Conservation of the cis-acting sequences of RNA viruses

Cis-acting sequences are remarkably well conserved

RNA viruses have extremely high mutation rates, estimated to be from 10-5 to as much as 10-3 errors per nucleotide polymerized [Holland, et al., 1992]. As a consequence, the virus populations include large numbers of mutants that allow rapid adaptation to new environmental conditions. This leads to rapid functional divergence and speciation of the RNA viruses, as reflected in the rapid sequence divergence among closely related virus species, and even among progeny of a single virus. The biomedical implications of this are that there are very many RNA viruses to contend with, they have increased likelihood of emergence as significant pathogens, and, as pathogens, drug-resistant variants arise readily.

Despite their high mutation rates, the cis-acting sequences of RNA viruses, recognized for initiation of transcription or replication, are remarkably well conserved. For example, the sequence of the minimal promoter of alphaviruses is as well conserved as the polymerase protein: the minimal promoter sequences of Sindbis and Semliki Forest viruses are identical at 83% of the nucleotides positions (range of 71-92% identity among the alphaviruses). In comparison, their nsP4 genes, that encode the elongation activity of the viral polymerase, have 65% identity at the RNA level, and the corresponding nsP4 proteins are identical at 74% of the amino acid residues, (83% homology if amino acid similarities are included).

The strong sequence conservation of the alphavirus promoter is not unusual, but is typical of the cis-acting sequences of RNA viruses in general. Conserved, probably cis-acting sequences are found in all families of RNA viruses. They are found at or close to the termini of the genomic RNA, probably recognized for initiation of replication; and at internal positions that are sites for transcription initiation or termination. This is documented in the following sequence compilation for some RNA virus families that include important human and animal pathogens.

Compilation of conserved cis-acting sequences of RNA viruses

  • Picornaviridae: Enteroviruses, Rhinoviruses, Apthoviruses, Cardioviruses, Hepatitis A viruses
  • Togaviridae: Alphaviruses, Rubella virus
  • Caliciviridae: Human and animal caliciviruses
  • Flaviviridae: Flaviviruses, Pestiviruses, Hepaciviruses
  • Nodaviridae: Nodaviruses
  • (unassigned): Benyviruses
  • Rhabdoviridae: Vesiculoviruses, Lyssaviruses, Novirhabdoviruses
  • Paramyxoviridae: Respiroviruses, Rubulaviruses, Morbilliviruses, Henipahviruses, Avulaviruses, "TPMV-like viruses", Pneumoviruses, Metapneumoviruses
  • Filoviridae: Marburg, Ebola viruses
  • Orthomyxoviridae: Influenza A, B, and C viruses; Thogoto virus
  • Arenaviridae: Lassa Fever, lymphocytic choriomeningitis, Junin, Tacaribe, Pichinde viruses
  • Bunyaviridae: Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tospoviruses
  • Reoviridae: Reoviruses, Orbiviruses, Rotaviruses, Coltivirus

Evolution of the cis-acting sequences

A picture of the evolution of RNA viruses emerges from these sequence comparisons, that emphasizes the extraordinary conservation of the cis-acting sequences. The pattern of sequence conservation is not correlated with geographic distribution (e.g., alphaviruses, Hantaviruses), nor with the host organisms (e.g., Rift Valley fever and the maize streak viruses), nor with the mode of transmission (e.g., arthropod-borne bunyaviruses versus rodent vectored Hantaviruses), nor with the virulence of, nor disease caused by the viruses (e.g., Sindbis versus the equine encephalitis viruses; Hantaan virus versus the Sin Nombre virus). Each group of viruses with clearly homologous cis-acting sequences appears to have evolved from a common progenitor. Evolutionary divergence of these related lineages resulted in viruses with different geographical distribution, host organisms, modes of transmission, virulence, and disease syndromes. Despite this enormous divergence, the cis-acting sequences of each group have changed little.

An analogy suggests itself: the cis-acting sequences (and the cognate proteins) of RNA viruses may be viewed as containers that change very slowly over time. The contents are variable, and serve to define each virus species. They consist of the phenotypes of usual concern: host range, tissue tropism, virulence etc.. Given the conservation of the container, however, it may be useful to focus attention on how it is so well conserved, and perhaps to exploit its conservation in the design of antiviral drugs.


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