The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

Atkinson, Nicky; Witteveldt, Jeroen; Evans, David J.; Simmonds, Peter

doi:10.1093/nar/gku075

Cited by 163 publications

(227 citation statements)

References 58 publications

(74 reference statements)

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“…However, because only existing codons are used in codon pair deoptimization, the additional dinucleotides map between the newly formed codon pairs as in xxCpGxx and xxUpAxx (Table S1). It has been proposed that increased CpG may activate in some tissue culture cells the innate immune response, thereby reducing viral replication (43,44). This is supported by data shown in Fig.…”

Section: Discussionsupporting

confidence: 53%

“…It has long been known that genomes of RNA viruses have low CpG and UpA dinucleotide frequencies (18,19), as do mammalian coding regions generally (17), a phenomenon which must be advantageous for viruses. Indeed, if the CpG or UpA content is raised in the poliovirus polyprotein by encoding it with synonymous rare CpG-and UpA-rich codons, the resulting variants are either debilitated in growth (43,44) or nonviable (45). We note that the recoded segments within the D2-syn hmin genomes also present with an increased frequency of CpG and UpA dinucleotides (Table S1).…”

Section: Discussionmentioning

confidence: 92%

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Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

Shen¹,

Stauft

Gorbatsevych³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

124

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The protein synthesis machineries of two distinct phyla of the Animal kingdom, insects of Arthropoda and mammals of Chordata, have different preferences for how to best encode proteins. Nevertheless, arboviruses (arthropod-borne viruses) are capable of infecting both mammals and insects just like arboviruses that use insect vectors to infect plants. These organisms have evolved carefully balanced genomes that can efficiently use the translational machineries of different phyla, even if the phyla belong to different kingdoms. Using dengue virus as an example, we have undone the genome encoding balance and specifically shifted the encoding preference away from mammals. These mammalian-attenuated viruses grow to high titers in insect cells but low titers in mammalian cells, have dramatically increased LD50s in newborn mice, and induce high levels of protective antibodies. Recoded arboviruses with a bias toward phylum-specific expression could form the basis of a new generation of live attenuated vaccine candidates.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 92%

Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

Shen¹,

Stauft

Gorbatsevych³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

124

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show abstract

“…Experimental evidence has supported this hypothesis (23,38,39). Recently we recast our analysis in the language of statistical physics in a way that is theoretically insightful and computationally efficient (15).…”

Section: Discussionmentioning

confidence: 80%

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Tanne

Muniz

Puzio-Kuter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogenassociated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.noncoding RNA | genome evolution | cancer immunology

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“…vertebrate sequences display a strong under-representation of UpA and CpG, whilst insect sequences display a strong under-representation of UpA but not of CpG (Simmen, 2008). RNA virus sequences often have preferences that mimic those of their native hosts (Greenbaum et al, 2008;Atkinson et al, 2014;Tulloch et al, 2014). Thus, analysis of dinucleotide frequencies in virus genomes may be used to infer host taxa (Kapoor et al, 2010).…”

Section: Dinucleotide Usage Preferences Of Merdvmentioning

confidence: 99%

Merida virus, a putative novel rhabdovirus discovered in Culex and Ochlerotatus spp. mosquitoes in the Yucatan Peninsula of Mexico

Charles

Firth

Loroño-Pino

et al. 2016

Journal of General Virology

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Sequences corresponding to a putative, novel rhabdovirus [designated Merida virus (MERDV)]were initially detected in a pool of Culex quinquefasciatus collected in the Yucatan Peninsula of Mexico. The entire genome was sequenced, revealing 11 798 nt and five major ORFs, which encode the nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and RNA-dependent RNA polymerase (L). The deduced amino acid sequences of the N, G and L proteins have no more than 24, 38 and 43 % identity, respectively, to the corresponding sequences of all other known rhabdoviruses, whereas those of the P and M proteins have no significant identity with any sequences in GenBank and their identity is only suggested based on their genome position. Using specific reverse transcription-PCR assays established from the genome sequence, 27 571 C. quinquefasciatus which had been sorted in 728 pools were screened to assess the prevalence of MERDV in nature and 25 pools were found positive. The minimal infection rate (calculated as the number of positive mosquito pools per 1000 mosquitoes tested) was 0.9, and similar for both females and males. Screening another 140 pools of 5484 mosquitoes belonging to four other genera identified positive pools of Ochlerotatus spp. mosquitoes, indicating that the host range is not restricted to C. quinquefasciatus. Attempts to isolate MERDV in C6/36 and Vero cells were unsuccessful. In summary, we provide evidence that a previously undescribed rhabdovirus occurs in mosquitoes in Mexico.

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The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

Cited by 163 publications

References 58 publications

Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells

Merida virus, a putative novel rhabdovirus discovered in Culex and Ochlerotatus spp. mosquitoes in the Yucatan Peninsula of Mexico

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