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Review
. 2021 Apr 3;22(7):3738.
doi: 10.3390/ijms22073738.

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

Sara Ramos-Lorente  1 , Cristina Romero-López  1 , Alfredo Berzal-Herranz  1
Affiliations
Review

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

Sara Ramos-Lorente et al. Int J Mol Sci. .

Abstract

The genus Flavivirus comprises numerous, small, single positive-stranded RNA viruses, many of which are important human pathogens. To store all the information required for their successful propagation, flaviviruses use discrete structural genomic RNA elements to code for functional information by the establishment of dynamic networks of long-range RNA-RNA interactions that promote specific folding. These structural elements behave as true cis-acting, non-coding RNAs (ncRNAs) and have essential regulatory roles in the viral cycle. These include the control of the formation of subgenomic RNAs, known as sfRNAs, via the prevention of the complete degradation of the RNA genome. These sfRNAs are important in ensuring viral fitness. This work summarizes our current knowledge of the functions performed by the genome conformations and the role of RNA-RNA interactions in these functions. It also reviews the role of RNA structure in the production of sfRNAs across the genus Flavivirus, and their existence in related viruses.

Keywords: Flavivirus; RNA genomes; interactome; long-distant RNA–RNA interactions; sfRNAs; structure/function of RNA domains.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural RNA elements of the 5′ end of representative flavivirus genomes. As a model for flaviviruses, a diagram of the WNV genome is shown at the top of the figure. The arrowhead indicates the position of the AUG translation initiation codon. The ORF is represented by a thick blue line. Enlarged are diagrams representing the main functional–structural RNA elements and sequence motifs identified at the 5′ end of the genome of representative members of the: (a) mosquito-borne flaviviruses group (represented by WNV, DENV-2 and YFV); (b) tick-borne flaviviruses group (represented by TBEV); (c) No-known vector flaviviruses group (represented by MODV); and (d) insect-specific flaviviruses group (represented by CFAV). The blue arrow line indicates the ORF. Structural elements and sequence motifs are named. Sequence motifs involved in genome cyclization (UAR, DAR and CS) are indicated by colored lines. Dotted lines indicate interactions involved in the formation of pseudoknot structures.
Figure 2
Figure 2
Secondary structure model of the 3′UTR of flavivirus genomes. As a model for flaviviruses, a diagram of the WNV genome is shown at the top of the figure. Below are detailed representations of the secondary structure of the genomic 3′UTR, indicating the identified secondary structural elements, the tertiary interactions and sequence motifs, for (a) WNV, DENV-2 and YFV, all members of the MBFV group; (b) TBEV, representative of the TBFV group; (c) MODV, a member of the NKFV group; and (d) CFAV, a member of the ISFV group. Secondary structural elements of each virus are indicated (thick black lines) on the secondary structure model of the WNV background (thick grey lines); note the differences between them. Structural elements and sequence motifs are named. Sequence motifs involved in genome cyclization (UAR, DAR and CS) are indicated by colored lines (same key as in Figure 1) to designate corresponding sequence partners in both figures. Dotted lines indicate interactions involved in the formation of pseudoknot structures. Thick dotted lines in the representation of YFV secondary structure indicate the presence of extra RYF elements in other members of the YFV clade.
Figure 3
Figure 3
Long-range RNA–RNA interactions involved in the cyclization of flavivirus genomes. The diagram shows the linear form of the RNA genomes of four representative flaviviruses: (a) WNV; (b) DENV-2; (c) YFV; and (d) TBEV. Colored boxes (same key as in Figure 1 and Figure 2) show different interacting sequences with their names. Long-range interactions are illustrated by thick colored lines. The dark blue box represents the ORF.
Figure 4
Figure 4
sfRNAs pattern. Diagram of the proposed xrRNA within the 3′UTR of the RNA genome of representative flaviviruses of: (a) the MFV; (b) TBFV; (c) NKFV and (d) ISFV groups. xrRNA elements are indicated by red scissors. xrRNA? denotes that the corresponding putative sfRNA has not been identified. sfRNAs are represented by dotted black lines. The key for the lines is as described for Figure 2.
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