]
    [Google Scholar]
  26. Nelson, J. A., Fleckenstein, B., Jahn, G., Galloway, D. A. & McDougall, J. K. ( 1984; ). Structure of the transforming region of human cytomegalovirus AD169. J Virol 49, 109–115.
    [Google Scholar]
  27. Nielsen, H., Engelbrecht, J., Brunak, S. & von Heijne, G. ( 1997; ). Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng 10, 1–6.[CrossRef]
    [Google Scholar]
  28. Pasquier, C. & Hamodrakas, S. J. ( 1999; ). An hierarchical artificial neural network system for the classification of transmembrane proteins. Protein Eng 12, 631–634.[CrossRef]
    [Google Scholar]
  29. Penfold, M. E., Dairaghi, D. J., Duke, G. M., Saederup, N., Mocarski, E. S., Kemble, G. W. & Schall, T. J. ( 1999; ). Cytomegalovirus encodes a potent α chemokine. Proc Natl Acad Sci U S A 96, 9839–9844.[CrossRef]
    [Google Scholar]
  30. Plachter, B., Traupe, B., Albrecht, J. & Jahn, G. ( 1988; ). Abundant 5 kb RNA of human cytomegalovirus without a major translational reading frame. J Gen Virol 69, 2251–2266.[CrossRef]
    [Google Scholar]
  31. Plotkin, S. A., Furukawa, T., Zygraich, N. & Huygelen, C. ( 1975; ). Candidate cytomegalovirus strain for human vaccination. Infect Immun 12, 521–527.
    [Google Scholar]
  32. Prichard, M. N., Penfold, M. E. T., Duke, G. M., Spaete, R. R. & Kemble, G. W. ( 2001; ). A review of genetic differences between limited and extensively passaged human cytomegalovirus strains. Rev Med Virol 11, 191–200.[CrossRef]
    [Google Scholar]
  33. Prix, L., Kuner, R., Speer, C. P., Jahn, G. & Hamprecht, K. ( 1998; ). Evaluation of restriction fragment length polymorphism analysis of the UL10-UL13 genomic region for rapid identification of human cytomegalovirus strains. Eur J Clin Microbiol Infect Dis 17, 525–528.[CrossRef]
    [Google Scholar]
  34. Quinnan, G. V., Jr, Delery, M., Rook, A. H. & 8 other authors ( 1984; ). Comparative virulence and immunogenicity of the Towne strain and a nonattenuated strain of cytomegalovirus. Ann Intern Med 101, 478–483.[CrossRef]
    [Google Scholar]
  35. Rowe, W. P., Hartley, J. W., Waterman, S., Turner, H. C. & Huebner, R. J. ( 1956; ). Cytopathogenic agent resembling human salivary gland virus recovered from tissue cultures of human adenoids. Proc Soc Exp Biol Med 92, 418–424.[CrossRef]
    [Google Scholar]
  36. Shinde, D., Lai, Y., Sun, F. & Arnheim, N. ( 2003; ). Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/TG)n and (A/T)n microsatellites. Nucleic Acids Res 31, 974–980.[CrossRef]
    [Google Scholar]
  37. Sinzger, C., Schmidt, K., Knapp, J., Kahl, M., Beck, R., Waldman, J., Hebart, H., Einsele, H. & Jahn, G. ( 1999; ). Modification of human cytomegalovirus tropism through propagation in vitro is associated with changes in the viral genome. J Gen Virol 80, 2867–2877.
    [Google Scholar]
  38. Sinzger, C., Kahl, M., Laib, K., Klingel, K., Rieger, P., Plachter, B. & Jahn, G. ( 2000; ). Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus. J Gen Virol 81, 3021–3035.
    [Google Scholar]
  39. Skaletskaya, A., Bartle, L. M., Chittenden, T., McCormick, A. L., Mocarski, E. S. & Goldmacher, V. S. ( 2001; ). A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc Natl Acad Sci U S A 98, 7829–7834.[CrossRef]
    [Google Scholar]
  40. Staden, R., Beal, K. F. & Bonfield, J. K. ( 2000; ). The Staden package, 1998. Methods Mol Biol 132, 115–130.
    [Google Scholar]
  41. Tamashiro, J. C. & Spector, D. H. ( 1986; ). Terminal structure and heterogeneity in human cytomegalovirus strain AD169. J Virol 59, 591–594.
    [Google Scholar]
  42. Taylor, P. ( 1986; ). A computer program for translating DNA sequences into protein. Nucleic Acids Res 14, 437–441.[CrossRef]
    [Google Scholar]
  43. Thompson, J. D., Higgins, D. G. & Gibson, T. J. ( 1994; ). clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22, 4673–4680.[CrossRef]
    [Google Scholar]
  44. Tomasec, P., Braud, V. M., Rickards, C. & 7 other authors ( 2000; ). Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031.[CrossRef]
    [Google Scholar]
  45. Wathen, M. W. & Stinski, M. F. ( 1982; ). Temporal patterns of human cytomegalovirus transcription: mapping the viral RNAs synthesized at immediate early, early, and late times after infection. J Virol 41, 462–477.
    [Google Scholar]
  46. Weller, T. H., Macauley, J. C., Craig, J. M. & Wirth, P. ( 1957; ). Isolation of intranuclear inclusion producing agents from infants with illnesses resembling cytomegalic inclusion disease. Proc Soc Exp Biol Med 94, 4–12.[CrossRef]
    [Google Scholar]
  47. Yu, D., Smith, G. A., Enquist, L. W. & Shenk, T. ( 2002; ). Construction of a self-excisable bacterial artificial chromosome containing the human cytomegalovirus genome and mutagenesis of the diploid TRL/IRL13 gene. J Virol 76, 2316–2328.[CrossRef]
    [Google Scholar]
  48. Yu, D., Silva, M. C. & Shenk, T. ( 2003; ). Functional map of human cytomegalovirus AD169 defined by global mutational analysis. Proc Natl Acad Sci U S A 100, 12396–12401.[CrossRef]
    [Google Scholar]
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