Abstract
An evolutionary arms race occurs between viruses and hosts. Hosts have developed an array of antiviral mechanisms aimed at inhibiting replication and spread of viruses, reducing their fitness, and ultimately minimising pathogenic effects. In turn, viruses have evolved sophisticated counter-measures that mediate evasion of host defence mechanisms. A key aspect of host defences is the ability to differentiate between self and non-self. Previous studies have demonstrated significant suppression of CpG and UpA dinucleotide frequencies in the coding regions of RNA and small DNA viruses. Artificially increasing these dinucleotide frequencies results in a substantial attenuation of virus replication, suggesting dinucleotide bias could facilitate recognition of non-self RNA. The interferon-inducible gene, zinc finger antiviral protein (ZAP) is the host factor responsible for sensing CpG dinucleotides in viral RNA and restricting RNA viruses through direct binding and degradation of the target RNA. Herpesviruses are large DNA viruses that comprise three subfamilies, alpha, beta and gamma, which display divergent CpG dinucleotide patterns within their genomes. ZAP has recently been shown to act as a host restriction factor against human cytomegalovirus (HCMV), a beta-herpesvirus, which in turn evades ZAP detection by suppressing CpG levels in the major immediate-early transcript IE1, one of the first genes expressed by the virus. While suppression of CpG dinucleotides allows evasion of ZAP targeting, synonymous changes in nucleotide composition that cause genome biases, such as low GC content, can cause inefficient gene expression, especially in unspliced transcripts. To maintain compact genomes, the majority of herpesvirus transcripts are unspliced. Here we discuss how the conflicting pressures of ZAP evasion, the need to maintain compact genomes through the use of unspliced transcripts and maintaining efficient gene expression may have shaped the evolution of herpesvirus genomes, leading to characteristic CpG dinucleotide patterns.
Highlights
Changes in the third nucleotide position of a codon often result in synonymous mutations, in which a change to the nucleotide sequence does not lead to a corresponding change in the amino acid sequence
Our studies showed that both ZAP short (ZAPS) and ZAP long (ZAPL) were able to inhibit the expression of human cytomegalovirus (HCMV) transcripts with high CpG content [34]
Similar to RNA viruses and small DNA viruses, the majority of gamma-herpesviruses suppress CpG dinucleotides throughout their genomes, which would be predicted to evade targeting by zinc finger antiviral protein (ZAP)
Summary
Accumulation of synonymous mutations can lead to genome compositional bias that can have fundamental effects on gene expression while leaving prosequence). Accumulation of synonymous mutations can lead tocodon genome compositional tein-coding unchanged These include nucleotide, dinucleotide, usage and codon biasbias. As viruses are obligate intracellular they are dependent on the cellular translational machinery and in some cases,pathogens, such as herpesviruses, the transcriptional matranslational machinery and in some cases, such as herpesviruses, the transcriptional chinery They are subject to the same effects caused by genomic compositional machinery. There are currently over viruses described, including clinically important portant human herpesviruses and several significant veterinary pathogens [3]. A central characteristic of herpesviruses is their ability to maintain life-long infections despite robust antiviral responses from the host. We will discuss the role of compositional genomic bias in herpesvirus genomes and how the targeting of viral RNA with high CpG dinucleotide frequencies by genomes and how the targeting of viral RNA with high CpG dinucleotide frequencies by ZAP may have shaped the evolution of herpesvirus genomes
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