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  • Review Article
  • OPEN ACCESS

Where To Stop: Occurrence and Evolution of Translational Recoding Signals in RNA Viruses of Eukaryotes

  • Alexey A. Agranovsky* 
 Author information
Gene Expression   2023;22(3):240-249

doi: 10.14218/GE.2023.00025

Abstract

Many (+)RNA viruses employ translational recoding mechanisms, such as programmed ribosomal readthrough and ribosomal frameshifting, to direct a fraction of translating ribosomes in the infected cell to recode or bypass a stop codon in the zero reading frame and continue translation, thus producing protein isoforms with distinct functions. This creates a means to regulate both the quantity and time of synthesis of canonical and fusion proteins. The viral programmed ribosomal readthrough and ribosomal frameshifting signals are variable, with some being just short RNA sequences encompassing a stop codon, whereas others require elaborate RNA-RNA and RNA-protein interactions. Within virus evolutionary lineages, a given type of recoding signal is not universal, and its presence may be specific to a virus family, species, or even strain. It is possible that the establishment of virus recoding mechanisms and expression patterns occurs after the appearance of extant virus lineages, and these recoding signals might be acquired on multiple occasions during evolution. Recoding signals are the key regulators of gene expression in several clinically important viruses, such as human immunodeficiency viruses 1 and 2, human T-cell lymphotropic retroviruses, and severe acute respiratory syndrome coronavirus 2, as well as in a number of other animal and plant viruses of concern. The knowledge of viral recoding mechanisms is expected to provide new perspectives for the development of antiviral and synthetic biology strategies.

Keywords

RNA virus, Genome expression, Programmed recoding, Ribosomal readthrough, Ribosomal frameshifting, Virus evolution

Introduction

Most RNA-containing viruses have small genomes that encode only the key proteins for RNA replication, packaging, and some essential accessory functions.1,2 The expansion of the (+)RNA genome size beyond a 12-kb limit is under restrictions imposed by packaging constraints.3,4 The low fidelity of RNA copying by viral RNA polymerases and the action of cell editing enzymes (e.g., deaminases) may be additional factors hampering the maintenance of large genomic RNAs.5–8 These evolutionary pressures dictate the economy of the coding space achieved by the use of overlapping open reading frames (ORFs) and non-canonical translation strategies in RNA viruses.6,9 Notwithstanding, creating a compact genome is not the only evolutionary trend in the world of RNA viruses. Large nidoviruses (e.g., coronaviruses) have RNA genomes of 30 to 41 kb with minimal or no gene overlaps.10,11

Regardless of their genome size and propensity to use overlapping genes, many (+)RNA viruses employ translational recoding mechanisms, such as programmed ribosomal readthrough (PRT) and ribosomal frameshifting (PRF), to regulate gene expression, primarily the gene for RNA-dependent RNA polymerase (Pol).9 Both PRT and PRF direct a fraction of translating ribosomes to recode or bypass a stop codon in the zero reading frame. As a result, two proteins are produced by translation from one initiation codon: the canonical smaller protein (CSP) and a larger fusion protein (LFP). This review focuses on the occurrence and evolution of PRT and PRF signals in (+)RNA viruses, with some examples from double-stranded RNA (dsRNA) viruses and retroviruses. Because of the limited space, many aspects of these non-canonical translation mechanisms are not discussed here; the reader is encouraged to refer to excellent recent reviews on the topic.9,12–14

Programmed ribosomal readthrough of leaky stop codons

PRT determinants

An occasional read-through of mRNA stop codons is an extremely rare event in both prokaryotes and eukaryotes; however, it increases by ∼1,000 times at specific PRT signals, thus allowing the production of CSPs and LFPs at ratios of 20:1 to 10:1.15 The idea that a termination codon in a viral gene can be suppressed to yield two proteins sharing the N-terminal portion comes from the early works on bacteriophage Qbeta,16 retroviruses,17 and tobacco mosaic virus (TMV).18 In the pioneering work by Hugh Pelham, in vitro translation of TMV RNA was shown to produce the 126-kDa CSP and 180-kDa LFP, with the larger protein generated by suppression of a UAG stop codon (Fig. 1).18 In tobamoviruses, the read-through requires the type I PRT signal with UAG_CAR_YYA consensus (R, purine; Y, pyrimidine).19,20 The PRT is mediated by a specific tRNATyr having a pseudouridine in the anticodon (G-psi-A).21 A type I signal also directs the PRT in the replicase gene of the Providence tetravirus (Table 1a).9,19,20,22–27

Genome maps and PRT signals of tobacco mosaic virus (<italic>Tobamovirus</italic>), wheat soil-borne mosaic virus (<italic>Furovirus</italic>), tomato bushy stunt virus (<italic>Tombusvirus</italic>), and murine leukemia virus (<italic>Gammaretrovirus</italic>).
Fig. 1  Genome maps and PRT signals of tobacco mosaic virus (Tobamovirus), wheat soil-borne mosaic virus (Furovirus), tomato bushy stunt virus (Tombusvirus), and murine leukemia virus (Gammaretrovirus).

Arrows denote the 3′-ends of genomic RNAs. ORFs are shown as boxes, with the related protein domains indicated in the same fill-in. Vertical dotted bar, leaky stop codon. CSP and LFP are shown by narrow boxes below the genome map; the width of a box roughly reflects the abundance of a protein. Drawn approximately to scale. CP, capsid protein(s); CSP, canonical smaller protein; Hel, RNA helicase domain; LFP, larger fusion protein; Mtr, methyltransferase domain; ORF, open reading frame; PRT, programmed ribosomal readthrough; Pol, RNA polymerase; RSE, RNA stimulatory element; RTD, readthrough domain.

Table 1

Examples of known and suspected cases of translational recoding signals in RNA viruses

(a) Programmed ribosomal readthrough
TaxonGenomeProductSignalNotesReference
Alphavirus
  Sindbis virus(+)ReplicasePRT type IIstem-loop RSE20,22
Tobamovirus(+)ReplicasePRT type Ilinear RNA signal19,20
Tobravirus(+)ReplicasePRT type IIstem-loop RSE20
Furovirus(+)RNA-1, replicase; RNA-2, CP-RTDPRT type I; PRT type IIstem-loop RSE; stem-loop RSE9
Pomovirus(+)RNA-1, replicase; RNA-2, CP-RTDPRT type II; PRT type Istem-loop RSE; linear RNA signal27
Benyvirus(+)CP-RTDPRT type Ilinear RNA signal26
Alphatetravirus
  Providence virus(+)replicasePRT type Ilinear RNA signal9
  Luteovirus(+)CP-RTDPRT type IIIpseudoknot RSE formed by distal RNA interactions24
Tombusviridae
  Tombusvirus(+)replicasePRT type IIIpseudoknot RSE formed by distal RNA interactions25
Reoviridae
  ColtivirusdsVP9-RTDPRT type IIstem-loop RSE9
Retroviridae
  GammaretrovirusrtreplicasePRT type IIIpseudoknot RSE23

(+), positive-sense RNA; CP-RTD, capsid protein readthrough domain; ds, double-stranded; RNA; rt, reverse-transcribed RNA; PRF, programmed ribosomal frameshifting; PRT, programmed ribosomal readthrough; RSE, RNA stimulatory element; RTD, readthrough domain.

In the Sindbis virus, Venezuelan equine encephalitis virus, and related alphaviruses, a UGA stop codon precedes the replicase gene portion coding for RNA polymerase.9 The type II PRT signal in alphaviruses includes the UGA_C sequence20 and a downstream secondary structure element (RNA stimulatory element, RSE).20,22 Similar type II signals exist in the replicase and/or capsid protein (CP) genes of plant furoviruses (Fig. 1), tobraviruses, pecluviruses, pomoviruses, and coltivirus RNA-9 segment gene (Table 1a).9,20 Notably, the divided RNA genomes of furoviruses and pomoviruses contain two PRT signals, one in the RNA-1 (replicase gene) and the other in the RNA-2 (CP-RTD gene) (Table 1a and Fig. 1). In tobacco rattle tobravirus infection, tRNATrp with a methylated cytosine in anticodon (Cm-C-A) promotes the readthrough.28

Type III PRT signals involve a G-rich sequence adjacent to a stop codon (usually UAG) and a downstream RSE. In the murine leukemia gammaretrovirus (MuLV) gag-pol gene, the RSE represents a compact pseudoknot (Fig. 1),23 whereas in the luteovirus CP-RTD gene, the pseudoknot is formed by a stem-loop and a 3′-sequence located ∼750 nt downstream (Table 1a).24 In the tombusvirus replicase gene, the RSE pseudoknot requires even more distant interactions across ∼3,500 nt (Fig. 1).25 The UAG in MuLV gag-pol is suppressed by a glutamine tRNA.29

Biological sense of PRT in viral genes

In MuLV, a leaky UAG codon allows the synthesis of Gag and Gag-Pol polyproteins at a fixed ratio of 10:1, thus providing a means to produce more viral structural proteins than enzymes (Fig. 1). This ratio is vital for virus replication, as artificial modulation of the wildtype ratio of Gag/Gag-Pol is tolerated only to a limited extent, with downregulation of the Gag-Pol fusion being significantly more sensitive than its upregulation.30 In line with this, MuLV RT is able to bind to the translation release factor eRF1, creating a positive feedback loop that increases the synthesis of Gag-Pol.31 Hence, retrovirus PRT-driven Gag-Pol synthesis increases with time, being a unique example of viral PRT regulation.

The replicase gene in the alpha-like (+)RNA virus supergroup (including alphaviruses, tobamoviruses, tobraviruses, and a number of other animal and plant viruses) encompasses the conserved domains of methyltransferase (Mtr), RNA helicase (Hel), and RNA polymerase (Pol).1 A subset of alpha-like virus replicase genes contains a leaky stop codon that drives the synthesis of Mtr-Hel and Mtr-Hel-Pol proteins at a ratio of 20:1 to 10:1 (Fig. 1). A tobamovirus UAG/UAC mutant producing only the 180-kDa Mtr-Hel was able to replicate in Nicotiana benthamiana and Arabidopsis thaliana but produced milder symptoms, was deficient in anti-silencing activity attributed to the 126-kDa protein, and was prone to reversion to the wildtype.32 It was suggested that the 126-kDa protein is involved in opposing the cell defense silencing mechanism rather than in tobamovirus RNA replication, which explains its predominance over the 180-kDa replicase.32 However, the PRT-driven expression of tobamovirus Mtr-Hel and Mtr-Hel-Pol may have an alternative explanation. In the related alpha-like brome mosaic bromovirus (BMV), genomic RNA-1 and RNA-2 code for the replication-associated proteins 1a (Mtr-Hel) and 2a (Pol), respectively.33 BMV 1a is produced in excess of 2aPol owing to the unequal translation activities of RNA-1 and RNA-2.33 BMV 1a is a multifunctional protein that drives the remodeling of endoplasmic reticulum (ER) membranes with the help of cellular ESCRT proteins and reticulons, the creation of replication-associated spherules (membrane invaginations whose interior is lined by hundreds of 1a copies), and the delivery of 2aPol and viral RNA templates to the membranes.33–36 Spherules, similar to those of bromoviruses are produced in infected cells by many (+)RNA viruses in the alphavirus superfamily (alphaviruses, tobamoviruses, and tobraviruses) and beyond (tombusviruses).33 Notably, the tobamovirus 126-kDa CSP is associated with membranes and forms a heterodimer with the 180-kDa LFP, resembling the 1a-2aPol complex in bromoviruses.32 The replicase of tombusviruses consists of the 33-kDa CSP and 92-kDa LFP, with the latter produced via PRT (Fig. 1).37 The N-termini of these proteins contain membrane-binding and dimerization domains.37 In a striking parallel with bromoviruses, the tombusvirus CSP (assisted by the ESCRT system) serves as the key organizer of spherule formation, and multiple copies of this protein cover the spherule interior.37 It is tempting to speculate that the replicative proteins produced by PRT-driven translation in alpha-like and tombus-like viruses play roles equivalent to those of the BMV 1a and 2aPol proteins. In other terms, the PRT in disparate virus groups may serve to produce multiple copies of a CSP that remodels the membranes and paves the spherule interior and a few copies of the LFP with RNA polymerase activity.

The C-terminally extended CP versions (CP-RTD) of plant furoviruses (Fig. 1), luteoviruses, pomoviruses, benyviruses, poleroviruses, and enamoviruses are produced by PRT (Table 1a).9,20 One or a few copies of CP-RTD have been detected by immunospecific electron microscopy at one end of the rod-like particles of beet necrotic yellow vein benyvirus and potato mop-top pomovirus.26,27 A small amount of CP-RTD is associated with icosahedral luterovirus, enamovirus, and polerovirus particles.38,39 Regardless of particle morphology, the virion-incorporated CP-RTD molecules serve to enhance virus interactions with and transmission by corresponding vectors - aphids (luteoviruses, enamoviruses, and poleroviruses) or the soil fungi Polymyxa betae (benyvirus) and Spongospora subterranea (pomovirus).26,27,38,39 Hence, the PRT in these virus systems produces the major CP and the minor CP-RTD at ratios providing for the assembly of viral particles competent for vector transmission.

Programmed ribosomal frameshifting −1 PRF driven by RNA signals

Ribosomal frameshifting occurs when the translating ribosome skips from the zero reading frame to the −1 or +1 reading frame and continues translation to produce a fusion protein. The chance for spontaneous frameshifting upon mRNA translation is quite low (10−3 to 10−7 per codon);40 however, the PRF signals in viral mRNAs promote ribosomes to change the reading frame at 5 to 30% frequencies. A classical −1 PRF signal that controls the ratio of Gag and Gag-Pol polyproteins was initially discovered and characterized in Rous sarcoma alpharetrovirus (Fig. 2).41,42 Similar signals have been found in several clinically important viruses, such as human immunodeficiency lentivirus-1 (HIV-1) and HIV-2, human T-cell lymphotropic deltaretrovirus types 1 and 2, SARS CoV-1, and SARS CoV-2, as well as in a number of other animal and plant viruses (Table 1b).9,12,41–62 The −1 PRF signals consist of a slippery site with X_XXY_YYZ consensus (where XXX denotes any three identical nucleotides, Y is A or U, and Z is A, C, or U; triplets are shown for the zero frame), a spacer of 5 to 9 nucleotides, and a downstream RSE (Fig. 2).42–48 It is postulated that, while the ribosome aminoacyl and peptidyl sites are occupied by the respective XXY and YYZ triplets, a difficult-to-unwind RSE exerts a translational pause, thus promoting backward shifting of two tRNAs in the P and A sites and decoding the slippery sequence as XXX YYY.41–47 RSE in different viral genes is represented by a stable stem-loop (HIV-1 and related lentiviruses, astroviruses, sobemoviruses, and dianthoviruses),49,63 a compact pseudoknot (alpharetroviruses, betaretroviruses, deltaretroviruses, and most nidoviruses),9,41,48,50 or an elaborated pseudoknot formed by RNA interactions across a ∼4 kb distance (luteoviruses) (Table 1b and Fig. 2).51

Genome maps and PRF signals of Rous sarcoma virus (<italic>Alpharetrovirus</italic>), barley yellow dwarf virus (<italic>Luteovirus</italic>), beet yellows virus (<italic>Closterovirus</italic>), and encephalomyocarditis virus (<italic>Cardiovirus</italic>).
Fig. 2  Genome maps and PRF signals of Rous sarcoma virus (Alpharetrovirus), barley yellow dwarf virus (Luteovirus), beet yellows virus (Closterovirus), and encephalomyocarditis virus (Cardiovirus).

Arrows denote the 3′-ends of genomic RNAs. ORFs are shown as boxes, with the related protein domains indicated in the same fill-in. 2B*TF is shown in blue color. Vertical bars denote the cleavage sites in the cardiovirus polyproteins (note that the 2A C-terminus is liberated by a non-proteolytic Stop-Go elongation mechanism9). In the luteovirus genome, the distal RNA-RNA contact required for −1 PRF is shown by a curved arrow. The translation products (CSP and LFP) are shown by narrow boxes below the genome map; the width of a box roughly reflects the abundance of a protein. Drawn approximately to scale. CP, capsid protein(s); CSP, canonical smaller protein; Hel, RNA helicase do- main; LFP, larger fusion protein; Mtr, methyltransferase domain; ORF, open reading frame; Pol, RNA polymerase; RSE, RNA stimulatory element; PRF, programmed ribosomal frameshifting; RTD, readthrough domain.

In most known cases, −1 PRF serves to express viral reverse transcriptase or RNA polymerase LFP (Table 1b and Fig. 2),9 yet this signal is used in some other viral genes. Thus, −1 PRF in Acyrthosiphon pisum virus (a picorna-like insect virus) is employed to synthesize minor capsid proteins.64 In the Sindbis virus and the related alphaviruses, −1 PRF allows the synthesis of a minor transframe (TF) protein, which is included in virions to assist virus budding and spread in animal hosts,52 whereas in flaviviruses it serves to downregulate the expression of RNA polymerase and to produce a TF NS1’ protein influencing virus pathogenicity (Table 1b).53

−1 PRF driven by RNA-protein complexes

An idea that a protein bound to RNA may promote ribosomal frameshifting has received attention in early works and was supported by studies with a synthetic system, where the lentivirus RSE was replaced with an iron-response element from ferritin mRNA to produce a −1 frameshifting signal stimulated by an iron-regulatory protein.65,66 PRF signals stimulated by trans-acting proteins were recently found in cardioviruses and arteriviruses. In porcine reproductive and respiratory syndrome arterivirus (PRRSV), in addition to a pseudoknot-driven −1 PRF regulating the ratio of 1a and 1ab polyproteins, an extra frameshifting occurs on a slippery site GG_GUU_UUU located in the 1a gene portion coding for the nsp2 replicase subunit (Table 1b).54 The −1/−2 PRF in PRRSV requires the interaction of a C-rich sequence, located 10 nucleotides downstream of the shift site, with the complex of cellular poly(C)-binding proteins (PCBP) and the virus-encoded nonstructural protein nsp1β.55,67 Binding of the trans-activating PCBP-nsp1β complex to the C-rich tract results in ribosome stalling on the slippery sequence.55

In encephalomyocarditis virus and Theiler’s murine encephalomyelitis virus (cardioviruses), the −1 PRF occurs on a conserved G_GUU_UUU sequence located within the 2B-coding region of the polyprotein gene and requires binding of the cardiovirus 2A protein to a downstream stem-loop separated from the shift site by a 13-nt spacer (Table 1b and Fig. 2).56,57 The frameshift efficiency in cardiovirus-infected cells gradually increases from 0 to 70% as the infection proceeds, apparently because of the utter dependence of PRF on the available amounts of the trans-activating 2a protein.57 Apart from stabilizing the RSE, 2A binds to small ribosomal subunits and may interfere with host translation factors to further enhance virus frameshifting.68

+1 PRF in viral mRNAs

+1 PRF signals are mechanistically less conserved and relatively uncommon in viruses. In a few groups of (+)RNA viruses and dsRNA viruses, the RNA polymerase is likely to be expressed as an LFP by +1 (or −2) ribosomal frameshifting. Thus, in members of the Closteroviridae family of plant viruses, which belongs to the alpha-like supergroup, the replication-associated Mtr and Hel domains are encoded in a zero-frame ORF 1a, whereas Pol is encoded in a +1-frame ORF 1b (Table 1b and Fig. 2).69,58 GUU_UAG_C is a putative frameshift site in the ORF 1a of beet yellows closterovirus, and PRF may involve ribosome stalling at the stop codon in the A-site and a slippage from GUU to UUU in the P-site.9 In support of this, most of the 110 closterovirus sequences currently available in the GeneBank contain a consensus G/CUU_stop_C at the putative frameshift sites. However, as deduced from amino acid conservation profiles in ORFs 1a and 1b in citrus tristeza closterovirus (CTV) ORF 1a, a predicted frameshift site is located 25 triplets upstream of the stop codon and is represented by a GUU_CGG_C sequence.70 It was proposed that in CTV, the ribosome pausing occurs on a rare arginine CGG codon,70 analogous with some yeast retroelements.71 These sequence comparisons imply that the determinants of the frameshifting signal are not strictly conserved in closteroviruses, although the principal mechanism of the CSP and LFP synthesis may be similar.

There are a number of dsRNA viruses and (−)RNA viruses containing +1 PRF signals in their replication-associated genes (Table 1b). In some members of the Totiviridae family of dsRNA viruses, the Gag-Pol fusion polyprotein is apparently synthesized by +1 (or −2) frameshifting. In Trichomonas vaginalis virus 1, the PRF takes place at the CC_CUU_UUU sequence adjacent to a stop codon, but no stimulating secondary structure was predicted,59 whereas in Leishmania virus 1, the PRF, in addition to a shifty site, may require a pseudoknot located downstream of a stop codon.60 The PA mRNA of the influenza A virus is translated into a conventional PA replicase component and the minor +1 frameshift product, PA-X, that modulates the host cell shut-off.61 The +1 PRF occurs on a conserved sequence UCC_UUU_CGU in the PA gene.62 Intriguingly, similar shifty sequences were found in RNA polymerase genes of disparate viruses of animals and plants, namely the chronic bee paralysis virus, fijiviruses, and amalgamaviruses, suggesting a novel +1 PRF mechanism that is conserved in diverse eukaryotes (Table 1b).62

Biological sense of PRF in viral genes

As is the case with programmed read-through, PRF allows the synthesis of protein isoforms at a fixed ratio. In most cases, this concerns reverse transcriptase and RNA polymerase precursors that are expressed as PRF fusions by the well-conserved ‘−1 simultaneous slippage’ and then undergo proteolytic maturation. Obviously, keeping the synthesis of structural and abundant nonstructural proteins relatively high compared to a polymerase fusion helps to maintain a balance between the proteins needed in stochiometric and enzymatic amounts. It is possible that the same holds true for closteroviruses that express more of the Mtr-Hel 1a polyprotein than an Mtr-Hel-Pol 1ab fusion. It should be noted that the 1a proteins of beet yellows closterovirus and closely related closteroviruses contain a conserved hydrophobic Zemlya domain that interacts with ER membranes and may be involved in their remodeling.72 This implies a potential parallel with other alpha-like viruses that express a bulk of proteins with the Mtr, Hel, and membrane binding domains and much lesser amounts of RNA polymerase.33–35,73

The ratio of shorter and longer polyproteins may change in time in PRF driven by RNA-protein signals such as those of arteriviruses and cardioviruses.54,56,57,67 Early in PRRSV infection, the 5′-terminal ORF1a is translated into a single 1a polyprotein whose processing results in equimolar amounts of mature proteins nsp1α to nsp8. At later stages, with the accumulation of the nsp1β, this protein complexes with PCBP and promotes −1 or −2 PRF, resulting in the predominant expression of nsp1α, nsp1β, and two nsp2 derivatives, nsp2N and nsp2TF.67 The nsp1α and nsp1β are involved in transcriptional control and innate immune evasion. The nsp2TF, representing the N-terminal two-thirds of nsp2 fused to a short trans-frame C-terminal sequence, has a membrane-binding domain and is involved in the formation of replication organelles and repression of interferon responses; mutations hampering the synthesis of the nsp2TF caused a 50- to 100-fold drop in the PRRSV replication in cell culture.67 Taken together, these data provide a good rationale for the elevated synthesis of nsp1α, nsp1β, nsp2N, and nsp2TF at late stages of arterivirus infection. Likewise, in cardioviruses, early translation produces structural and nonstructural proteins in equimolar amounts. At later stages, the accumulated 2A protein binds to a stem-loop within the 2B-coding region, which results in −1 PRF-driven overexpression of the structural proteins at the expense of RNA polymerase and other replication-associated proteins (Fig. 2).57 Conceivably, this mechanism will also lead to upregulation of the cardiovirus 2A and leader protein (L) expression needed for their success in the shut-off of cap-dependent translation of host mRNAs, inhibition of apoptosis, and interference with cell nucleocytoplasmic trafficking.74

Evolution of translational recoding mechanisms in viruses

The use of translational recoding signals by viruses has obvious advantages as it expands the RNA coding capacity and provides a means to regulate protein expression. However, it has some inherent drawbacks that have had to be attended in the course of virus evolution. In cells, mutation or aberrant splicing creates mRNAs with illegal stop codons and extended 3′-untranslated regions that are targets for nonsense-mediated decay (NMD).75 Many virus mRNAs are naturally polycistronic and contain 3′-distal stop codons, including those associated with PRT and PRF. However, their genomes are obviously not sensitive to NMD, at least in part, due to evolving specific RNA signals that inhibit NMD.76 Another example of a host factor that opposes translational recoding is the antiviral protein Shiftless, which specifically inhibits the −1 PRF in HIV-1 and a number of other virus and cell mRNAs.77 The question of whether viruses have mechanisms to evade the action of Shiftless remains open.

PRT and PRF signals are present in viruses and across all kingdoms of life, with −1 PRF being most common in viruses (Table 1) and PRT being predominant in eukaryotic mRNAs.9,12–14,78–81 Some eukaryotic recoding signals resemble those in RNA viruses, e.g., the −1 shifty site-spacer-pseudoknot arrays in the human paraneoplastic Ma3 gene and mouse Edr gene.82,83 It could be postulated that these recoding signals can be exchanged among viruses and cells by horizontal flow. RNA-to-RNA transfer is quite possible, as RNA viruses are prone to recombination and may acquire non-coding sequences, gene fragments, and even entire genes from other viruses or cell mRNAs.1,58,84 RNA-to-DNA transfer of recoding signals resulting from the interplay of retroelements, retroviruses, and the cell genome also cannot be excluded. On the other hand, PRT and PRF signals might have been ‘invented’ independently on several occasions in virus gene evolution. In support of the recombination hypothesis, experimental swapping of recoding signals (i.e., replacement of a natural PRT signal for a heterologous PRT or PRF signal) may create viable retrovirus and (+)RNA virus phenotypes.85,86

The expression mechanisms in RNA viruses evolve faster than the conserved amino acid sequences of the replication-associated enzymes. This may result in quite dissimilar patterns of protein synthesis in the related viruses. In the alpha-like supergroup, the RNA polymerase expression in tobamoviruses,18 tobraviruses,28 and some (but not all) alphaviruses employs PRT,9 whereas in closteroviruses it requires +1 PRF (Table 1 and Figs. 1 and 2). The same applies to totiviruses, of which some use −1 PRF and others +1 PRF to express the Gag-Pol fusion.9 Most members of the family Tombusviridae employ PRT to express RNA polymerase, with the exception of dianthoviruses, which use −1 PRF (Table 1).9 Within an evolutionary compact virus lineage, some conserved genes may be devoid of the recoding signals that exist in their relatives. The largest known (+)RNA genome of planarian secretory cell nidovirus does not have a −1 PRF signal, which is ubiquitous in other nidovirus replicase genes, nor does it have any other apparent recoding signals.11 Likewise, the alpha-like replicases of tymoviruses, potexviruses, and carlaviruses result from the orthodox translation of single uninterrupted genes. Even more strikingly, the presence of recoding signals may vary on the subspecies level, as is the case with the Semliki Forest alphavirus complex, where some strains encompass a leaky stop codon between the Mtr-Hel- and Pol-coding genes, whereas others have none.22,87 Hence, the programmed recoding signals may be retired in some members of evolutionary compact RNA virus groups, and whether and how their absence is compensated, remains unknown. The establishment of virus expression patterns occurred long after the appearance of extant virus lineages, and the recoding signals might have been acquired or dismissed on multiple occasions in evolution.

Conclusion

In the past decade, the use of bioinformatic methods and databases, dual reporter systems, ribosome profiling, and other experimental approaches has greatly expanded our knowledge of non-canonical translation mechanisms in viruses. Further studies are expected to provide new perspectives on antiviral strategies targeted at viral PRT and PRF and the use of recoding mechanisms in synthetic biology.

Abbreviations

BMV: 

brome mosaic bromovirus

CP: 

capsid protein

CP-RTD: 

capsid protein readthrough domain

CSP: 

canonical smaller protein

CTV: 

citrus tristeza virus

dsRNA: 

double-stranded RNA

ER: 

endoplasmic reticulum

Hel: 

RNA helicase domain

HIV: 

human immunodeficiency lentivirus

LFP: 

larger fusion protein

Mtr: 

methyltransferase domain

MuLV: 

murine leukemia gammaretrovirus

NMD: 

nonsense-mediated decay

ORF: 

open reading frame

Pol: 

polymerase

PCBP: 

poly(C)-binding proteins

PRF: 

programmed ribosomal frameshifting

PRRSV: 

porcine reproductive and respiratory syndrome arterivirus

PRT: 

programmed ribosomal readthrough

RSE: 

RNA stimulatory element

RSV: 

Rous sarcoma virus

RTD: 

readthrough domain

TF: 

transframe

TMV: 

tobacco mosaic virus

Declarations

Acknowledgement

The author is grateful to Professor Andrey Vartapetian for his critical reading of the manuscript.

Funding

There is nothing to declare.

Conflict of interest

There is nothing to declare.

References

  1. Koonin EV, Dolja VV. Evolution and taxonomy of positive-strand RNA viruses: implications of comparative analysis of amino acid sequences. Crit Rev Biochem Mol Biol 1993;28(5):375-430 View Article PubMed/NCBI
  2. Zhang YZ, Shi M, Holmes EC. Using Metagenomics to Characterize an Expanding Virosphere. Cell 2018;172(6):1168-1172 View Article PubMed/NCBI
  3. Godeny EK, Chen L, Kumar SN, Methven SL, Koonin EV, Brinton MA. Complete genomic sequence and phylogenetic analysis of the lactate dehydrogenase-elevating virus (LDV). Virology 1993;194(2):585-596 View Article PubMed/NCBI
  4. Chirico N, Vianelli A, Belshaw R. Why genes overlap in viruses. Proc Biol Sci 2010;277(1701):3809-3817 View Article PubMed/NCBI
  5. Drake JW. Rates of spontaneous mutation among RNA viruses. Proc Natl Acad Sci U S A 1993;90(9):4171-4175 View Article PubMed/NCBI
  6. Holmes EC. Error thresholds and the constraints to RNA virus evolution. Trends Microbiol 2003;11(12):543-546 View Article PubMed/NCBI
  7. Klimczak LJ, Randall TA, Saini N, Li JL, Gordenin DA. Similarity between mutation spectra in hypermutated genomes of rubella virus and in SARS-CoV-2 genomes accumulated during the COVID-19 pandemic. PLoS One 2020;15(10):e0237689 View Article PubMed/NCBI
  8. Simmonds P. Rampant C→U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for Their Short- and Long-Term Evolutionary Trajectories. mSphere 2020;5(3):e00408-20 View Article PubMed/NCBI
  9. Firth AE, Brierley I. Non-canonical translation in RNA viruses. J Gen Virol 2012;93(Pt 7):1385-1409 View Article PubMed/NCBI
  10. Gorbalenya AE, Enjuanes L, Ziebuhr J, Snijder EJ. Nidovirales: evolving the largest RNA virus genome. Virus Res 2006;117(1):17-37 View Article PubMed/NCBI
  11. Saberi A, Gulyaeva AA, Brubacher JL, Newmark PA, Gorbalenya AE. A planarian nidovirus expands the limits of RNA genome size. PLoS Pathog 2018;14(11):e1007314 View Article PubMed/NCBI
  12. Atkins JF, Loughran G, Bhatt PR, Firth AE, Baranov PV. Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use. Nucleic Acids Res 2016;44(15):7007-7078 View Article PubMed/NCBI
  13. Penn WD, Mukhopadhyay S. Abracadabra, One Becomes Two: The Importance of Context in Viral -1 Programmed Ribosomal Frameshifting. mBio 2022;13(4):e0246821 View Article PubMed/NCBI
  14. Allan MF, Brivanlou A, Rouskin S. RNA levers and switches controlling viral gene expression. Trends Biochem Sci 2023;48(4):391-406 View Article PubMed/NCBI
  15. Wills NM, Gesteland RF, Atkins JF. Pseudoknot-dependent read-through of retroviral gag termination codons: importance of sequences in the spacer and loop 2. EMBO J 1994;13(17):4137-4144 View Article PubMed/NCBI
  16. Weiner AM, Weber K. Natural read-through at the UGA termination signal of Q-beta coat protein cistron. Nat New Biol 1971;234(50):206-209 View Article PubMed/NCBI
  17. Oppermann H, Bishop JM, Varmus HE, Levintow L. A joint produce of the genes gag and pol of avian sarcoma virus: a possible precursor of reverse transcriptase. Cell 1977;12(4):993-1005 View Article PubMed/NCBI
  18. Pelham HR. Leaky UAG termination codon in tobacco mosaic virus RNA. Nature 1978;272(5652):469-471 View Article PubMed/NCBI
  19. Skuzeski JM, Nichols LM, Gesteland RF, Atkins JF. The signal for a leaky UAG stop codon in several plant viruses includes the two downstream codons. J Mol Biol 1991;218(2):365-373 View Article PubMed/NCBI
  20. Beier H, Grimm M. Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs. Nucleic Acids Res 2001;29(23):4767-4782 View Article PubMed/NCBI
  21. Zerfass K, Beier H. Pseudouridine in the anticodon G psi A of plant cytoplasmic tRNA(Tyr) is required for UAG and UAA suppression in the TMV-specific context. Nucleic Acids Res 1992;20(22):5911-5918 View Article PubMed/NCBI
  22. Firth AE, Wills NM, Gesteland RF, Atkins JF. Stimulation of stop codon readthrough: frequent presence of an extended 3′ RNA structural element. Nucleic Acids Res 2011;39(15):6679-6691 View Article PubMed/NCBI
  23. Alam SL, Wills NM, Ingram JA, Atkins JF, Gesteland RF. Structural studies of the RNA pseudoknot required for readthrough of the gag-termination codon of murine leukemia virus. J Mol Biol 1999;288(5):837-852 View Article PubMed/NCBI
  24. Brown CM, Dinesh-Kumar SP, Miller WA. Local and distant sequences are required for efficient readthrough of the barley yellow dwarf virus PAV coat protein gene stop codon. J Virol 1996;70(9):5884-5892 View Article PubMed/NCBI
  25. Cimino PA, Nicholson BL, Wu B, Xu W, White KA. Multifaceted regulation of translational readthrough by RNA replication elements in a tombusvirus. PLoS Pathog 2011;7(12):e1002423 View Article PubMed/NCBI
  26. Haeberlé AM, Stussi-Garaud C, Schmitt C, Garaud JC, Richards KE, Guilley H, et al. Detection by immunogold labelling of P75 readthrough protein near an extremity of beet necrotic yellow vein virus particles. Arch Virol 1994;134(1-2):195-203 View Article PubMed/NCBI
  27. Cowan GH, Torrance L, Reavy B. Detection of potato mop-top virus capsid readthrough protein in virus particles. J Gen Virol 1997;78(Pt 7):1779-1783 View Article PubMed/NCBI
  28. Zerfass K, Beier H. The leaky UGA termination codon of tobacco rattle virus RNA is suppressed by tobacco chloroplast and cytoplasmic tRNAs(Trp) with CmCA anticodon. EMBO J 1992;11(11):4167-4173 View Article PubMed/NCBI
  29. Yoshinaka Y, Katoh I, Copeland TD, Oroszlan S. Murine leukemia virus protease is encoded by the gag-pol gene and is synthesized through suppression of an amber termination codon. Proc Natl Acad Sci U S A 1985;82(6):1618-1622 View Article PubMed/NCBI
  30. Csibra E, Brierley I, Irigoyen N. Modulation of stop codon read-through efficiency and its effect on the replication of murine leukemia virus. J Virol 2014;88(18):10364-10376 View Article PubMed/NCBI
  31. Orlova M, Yueh A, Leung J, Goff SP. Reverse transcriptase of Moloney murine leukemia virus binds to eukaryotic release factor 1 to modulate suppression of translational termination. Cell 2003;115(3):319-331 View Article PubMed/NCBI
  32. Malpica-López N, Rajeswaran R, Beknazariants D, Seguin J, Golyaev V, Farinelli L, et al. Revisiting the Roles of Tobamovirus Replicase Complex Proteins in Viral Replication and Silencing Suppression. Mol Plant Microbe Interact 2018;31(1):125-144 View Article PubMed/NCBI
  33. Schwartz M, Chen J, Janda M, Sullivan M, den Boon J, Ahlquist P. A positive-strand RNA virus replication complex parallels form and function of retrovirus capsids. Mol Cell 2002;9(3):505-514 View Article PubMed/NCBI
  34. Diaz A, Zhang J, Ollwerther A, Wang X, Ahlquist P. Host ESCRT proteins are required for bromovirus RNA replication compartment assembly and function. PLoS Pathog 2015;11(3):e1004742 View Article PubMed/NCBI
  35. Diaz A, Wang X. Bromovirus-induced remodeling of host membranes during viral RNA replication. Curr Opin Virol 2014;9:104-110 View Article PubMed/NCBI
  36. Restrepo-Hartwig M, Ahlquist P. Brome mosaic virus RNA replication proteins 1a and 2a colocalize and 1a independently localizes on the yeast endoplasmic reticulum. J Virol 1999;73(12):10303-10309 View Article PubMed/NCBI
  37. Gunawardene CD, Donaldson LW, White KA. Tombusvirus polymerase: Structure and function. Virus Res 2017;234:74-86 View Article PubMed/NCBI
  38. Gray S, Gildow FE. Luteovirus-aphid interactions. Annu Rev Phytopathol 2003;41:539-566 View Article PubMed/NCBI
  39. Agranovsky A. Enhancing Capsid Proteins Capacity in Plant Virus-Vector Interactions and Virus Transmission. Cells 2021;10(1):90 View Article PubMed/NCBI
  40. Caliskan N, Peske F, Rodnina MV. Changed in translation: mRNA recoding by -1 programmed ribosomal frameshifting. Trends Biochem Sci 2015;40(5):265-274 View Article PubMed/NCBI
  41. Jacks T, Varmus HE. Expression of the Rous sarcoma virus pol gene by ribosomal frameshifting. Science 1985;230(4731):1237-1242 View Article PubMed/NCBI
  42. Jacks T, Madhani HD, Masiarz FR, Varmus HE. Signals for ribosomal frameshifting in the Rous sarcoma virus gag-pol region. Cell 1988;55(3):447-458 View Article PubMed/NCBI
  43. Brierley I, Digard P, Inglis SC. Characterization of an efficient coronavirus ribosomal frameshifting signal: requirement for an RNA pseudoknot. Cell 1989;57(4):537-547 View Article PubMed/NCBI
  44. Dinman JD. Mechanisms and implications of programmed translational frameshifting. Wiley Interdiscip Rev RNA 2012;3(5):661-673 View Article PubMed/NCBI
  45. Rodnina MV, Korniy N, Klimova M, Karki P, Peng BZ, Senyushkina T, et al. Translational recoding: canonical translation mechanisms reinterpreted. Nucleic Acids Res 2020;48(3):1056-1067 View Article PubMed/NCBI
  46. Brierley I, Jenner AJ, Inglis SC. Mutational analysis of the “slippery-sequence” component of a coronavirus ribosomal frameshifting signal. J Mol Biol 1992;227(2):463-479 View Article PubMed/NCBI
  47. Namy O, Moran SJ, Stuart DI, Gilbert RJ, Brierley I. A mechanical explanation of RNA pseudoknot function in programmed ribosomal frameshifting. Nature 2006;441(7090):244-247 View Article PubMed/NCBI
  48. Lin Z, Gilbert RJ, Brierley I. Spacer-length dependence of programmed -1 or -2 ribosomal frameshifting on a U6A heptamer supports a role for messenger RNA (mRNA) tension in frameshifting. Nucleic Acids Res 2012;40(17):8674-8689 View Article PubMed/NCBI
  49. Marcheschi RJ, Staple DW, Butcher SE. Programmed ribosomal frameshifting in SIV is induced by a highly structured RNA stem-loop. J Mol Biol 2007;373(3):652-663 View Article PubMed/NCBI
  50. Jacks T, Townsley K, Varmus HE, Majors J. Two efficient ribosomal frameshifting events are required for synthesis of mouse mammary tumor virus gag-related polyproteins. Proc Natl Acad Sci U S A 1987;84(12):4298-4302 View Article PubMed/NCBI
  51. Barry JK, Miller WA. A -1 ribosomal frameshift element that requires base pairing across four kilobases suggests a mechanism of regulating ribosome and replicase traffic on a viral RNA. Proc Natl Acad Sci U S A 2002;99(17):11133-11138 View Article PubMed/NCBI
  52. Firth AE, Chung BY, Fleeton MN, Atkins JF. Discovery of frameshifting in Alphavirus 6K resolves a 20-year enigma. Virol J 2008;5:108 View Article PubMed/NCBI
  53. Moomau C, Musalgaonkar S, Khan YA, Jones JE, Dinman JD. Structural and Functional Characterization of Programmed Ribosomal Frameshift Signals in West Nile Virus Strains Reveals High Structural Plasticity Among cis-Acting RNA Elements. J Biol Chem 2016;291(30):15788-15795 View Article PubMed/NCBI
  54. Fang Y, Treffers EE, Li Y, Tas A, Sun Z, van der Meer Y, et al. Efficient -2 frameshifting by mammalian ribosomes to synthesize an additional arterivirus protein. Proc Natl Acad Sci U S A 2012;109(43):E2920-E2928 View Article PubMed/NCBI
  55. Napthine S, Treffers EE, Bell S, Goodfellow I, Fang Y, Firth AE, et al. A novel role for poly(C) binding proteins in programmed ribosomal frameshifting. Nucleic Acids Res 2016;44(12):5491-5503 View Article PubMed/NCBI
  56. Loughran G, Firth AE, Atkins JF. Ribosomal frameshifting into an overlapping gene in the 2B-encoding region of the cardiovirus genome. Proc Natl Acad Sci U S A 2011;108(46):E1111-E1119 View Article PubMed/NCBI
  57. Napthine S, Ling R, Finch LK, Jones JD, Bell S, Brierley I, et al. Protein-directed ribosomal frameshifting temporally regulates gene expression. Nat Commun 2017;8:15582 View Article PubMed/NCBI
  58. Agranovsky AA. Plant Viruses: Evolution and Management. Singapore: Springer Science and Business Media; 2016, 231-252 View Article
  59. Goodman RP, Freret TS, Kula T, Geller AM, Talkington MW, Tang-Fernandez V, et al. Clinical isolates of Trichomonas vaginalis concurrently infected by strains of up to four Trichomonasvirus species (Family Totiviridae). J Virol 2011;85(9):4258-4270 View Article PubMed/NCBI
  60. Lee SE, Suh JM, Scheffter S, Patterson JL, Chung IK. Identification of a ribosomal frameshift in Leishmania RNA virus 1-4. J Biochem 1996;120(1):22-25 View Article PubMed/NCBI
  61. Jagger BW, Wise HM, Kash JC, Walters KA, Wills NM, Xiao YL, et al. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science 2012;337(6091):199-204 View Article PubMed/NCBI
  62. Firth AE, Jagger BW, Wise HM, Nelson CC, Parsawar K, Wills NM, et al. Ribosomal frameshifting used in influenza A virus expression occurs within the sequence UCC_UUU_CGU and is in the +1 direction. Open Biol 2012;2(10):120109 View Article PubMed/NCBI
  63. Miras M, Miller WA, Truniger V, Aranda MA. Non-canonical Translation in Plant RNA Viruses. Front Plant Sci 2017;8:494 View Article PubMed/NCBI
  64. van der Wilk F, Dullemans AM, Verbeek M, Van den Heuvel JF. Nucleotide sequence and genomic organization of Acyrthosiphon pisum virus. Virology 1997;238(2):353-362 View Article PubMed/NCBI
  65. Farabaugh PJ. Programmed Alternative Reading of the Genetic Code. Boston: Springer; 1997, 69-101 View Article
  66. Kollmus H, Hentze MW, Hauser H. Regulated ribosomal frameshifting by an RNA-protein interaction. RNA 1996;2(4):316-323 PubMed/NCBI
  67. Li Y, Treffers EE, Napthine S, Tas A, Zhu L, Sun Z, et al. Transactivation of programmed ribosomal frameshifting by a viral protein. Proc Natl Acad Sci U S A 2014;111(21):E2172-E2181 View Article PubMed/NCBI
  68. Hill CH, Pekarek L, Napthine S, Kibe A, Firth AE, Graham SC, et al. Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch. Nat Commun 2021;12(1):7166 View Article PubMed/NCBI
  69. Agranovsky AA, Koonin EV, Boyko VP, Maiss E, Frötschl R, Lunina NA, et al. Beet yellows closterovirus: complete genome structure and identification of a leader papain-like thiol protease. Virology 1994;198(1):311-324 View Article PubMed/NCBI
  70. Karasev AV, Boyko VP, Gowda S, Nikolaeva OV, Hilf ME, Koonin EV, et al. Complete sequence of the citrus tristeza virus RNA genome. Virology 1995;208(2):511-520 View Article PubMed/NCBI
  71. Farabaugh PJ. Programmed translational frameshifting. Annu Rev Genet 1996;30:507-528 View Article PubMed/NCBI
  72. Gushchin VA, Karlin DG, Makhotenko AV, Khromov AV, Erokhina TN, Solovyev AG, et al. A conserved region in the Closterovirus 1a polyprotein drives extensive remodeling of endoplasmic reticulum membranes and induces motile globules in Nicotiana benthamiana cells. Virology 2017;502:106-113 View Article PubMed/NCBI
  73. Ahola T, Karlin DG. Sequence analysis reveals a conserved extension in the capping enzyme of the alphavirus supergroup, and a homologous domain in nodaviruses. Biol Direct 2015;10:16 View Article PubMed/NCBI
  74. Caliskan N, Hill CH. Insights from structural studies of the cardiovirus 2A protein. Biosci Rep 2022;42(1):BSR20210406 View Article PubMed/NCBI
  75. Kervestin S, Jacobson A. NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 2012;13(11):700-712 View Article PubMed/NCBI
  76. May JP, Yuan X, Sawicki E, Simon AE. RNA virus evasion of nonsense-mediated decay. PLoS Pathog 2018;14(11):e1007459 View Article PubMed/NCBI
  77. Wang X, Xuan Y, Han Y, Ding X, Ye K, Yang F, et al. Regulation of HIV-1 Gag-Pol Expression by Shiftless, an Inhibitor of Programmed -1 Ribosomal Frameshifting. Cell 2019;176(3):625-635.e14 View Article PubMed/NCBI
  78. Dunn JG, Foo CK, Belletier NG, Gavis ER, Weissman JS. Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster. Elife 2013;2:e01179 View Article PubMed/NCBI
  79. Loughran G, Chou MY, Ivanov IP, Jungreis I, Kellis M, Kiran AM, et al. Evidence of efficient stop codon readthrough in four mammalian genes. Nucleic Acids Res 2014;42(14):8928-8938 View Article PubMed/NCBI
  80. Eswarappa SM, Potdar AA, Koch WJ, Fan Y, Vasu K, Lindner D, et al. Programmed translational readthrough generates antiangiogenic VEGF-Ax. Cell 2014;157(7):1605-1618 View Article PubMed/NCBI
  81. Jungreis I, Lin MF, Spokony R, Chan CS, Negre N, Victorsen A, et al. Evidence of abundant stop codon readthrough in Drosophila and other metazoa. Genome Res 2011;21(12):2096-2113 View Article PubMed/NCBI
  82. Wills NM, Moore B, Hammer A, Gesteland RF, Atkins JF. A functional -1 ribosomal frameshift signal in the human paraneoplastic Ma3 gene. J Biol Chem 2006;281(11):7082-7088 View Article PubMed/NCBI
  83. Manktelow E, Shigemoto K, Brierley I. Characterization of the frameshift signal of Edr, a mammalian example of programmed -1 ribosomal frameshifting. Nucleic Acids Res 2005;33(5):1553-1563 View Article PubMed/NCBI
  84. Gorbalenya AE. Host-related sequences in RNA virus genomes. Seminars Virol 1992;3:359-371 View Article
  85. Gendron K, Dulude D, Lemay G, Ferbeyre G, Brakier-Gingras L. The virion-associated Gag-Pol is decreased in chimeric Moloney murine leukemia viruses in which the readthrough region is replaced by the frameshift region of the human immunodeficiency virus type 1. Virology 2005;334(2):342-352 View Article PubMed/NCBI
  86. Newburn LR, Nicholson BL, Yosefi M, Cimino PA, White KA. Translational readthrough in Tobacco necrosis virus-D. Virology 2014;450-451:258-265 View Article PubMed/NCBI
  87. Kim KH, Rümenapf T, Strauss EG, Strauss JH. Regulation of Semliki Forest virus RNA replication: a model for the control of alphavirus pathogenesis in invertebrate hosts. Virology 2004;323(1):153-163 View Article PubMed/NCBI
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Where To Stop: Occurrence and Evolution of Translational Recoding Signals in RNA Viruses of Eukaryotes

Alexey A. Agranovsky
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