A functional investigation of the suppression of CpG and UpA dinucleotide frequencies in plant RNA virus genomes

Ibrahim, Ahmad; Fros, Jelke J.; Bertran, André; Sechan, Ferdyansyah; Odon, Valerie; Torrance, L.; Kormelink, Richard; Simmonds, Peter

doi:10.1038/s41598-019-54853-0

Cited by 19 publications

(17 citation statements)

References 63 publications

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“…In both datasets, the SDU calculations show a greater depletion of CpG in the vertebrate-specific viruses. Even though there is no experimental evidence that a CpG-recognising immune response is acting on flaviviruses or rhabdoviruses in vertebrates, other RNA viruses seem to be affected by such a mechanism [10,12,29]. Thus, we hypothesise that this immune mechanism is responsible for the difference in CpG SDU values between the two virus groups.…”

Section: Discussionmentioning

confidence: 78%

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

Lytras

Hughes

2020

Viruses

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Distinct patterns of dinucleotide representation, such as CpG and UpA suppression, are characteristic of certain viral genomes. Recent research has uncovered vertebrate immune mechanisms that select against specific dinucleotides in targeted viruses. This evidence highlights the importance of systematically examining the dinucleotide composition of viral genomes. We have developed a novel metric, called synonymous dinucleotide usage (SDU), for quantifying dinucleotide representation in coding sequences. Our method compares the abundance of a given dinucleotide to the null hypothesis of equal synonymous codon usage in the sequence. We present a Python3 package, DinuQ, for calculating SDU and other relevant metrics. We have applied this method on two sets of invertebrate- and vertebrate-specific flaviviruses and rhabdoviruses. The SDU shows that the vertebrate viruses exhibit consistently greater under-representation of CpG dinucleotides in all three codon positions in both datasets. In comparison to existing metrics for dinucleotide quantification, the SDU allows for a statistical interpretation of its values by comparing it to a null expectation based on the codon table. Here we apply the method to viruses, but coding sequences of other living organisms can be analysed in the same way.

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Section: Discussionmentioning

confidence: 78%

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

Lytras

Hughes

2020

Viruses

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“…In both datasets, the SDU calculations show a greater depletion of CpG in the vertebrate-specific viruses. Even though there is no experimental evidence that a CpG-recognising immune response is acting on flaviviruses or rhabdoviruses in vertebrates, other RNA viruses seem to be affected by such a mechanism [10,12,28]. Thus, we hypothesise that this immune mechanism is responsible for the difference in CpG SDU values between the two virus groups.…”

Section: Discussionmentioning

confidence: 87%

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

Lytras

Hughes

2020

Preprint

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9Distinct patterns of dinucleotide representation, such as CpG and UpA suppression, are characteristic 10 of certain viral genomes. Recent research has uncovered vertebrate immune mechanisms that select 11 against specific dinucleotides in targeted viruses. This evidence highlights the importance of 12 systematically examining the dinucleotide composition of viral genomes. We have developed a novel 13 metric, called Synonymous Dinucleotide Usage (SDU), for quantifying dinucleotide representation in 14 coding sequences. Our method compares the abundance of a given dinucleotide to the null 15 hypothesis of equal synonymous codon usage in the sequence. We present a Python3 package, 16DinuQ, for calculating SDU and other relevant metrics. We have applied this method on two sets of 17 invertebrate-and vertebrate-specific flaviviruses and rhabdoviruses. The SDU shows that the 18 vertebrate viruses exhibit consistently greater under-representation of CpG dinucleotides in all three 19 codon positions in both datasets. In comparison to existing metrics for dinucleotide quantification, the 20 SDU allows for a biologically informed interpretation of its values by comparing representation to an 21 expectation based on the codon table. Here we apply the method to viruses, but coding sequences 22 of other living organisms can be analysed in the same way. 23 24 Introduction 25 Certain dinucleotides, two nucleotides adjacent in a sequence, are known to be over-or under-26 represented in the genomes of living organisms, creating distinct compositional patterns [1]. 27Organisms with methylated genomes such as vertebrates and plants have low levels of CpG 28 dinucleotides. This is not the case for methylase-absent organisms like invertebrates, bacteria and 29 fungi [2,3]. The cause of CpG suppression lies in the DNA methylation mechanisms of vertebrates 30 and plants, where cytosine is frequently converted to thymine by DNA methyltransferases [4,5]. UpA 31 deprivation is consistently present in most living organisms, including prokaryotes. This bias is 32 suspected to be due to UpA-rich mRNA being unstable and more prone to degradation by cytoplasmic 33 RNAses [6,7].34 Similar patterns of dinucleotide composition have been observed in RNA and DNA viruses, and 35 appear to have a functional role in the infection and propagation of the viruses [8]. Studies have 36 shown that experimentally increasing UpA and CpG levels in RNA viruses leads to a decrease in 37 replication and subsequent viral attenuation, while decreasing their abundance has the opposite 38 effect [9-11]. Influenza CpG-/UpA-rich sequences have also been shown to have reduced replication 39 in vivo, causing a more powerful immune response, and in the case of CpG increase, showing 40 reduced clinical severity [12]. A similar decrease in replication and virulence has been observed in 41 CpG-/UpA-increased yellow fever virus [13]. 42Recently, a host immune mechanism of vertebrates which acts on viral genomes on the dinucleotide 43 level, has been uncovered. The Zinc-finge...

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“…The same constraints may operate in other dual-host viruses. For example, we and others recently discovered that the replication of potato virus Y and plum pox virus (genus Potyvirus) in plants was similarly attenuated by the synonymous introduction of CpG and UpA dinucleotides [46,47]. Plant transcriptomes also display CpG suppression that is also reflected in the majority of plant RNA viruses.…”

Section: Plos Biologymentioning

confidence: 99%

The dinucleotide composition of the Zika virus genome is shaped by conflicting evolutionary pressures in mammalian hosts and mosquito vectors

et al. 2021

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Most vertebrate RNA viruses show pervasive suppression of CpG and UpA dinucleotides, closely resembling the dinucleotide composition of host cell transcriptomes. In contrast, CpG suppression is absent in both invertebrate mRNA and RNA viruses that exclusively infect arthropods. Arthropod-borne (arbo) viruses are transmitted between vertebrate hosts by invertebrate vectors and thus encounter potentially conflicting evolutionary pressures in the different cytoplasmic environments. Using a newly developed Zika virus (ZIKV) model, we have investigated how demands for CpG suppression in vertebrate cells can be reconciled with potentially quite different compositional requirements in invertebrates and how this affects ZIKV replication and transmission. Mutant viruses with synonymously elevated CpG or UpA dinucleotide frequencies showed attenuated replication in vertebrate cell lines, which was rescued by knockout of the zinc-finger antiviral protein (ZAP). Conversely, in mosquito cells, ZIKV mutants with elevated CpG dinucleotide frequencies showed substantially enhanced replication compared to wild type. Host-driven effects on virus replication attenuation and enhancement were even more apparent in mouse and mosquito models. Infections with CpG- or UpA-high ZIKV mutants in mice did not cause typical ZIKV-induced tissue damage and completely protected mice during subsequent challenge with wild-type virus, which demonstrates their potential as live-attenuated vaccines. In contrast, the CpG-high mutants displayed enhanced replication in Aedes aegypti mosquitoes and a larger proportion of mosquitoes carried infectious virus in their saliva. These findings show that mosquito cells are also capable of discriminating RNA based on dinucleotide composition. However, the evolutionary pressure on the CpG dinucleotides of viral genomes in arthropod vectors directly opposes the pressure present in vertebrate host cells, which provides evidence that an adaptive compromise is required for arbovirus transmission. This suggests that the genome composition of arbo flaviviruses is crucial to maintain the balance between high-level replication in the vertebrate host and persistent replication in the mosquito vector.

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A functional investigation of the suppression of CpG and UpA dinucleotide frequencies in plant RNA virus genomes

Cited by 19 publications

References 63 publications

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses

The dinucleotide composition of the Zika virus genome is shaped by conflicting evolutionary pressures in mammalian hosts and mosquito vectors

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