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Nucleotide composition of the Zika virus RNA genome and its codon usage.

ABSTRACT: RNA viruses have genomes with a distinct nucleotide composition and codon usage. We present the global characteristics of the RNA genome of Zika virus (ZIKV), an emerging pathogen within the Flavivirus genus. ZIKV was first isolated in 1947 in Uganda, caused a widespread epidemic in South and Central America and the Caribbean in 2015 and has recently been associated with microcephaly in newborns.The nearly 11 kb positive-stranded RNA genome of ZIKV was analyzed for its nucleotide composition, also in the context of the folded RNA molecule. Nucleotide trends were investigated along the genome length by skew analyses and we analyzed the codons used for translation of the ZIKV proteins.ZIKV RNA has a biased nucleotide composition in being purine-rich and pyrimidine-poor. This preference for purines is a general characteristic of the mosquito-borne and tick-borne flaviviruses. The virus-specific nucleotide bias is further enriched in the unpaired, single-stranded regions of the structured ZIKV RNA genome, thus further imposing this ZIKV-specific signature. The codons used for translation of the ZIKV proteins is also unusual, but we show that it is the underlying bias in nucleotide composition of the viral RNA that largely dictates these codon preferences.The ZIKV RNA genome has a biased nucleotide composition that dictates the codon usage of this flavivirus. We discuss the evolutionary scenarios and molecular mechanisms that may be responsible for these distinctive ZIKV RNA genome features.

SUBMITTER: van Hemert F

PROVIDER: S-EPMC4898363 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Nucleotide composition of the Zika virus RNA genome and its codon usage.

van Hemert Formijn F Berkhout Ben B

Virology journal 20160608

<h4>Background</h4>RNA viruses have genomes with a distinct nucleotide composition and codon usage. We present the global characteristics of the RNA genome of Zika virus (ZIKV), an emerging pathogen within the Flavivirus genus. ZIKV was first isolated in 1947 in Uganda, caused a widespread epidemic in South and Central America and the Caribbean in 2015 and has recently been associated with microcephaly in newborns.<h4>Methods</h4>The nearly 11 kb positive-stranded RNA genome of ZIKV was analyzed ...[more]

PMID: 27278486

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Project description:The genetic material of the three domains of life (Bacteria, Archaea, and Eukaryota) is always double-stranded DNA, and their GC content (molar content of guanine plus cytosine) varies between ≈ 13% and ≈ 75%. Nucleotide composition is the simplest way of characterizing genomes. Despite this simplicity, it has several implications. Indeed, it is the main factor that determines, among other features, dinucleotide frequencies, repeated short DNA sequences, and codon and amino acid usage. Which forces drive this strong variation is still a matter of controversy. For rather obvious reasons, most of the studies concerning this huge variation and its consequences, have been done in free-living organisms. However, no recent comprehensive study of all known viruses has been done (that is, concerning all available sequences). Viruses, by far the most abundant biological entities on Earth, are the causative agents of many diseases. An overview of these entities is important also because their genetic material is not always double-stranded DNA: indeed, certain viruses have as genetic material single-stranded DNA, double-stranded RNA, single-stranded RNA, and/or retro-transcribing. Therefore, one may wonder if what we have learned about the evolution of GC content and its implications in prokaryotes and eukaryotes also applies to viruses. In this contribution, we attempt to describe compositional properties of ∼ 10,000 viral species: base composition (globally and according to Baltimore classification), correlations among non-coding regions and the three codon positions, and the relationship of the nucleotide frequencies and codon usage of viruses with the same feature of their hosts. This allowed us to determine how the base composition of phages strongly correlate with the value of their respective hosts, while eukaryotic viruses do not (with fungi and protists as exceptions). Finally, we discuss some of these results concerning codon usage: reinforcing previous results, we found that phages and hosts exhibit moderate to high correlations, while for eukaryotes and their viruses the correlations are weak or do not exist.

Project description:Negative-strand RNA viruses (NSVs) include some of the most pathogenic human viruses known. NSVs completely rely on the host cell for protein translation, but their codon usage bias is often different from that of the host. This discrepancy may have originated from the unique mechanism of NSV RNA synthesis in that the genomic RNA sequestered in the nucleocapsid serves as the template. The stability of the genomic RNA in the nucleocapsid appears to regulate its accessibility to the viral RNA polymerase, thus placing constraints on codon usage to balance viral RNA synthesis. By in situ analyses of vesicular stomatitis virus RNA synthesis, specific activities of viral RNA synthesis were correlated with the genomic RNA sequence. It was found that by simply altering the sequence and not the amino acid that it encoded, a significant reduction, up to an ?750-fold reduction, in viral RNA transcripts occurred. Through subsequent sequence analysis and thermal shift assays, it was found that the purine/pyrimidine content modulates the overall stability of the polymerase complex, resulting in alteration of the activity of viral RNA synthesis. The codon usage is therefore constrained by the obligation of the NSV genome for viral RNA synthesis.IMPORTANCE Negative-strand RNA viruses (NSVs) include the most pathogenic viruses known. New methods to monitor their evolutionary trends are urgently needed for the development of antivirals and vaccines. The protein translation machinery of the host cell is currently recognized as a main genomic regulator of RNA virus evolution, which works especially well for positive-strand RNA viruses. However, this approach fails for NSVs because it does not consider the unique mechanism of their viral RNA synthesis. For NSVs, the viral RNA-dependent RNA polymerase (vRdRp) must gain access to the genome sequestered in the nucleocapsid. Our work suggests a paradigm shift that the interactions between the RNA genome and the nucleocapsid protein regulate the activity of vRdRp, which selects codon usage.

Project description:BACKGROUND: Despite the fact that the organization of the ciliate mitochondrial genome is exceptional, only few ciliate mitochondrial genomes have been sequenced until today. All ciliate mitochondrial genomes are linear. They are 40 kb to 47 kb long and contain some 50 tightly packed genes without introns. Earlier studies documented that the mitochondrial guanine + cytosine contents are very different between Paramecium tetraurelia and all studied Tetrahymena species. This raises the question of whether the high mitochondrial G+C content observed in P. tetraurelia is a characteristic property of Paramecium mtDNA, or whether it is an exception of the ciliate mitochondrial genomes known so far. To test this question, we determined the mitochondrial genome sequence of Paramecium caudatum and compared the gene content and sequence properties to the closely related P. tetraurelia. RESULTS: The guanine + cytosine content of the P. caudatum mitochondrial genome was significantly lower than that of P. tetraurelia (22.4% vs. 41.2%). This difference in the mitochondrial nucleotide composition was accompanied by significantly different codon usage patterns in both species, i.e. within P. caudatum clearly A/T ending codons dominated, whereas for P. tetraurelia the synonymous codons were more balanced with a higher number of G/C ending codons. Further analyses indicated that the nucleotide composition of most members of the genus Paramecium resembles that of P. caudatum and that the shift observed in P. tetraurelia is restricted to the P. aurelia species complex. CONCLUSIONS: Surprisingly, the codon usage bias in the P. caudatum mitochondrial genome, exemplified by the effective number of codons, is more similar to the distantly related T. pyriformis and other single-celled eukaryotes such as Chlamydomonas, than to the closely related P. tetraurelia. These differences in base composition and codon usage bias were, however, not reflected in the amino acid composition. Most probably, the observed picture is best explained by a hitherto unknown (neutral or adaptive) mechanism that increased the guanine + cytosine content in P. tetraurelia mtDNA on the one hand, and strong purifying selection on the ancestral amino acid composition on the other hand. These contradicting forces are counterbalanced by a considerably altered codon usage pattern.

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Nucleotide composition of the Zika virus RNA genome and its codon usage.

Publications

Nucleotide composition of the Zika virus RNA genome and its codon usage.

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