Transcription, mRNA Export, and Immune Evasion Shape the Codon Usage of Viruses

Abstract

The nucleotide composition, dinucleotide composition, and codon usage of many viruses differs from their hosts. These differences arise because viruses are subject to unique mutation and selection pressures that do not apply to host genomes; however, the molecular mechanisms that underlie these evolutionary forces are unclear. Here, we analysed the patterns of codon usage in 1,520 vertebrate-infecting viruses, focusing on parameters known to be under selection and associated with gene regulation. We find that GC content, dinucleotide content, and splicing and m6A modification-related sequence motifs are associated with the type of genetic material (DNA or RNA), strandedness, and replication compartment of viruses. In an experimental follow-up, we find that the effects of GC content on gene expression depend on whether the genetic material is delivered to the cell as DNA or mRNA, whether it is transcribed by endogenous or exogenous RNA polymerase, and whether transcription takes place in the nucleus or cytoplasm. Our results suggest that viral codon usage cannot be explained by a simple adaptation to the codon usage of the host – instead, it reflects the combination of multiple selective and mutational pressures, including the need for efficient transcription, export, and immune evasion.

Evolutionary Signatures Governing the Codon Usage Bias in Coronaviruses and Their Implications for Viruses Infecting Various Bat Species

“…These evolutionary signatures make the viruses genetically and biochemically adapted to circulate in their hosts, in particular, reservoir hosts [ 16 ]. Furthermore, these viral evolutionary signatures have been revealed to influence a variety of biological processes in their hosts [ 17 , 18 ]. Deciphering these signatures is of particular interest for gaining insights into the evolutionary processes of synonymous codon usage and host-adapted evolution.…”

Bias at the third nucleotide of codon pairs in virus and host genomes

“…Similar observations have reported by others 14 , 15 , indicating that the similarity we observed between Flaviviridae and host biases may be the exception rather than the rule. Differences between virus families may relate to the importance of fast protein production and if it is regulated via the availability of the transcripts or post-transcriptionally 16 – 18 . This may be investigated through more detailed comparisons of ORFs that are translated at different times during viral infection, or by comparison of viruses with short and long infection cycles.…”

“…And the depletion of CpG which has been shown to result in viral attenuation 13 , 16 , 27 . However, the extent of CpG depletion in viral genomes and impact on viral viability may depend on the viral host species 17 , 18 , 28 . From our heatmaps we would expect to see CpG depletion as a pyrimidine preference for C over T at the third codon position of the 1st codon when the second codon is ‘strong’ or a purine preference for A over G at the third nucleotide of CCR (alanine), GGR (proline), ACR (threonine), and TCR (serine) codons.…”

“…However, studies with codon-pair deoptimization HIV genomes (controlling for CpG content) demonstrate that attenuation is associated with reduced translation efficiency 17 . Thus, the impact codon pairs have on virus viability depends on several factors including the type of virus, the position of the codon pairs within the genome, the impact on dinucleotide content, and how codon pairs affect translation 18 .…”

SARS-CoV-2 host prediction based on virus-host genetic features

“…To explore the same approach 12 , but now refining it to be precise in identifying hosts with a description known and sustained in the literature, we used a new group of features associated with virus-host specificity, the RSCU signature, which is a method to calculate the relative frequences of occurrence of the synonymous codons for each amino acid 24 , 25 . Beyond that, although the virus-host association can be recovered from nucleotide composition 26 , such as the RSCU used here, the codon usage is not restricted to adaptation to a host, but is critical for several biological processes, which reflect the combination of multiple selection and mutational pressure, which are critical for efficient transcription, nuclear export of virus RNA, tolerance to translation errors, and immune evasion 27 , 28 .…”