Abstract
The presence of CpG and UpA dinucleotides is restricted in the genomes of animal RNA viruses to avoid specific host defenses. We wondered whether a similar phenomenon exists in nonanimal RNA viruses. Here, we show that these two dinucleotides, especially UpA, are underrepresented in the family Potyviridae, the most important group of plant RNA viruses. Using plum pox virus (PPV; Potyviridae family) as a model, we show that an increase in UpA frequency strongly diminishes virus accumulation. Remarkably, unlike previous observations in animal viruses, PPV variants harboring CpG-rich fragments display just faint (or no) attenuation. The anticorrelation between UpA frequency and viral fitness additionally demonstrates the relevance of this particular dinucleotide: UpA-high mutants are attenuated in a dose-dependent manner, whereas a UpA-low variant displays better fitness than its parental control. Using high-throughput sequencing, we also show that UpA-rich PPV variants are genetically stable, without apparent changes in sequence that revert and/or compensate for the dinucleotide modification despite its attenuation. In addition, we also demonstrate here that the PPV restriction of UpA-rich variants works independently of the classical RNA silencing pathway. Finally, we show that the anticorrelation between UpA frequency and RNA accumulation applies to mRNA-like fragments produced by the host RNA polymerase II. Together, our results inform us about a dinucleotide-based system in plant cells that controls diverse RNAs, including RNA viruses.IMPORTANCE Dinucleotides (combinations of two consecutive nucleotides) are not randomly present in RNA viruses; in fact, the presence of CpG and UpA is significantly repressed in their genomes. Although the meaning of this phenomenon remains obscure, recent studies with animal-infecting viruses have revealed that their low CpG/UpA frequency prevents virus restriction via a host antiviral system that recognizes, and promotes the degradation of, CpG/UpA-rich RNAs. Whether similar systems act in organisms from other life kingdoms has been unknown. To fill this gap in our knowledge, we built several synthetic variants of a plant RNA virus with deoptimized dinucleotide frequencies and analyzed their viral fitness and genome adaptation. In brief, our results inform us for the first time about an effective dinucleotide-based system that acts in plants against viruses. Remarkably, this viral restriction in plants is reminiscent of, but not identical to, the equivalent antiviral response in animals.
Highlights
The presence of CpG and UpA dinucleotides is restricted in the genomes of animal RNA viruses to avoid specific host defenses
Given that zinc-finger antiviral protein (ZAP) interacts with CpG- and UpA-rich RNAs, the suppression of these dinucleotides in RNA virus genomes comprises a strategy that animal viruses developed to escape from the antiviral action of these proteins [13, 14]
The observed CpG and UpA constraints in the genome of animal RNA viruses may serve mbio.asm.org to mimic dinucleotide frequencies of host RNAs in order to escape from the action of ZAP and OAS3-coupled restriction pathways
Summary
The presence of CpG and UpA dinucleotides is restricted in the genomes of animal RNA viruses to avoid specific host defenses. With mutation rates varying between 10Ϫ4 and 10Ϫ6 errors per nucleotide, RNA virus infection produces a genetically heterogeneous population (quasispecies or mutant swarm or cloud) wherein individual RNA molecules differ from the consensus genome sequence at a few randomly mutated sites [3] Despite this flexibility, the genome sequences of RNA viruses are subject to poorly understood constraints observed through restrictions to certain synonymous mutations. It has long been reported that the frequency of certain dinucleotides (two adjacent nucleotides in a linear sequence), CpG and UpA, are pervasively suppressed in the genomes of many RNA viruses [5, 6] Such constraints have been hypothesized to be due to enzymatic modifications, dinucleotide stacking energies, and/or preferential mutations [5]. Given that ZAP interacts with CpG- and UpA-rich RNAs, the suppression of these dinucleotides in RNA virus genomes comprises a strategy that animal viruses developed to escape from the antiviral action of these proteins [13, 14]
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