CpG Dinucleotide Frequencies Reveal the Role of Host Methylation Capabilities in Parvovirus Evolution

Abstract

Parvoviruses are rapidly evolving viruses that infect a wide range of hosts, including vertebrates and invertebrates. Extensive methylation of the parvovirus genome has been recently demonstrated. A global pattern of methylation of CpG dinucleotides is seen in vertebrate genomes, compared to "fractional" methylation patterns in invertebrate genomes. It remains unknown if the loss of CpG dinucleotides occurs in all viruses of a given DNA virus family that infect host species spanning across vertebrates and invertebrates. We investigated the link between the extent of CpG dinucleotide depletion among autonomous parvoviruses and the evolutionary lineage of the infected host. We demonstrate major differences in the relative abundance of CpG dinucleotides among autonomous parvoviruses which share similar genome organization and common ancestry, depending on the infected host species. Parvoviruses infecting vertebrate hosts had significantly lower relative abundance of CpG dinucleotides than parvoviruses infecting invertebrate hosts. The strong correlation of CpG dinucleotide depletion with the gain in TpG/CpA dinucleotides and the loss of TpA dinucleotides among parvoviruses suggests a major role for CpG methylation in the evolution of parvoviruses. Our data present evidence that links the relative abundance of CpG dinucleotides in parvoviruses to the methylation capabilities of the infected host. In sum, our findings support a novel perspective of host-driven evolution among autonomous parvoviruses.T he relative abundance of dinucleotides, particularly the CpG dinucleotide, has received much attention recently. The CpG dinucleotide content is normally expressed as a ratio of the actual (observed) number of CpG dinucleotides and the expected number of CpG dinucleotides (O/E ratio). The relative abundance of CpG dinucleotides varies greatly across viruses (1, 2). Depletion of CpG dinucleotides has been reported to occur in all small DNA viruses (Ͻ30 kb) infecting humans (2), while most large DNA viruses (Ͼ30 kb) infecting humans show little or no CpG dinucleotide depletion. Several possible reasons have been suggested to play a role in the depletion of CpG dinucleotides, including (i) lower transcription rate for CpG-containing codons (3), (ii) stimulation of Toll-like receptor 9-mediated innate immune response by unmethylated CpGs (4), and (iii) spontaneous deamination of methylated cytosines in CpG dinucleotides (5). Deamination of unmethylated cytosines results in C-to-U transitions which are amenable to mismatch repair mechanisms, whereas the deamination of 5-methylcytosine leads to C-to-T transitions that are often irreversible, resulting in high mutation rates in methylated CpGs and a depletion of CpG dinucleotides (6, 7).In most vertebrate genomes, the O/E ratio for CpG dinucleotides is Ͻ0.35, suggesting that vertebrate genomes have lost about two-thirds of CpG dinucleotides (5, 8). In contrast, invertebrate genomes show minor or no depletion of CpG dinucleotides (5). Early investigations on insects showed that...

Role of the host restriction factor APOBEC3 on papillomavirus evolution

“…This finding is consistent with others that have reported a significant depletion in CG residues across many small (<30 kb) DNA virus genomes (Karlin, Doerfler, Cardon 1994; Hoelzer, Shackelton, and Parrish 2008; Upadhyay et al 2013). Previous work suggests that 5-methylcytosine modifications can negatively influence gene expression and lead to mutation via spontaneous deamination, both of which would negatively impact the course of a viral infection (Karlin, Doerfler, Cardon 1994).…”

“…1A and Supplementary Table S1; depletion of the CG or TC dinucleotide compared with any other dinucleotide, P <0.0001 by two-way ANOVA with Tukey correction). CG depletion has been previously noted for several small DNA viruses (Karlin, Doerfler, and Cardon 1994; Hoelzer, Shackelton, and Parrish 2008; Upadhyay et al 2013), including PVs (Shackelton, Parrish, and Holmes 2006). Given that T C dinucleotides are preferred or specific targets of APOBEC3 DNA editing, these results imply that the PV genomes may be greatly affected by the host restriction functions of APOBEC3.…”

Evasion of host immune defenses by human papillomavirus

“…However, since TLR9 expression is significantly downregulated in cells expressing the HPV oncoprotein E7 as described above, it is likely that HPV infection and viral gene expression may be influenced by TLR9 responses. Similar to many other small DNA viruses, such as adenovirus and parvovirus, papillomavirus genomes have significantly lower contents of CpG dinucleotides than expected by random chance (Upadhyay et al, 2013; Upadhyay and Vivekanandan, 2015; Warren et al, 2015a). In a recent publication, we calculated the ratio of observed vs. expected (O/E) counts of all dinucleotides in the genomes of all 274 PVs deposited in the Papillomavirus Episteme (PaVE) database (Warren et al, 2015a).…”

Characterization of a novel adenovirus isolated from a skunk

“…This similar phenotype was noted with SkAdV-1, although when the number of CG nucleotides was analyzed using EMBOSS 6.3.1 geecee (〈http://mobyle.pasteur.fr〉), SkAdV-1 had fewer GC dinucleotides than any BtAdV species (Table 1). It has been noted that reduction in the number of CpG dinucleotides is often linked to viral adaptation and stability within a particular host species, suggesting SkAdV-1 may be adapting to the skunk host (Karlin et al, 1994;Upadhyay et al, 2013).…”