Compositional biases in RNA viruses: Causes, consequences and applications

Abstract

If each of the four nucleotides were represented equally in the genomes of viruses and the hosts they infect, each base would occur at a frequency of 25%. However, this is not observed in nature. Similarly, the order of nucleotides is not random (e.g., in the human genome, guanine follows cytosine at a frequency of ~0.0125, or a quarter the number of times predicted by random representation). Codon usage and codon order are also nonrandom. Furthermore, nucleotide and codon biases vary between species. Such biases have various drivers, including cellular proteins that recognize specific patterns in nucleic acids, that once triggered, induce mutations or invoke intrinsic or innate immune responses. In this review we examine the types of compositional biases identified in viral genomes and current understanding of the evolutionary mechanisms underpinning these trends. Finally, we consider the potential for large scale synonymous recoding strategies to engineer RNA virus vaccines, including those with pandemic potential, such as influenza A virus and Severe Acute Respiratory Syndrome Coronavirus Virus 2. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > Computational Analyses of RNA RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition

Does the Zinc Finger Antiviral Protein (ZAP) Shape the Evolution of Herpesvirus Genomes?

“…Finally, future studies could investigate whether altering the nucleotide composition of herpes viruses through synonymous mutations could be an effective platform for the generation of rational herpesvirus vaccine candidates or vectors. Modifying codon usage bias through the introduction of synonymous mutations could allow tuneable alterations to expression levels of viral target genes and levels of attenuation, as well as increasing the visibility of viruses to the host’s immune response while maintaining the natural antigenic profile of the virus [ 2 ].…”

“…Previous studies have demonstrated significant suppression of CpG and UpA/TpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses, which mimics suppression in mammalian genomes [ 12 ]. Artificially increasing dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias facilitates recognition of non-self RNA and that viruses have evolved to counter this [ 2 , 16 , 17 , 18 ]. Recently, the antiviral protein ZAP (also known as PARP13), expressed from the ZC3HAV1 gene, was identified as the host factor responsible for sensing CpG dinucleotides in viral RNA [ 19 ].…”

“…The role of codon bias and codon pair bias in virus replication and gene expression was also investigated [ 2 ]. Synonymous codons of the same amino acid do not occur with equal frequency and reflect the variable concentration of tRNAs within a cell, with highly expressed genes preferentially encoding codons that correspond to abundant tRNAs.…”

“…They are therefore subject to the same effects caused by genomic compositional bias. Nevertheless, such biases were shown to play an important role in cellular defences against viruses, while viruses also manipulate compositional biases within their own genomes to evade host defence mechanisms [ 2 ].…”

CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy

“…Over the past decade, many groups have investigated the impact of synonymously increasing the CpG content in the genomes of RNA viruses. Without exception, these studies have determined that genomic CpG 2 enrichment causes viral replication deficiencies (reviewed in (4)). To explain this, it was hypothesised that a cellular antiviral sensor may detect CpG motifs in viral RNAs (5), and in 2017 this idea was confirmed through identification of the cellular protein ZAP (zinc-finger antiviral protein) as a selective binder of CpG motifs in viral RNA transcripts (6).…”