CpG Usage in RNA Viruses: Data and Hypotheses

Abstract

CpG repression in RNA viruses has been known for decades, but a reasonable explanation has not yet been proposed to explain this phenomenon. In this study, we calculated the CpG odds ratio of all RNA viruses that have available genome sequences and analyzed the correlation with their genome polarity, base composition, synonymous codon usage, phylogenetic relationship, and host. The results indicated that the viral base composition, synonymous codon usage and host selection were the dominant factors that determined the CpG bias in RNA viruses. CpG usage variation between the different viral groups was caused by different combinations of these pressures, which also differed from each other in strength. The consistent under-representation of CpG usage in −ssRNA viruses is determined predominantly by base composition, which may be a consequence of the U/A preferred mutation bias of −ssRNA viruses, whereas the CpG usage of +ssRNA viruses is affected greatly by their hosts. As a result, most +ssRNA viruses mimic their hosts' CpG usage. Unbiased CpG usage in dsRNA viruses is most likely a result of their dsRNA genome, which allows the viruses to escape from the host-driven CpG elimination pressure. CpG was under-represented in all reverse-transcribing viruses (RT viruses), suggesting that DNA methylation is an important factor affecting the CpG usage of retroviruses. However, vertebrate-infecting RT viruses may also suffer host' CpG elimination pressure that also acts on +ssRNA viruses, which results in further under-representation of CpG in the vertebrate-infecting RT viruses.

Analysis of Synonymous Codon Usage Bias of Zika Virus and Its Adaption to the Hosts

“…In our study, we found the relative low abundances of CpG and UpA in ZIKV, which may be beneficial for the virus to escape the host anti-viral immune response and complete virus transcription reaction efficiently [43]. The unmethylated CpG can be recognized by the host innate immune system as a pathogen signature, and activates various immune response pathways [42, 44]. UpA deficiency was proposed to avail virus by reducing the risk of nonsense mutations, minimizing the improper transcription and decreasing the opportunities of cleavage by RNase L [45].…”

Dinucleotide Composition in Animal RNA Viruses Is Shaped More by Virus Family than by Host Species

“…Given their potential impact on fitness, dinucleotide composition may represent a specific form of host adaptation. This is supported by several studies showing that the dinucleotide composition of viruses generally matches that of their hosts (15)(16)(17). For example, the base composition of iridoviruses matches that of the host tRNA population (18), and it was recently shown that host-induced methylation is the major factor shaping CpG depletion patterns in human and simian immunodeficiency viruses (19).…”

The Evolutionary Pathway to Virulence of an RNA Virus

“…S7B-E), and a more complex pattern for UpA observed over the entire six years. Several recent studies have indeed indicated that an increase in CpG or UpA dinucleotides lead to attenuation of various RNA viruses (Atkinson et al, 2014; Burns et al, 2009; Cheng et al, 2013; Tulloch et al, 2014), and an as-yet unidentified cellular pathway may recognize and target viral genomes containing CpG or UpA sites. Accordingly, our data supports the hypothesis that cVPDVs are under selection to reduce the frequency of CpGs and to some extent also of UpAs in their genomes.…”

“…Dashed blue lines reflect significance cutoffs based on (Cheng et al, 2013). (B-E) The CpG and UpA dinucleotides O/E in the first two years (C & D, respectively) and over more than six years (D & E respectively), plotted against the distance of each sequence from the OPV2 root sequence.…”