Abstract
CpG dinucleotides are under-represented in the genomes of single-stranded RNA viruses, and SARS-CoV-2 is no exception to this. Artificial modification of CpG frequency is a valid approach for live attenuated vaccine development; if this is to be applied to SARS-CoV-2, we must first understand the role CpG motifs play in regulating SARS-CoV-2 replication. Accordingly, the CpG composition of the SARS-CoV-2 genome was characterised. CpG suppression among coronaviruses does not differ between virus genera but does vary with host species and primary replication site (a proxy for tissue tropism), supporting the hypothesis that viral CpG content may influence cross-species transmission. Although SARS-CoV-2 exhibits overall strong CpG suppression, this varies considerably across the genome, and the Envelope (E) open reading frame (ORF) and ORF10 demonstrate an absence of CpG suppression. Across the Coronaviridae, E genes display remarkably high variation in CpG composition, with those of SARS and SARS-CoV-2 having much higher CpG content than other coronaviruses isolated from humans. This is an ancestrally derived trait reflecting their bat origins. Conservation of CpG motifs in these regions suggests that they have a functionality which over-rides the need to suppress CpG; an observation relevant to future strategies towards a rationally attenuated SARS-CoV-2 vaccine.
Highlights
CpG dinucleotides are under-represented in the DNA genomes of vertebrates (Cooper and Krawczak, 1989; Simmonds et al, 2013)
Variation in CpG composition between coronaviruses detected in different host species was evident across and between groups, with coronaviruses detected in canine and human species having lower CpG content and rodent and bat coronaviruses having the highest (Fig. 2C)
If coronaviruses produce a protein with anti-Zinc-finger Antiviral Protein (ZAP) activity, it is possible that this has variable efficacy between strains, explaining the ability of coronaviruses to fluctuate CpG composition considerably
Summary
CpG dinucleotides are under-represented in the DNA genomes of vertebrates (Cooper and Krawczak, 1989; Simmonds et al, 2013). Methylated cytosines have a propensity to undergo spontaneous deamination (and so conversion to a thymine) Over evolutionary time, this has reduced the frequency of CpGs in vertebrate genomes (Cooper and Krawczak, 1989). It was hypothesised that this is because vertebrates have evolved a CpG sensor which flags transcripts with aberrant CpG frequencies (Atkinson et al, 2014; Gaunt et al, 2016) This idea was strengthened by the discovery that the cellular protein Zinc-finger Antiviral Protein (ZAP) binds CpG motifs on viral RNA and directs them for degradation (Takata et al, 2017), and further supported by observations that CpGs can be synonymously introduced into a viral genome to the detriment of virus replication without negatively impacting transcriptional or translational efficiency (Gaunt et al, 2016; Tulloch et al, 2014). Whether the two phenomena of CpG suppression and codon pair bias (CPB) are discrete remains controversial (Futcher et al, 2015; Groenke et al, 2020; Kunec and Osterrieder, 2016)
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