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. 2014 Mar 19;9(3):e92056.
doi: 10.1371/journal.pone.0092056. eCollection 2014.

Molecular archaeology of Flaviviridae untranslated regions: duplicated RNA structures in the replication enhancer of flaviviruses and pestiviruses emerged via convergent evolution

Dmitri J Gritsun  1 , Ian M Jones  1 , Ernest A Gould  2 , Tamara S Gritsun  1
Affiliations

Molecular archaeology of Flaviviridae untranslated regions: duplicated RNA structures in the replication enhancer of flaviviruses and pestiviruses emerged via convergent evolution

Dmitri J Gritsun et al. PLoS One. .

Abstract

RNA secondary structures in the 3'untranslated regions (3'UTR) of the viruses of the family Flaviviridae, previously identified as essential (promoters) or beneficial (enhancers) for replication, have been analysed. Duplicated enhancer elements are revealed as a global feature in the evolution of the 3'UTR of distantly related viruses within the genera Flavivirus and Pestivirus. For the flaviviruses, duplicated structures occur in the 3'UTR of all four distantly related ecological virus subgroups (tick-borne, mosquito-borne, no known vector and insect-specific flaviviruses (ISFV). RNA structural differences distinguish tick-borne flaviviruses with discrete pathogenetic characteristics. For Aedes- and Culex-associated ISFV, secondary RNA structures with different conformations display numerous short ssRNA direct repeats, exposed as loops and bulges. Long quadruplicate regions comprise almost the entire 3'UTR of Culex-associated ISFV. Extended duplicated sequence and associated RNA structures were also discovered in the 3'UTR of pestiviruses. In both the Flavivirus and Pestivirus genera, duplicated RNA structures were localized to the enhancer regions of the 3'UTR suggesting an adaptive role predominantly in wild-type viruses. We propose sequence reiteration might act as a scaffold for dimerization of proteins involved in assembly of viral replicase complexes. Numerous nucleotide repeats exposed as loops/bulges might also interfere with host immune responses acting as a molecular sponge to sequester key host proteins or microRNAs.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Predicted RNA structures for TBFV.
Adapted from the Figure S1 for A) TBEV, B) LGTV and C) OHFV. The 3′UTR and adjacent NS5pol gene region is shown and annotated with the LRSs, DRs, conserved and variable, enhancer and promoter regions. The areas where LGTV and OHFV show different folding are framed.
Figure 2
Figure 2. Evolution of ISFV direct repeats and RNA structures.
The alignment between Aedes-and Culex-associated ISFV 3′UTRs is presented schematically based on the alignment in Figure S4A. The CxFV DRs1-4 are designated as black boxes and Aedes-associated R1/R2 as grey boxes; different box shadows reflect the independent origin of the CxFV DRs as discovered by the alignments in Figure S5A. The regions of very low sequence homology between Aedes- and Culex-associated ISFV are shown as dashed lines and the deletions as gaps. RNA conformations conserved between all ISFV are scheduled and specified based on the MFold-generated images in Figure S3. The RNA structures upstream of DB1 vary significantly between the ISFV and are not presented.
Figure 3
Figure 3. Diversification of Aedes- and Culex-associated 3′UTRs from the primordial flavivirus precursor.
As previously proposed the primordial 3′UTR formed due to numerous (9 times) duplication of the C-terminal region (LRS) of the NS5pol gene named the primordial LRS (pLRS) , . The remnants of pLRSs are most highly preserved among TBFVs which also developed 6 additional short DRs (dark small grey boxes). The development of the ISFV 3′UTR may have occurred via a primordial precursor that, after significant regression, self-duplicated as described in ; KRV is one direct extant descendent of the ancient ISFV precursor which also gave rise to CFAV. The CxFV 3′UTR is a second direct descendant which evolved independently from the KRV/CFAV precursor by duplication of the LRS2-like region as revealed by the alignment between TBFV and ISFV in Figures S4B and S4C. Different box shading reflects the evolution of original LRSs and DRs descendants by the accumulation of nucleotide alterations.
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