Hepatitis C virus F protein sequence reveals a lack of functional constraints and a variable pattern of amino acid substitution

Cristina, Juan; López, Francisco Martín; Moratorio, Gonzalo; López, Lilia; Vásquez, Silvia; García-Aguirre, Laura; Chunga, Ausberto

doi:10.1099/vir.0.80510-0

Cited by 15 publications

(8 citation statements)

References 22 publications

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“…We deliberately ignored the alternate open reading frame in the Core gene, as its molecular evolution is under no selective constraints (e.g. [29]). This ORF therefore has no effect on the evolution of the HCV main reading frame…”

Section: Methodsmentioning

confidence: 99%

The mode and tempo of hepatitis C virus evolution within and among hosts

Parker²,

et al. 2011

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BackgroundHepatitis C virus (HCV) is a rapidly-evolving RNA virus that establishes chronic infections in humans. Despite the virus' public health importance and a wealth of sequence data, basic aspects of HCV molecular evolution remain poorly understood. Here we investigate three sets of whole HCV genomes in order to directly compare the evolution of whole HCV genomes at different biological levels: within- and among-hosts. We use a powerful Bayesian inference framework that incorporates both among-lineage rate heterogeneity and phylogenetic uncertainty into estimates of evolutionary parameters.ResultsMost of the HCV genome evolves at ~0.001 substitutions/site/year, a rate typical of RNA viruses. The antigenically-important E1/E2 genome region evolves particularly quickly, with correspondingly high rates of positive selection, as inferred using two related measures. Crucially, in this region an exceptionally higher rate was observed for within-host evolution compared to among-host evolution. Conversely, higher rates of evolution were seen among-hosts for functionally relevant parts of the NS5A gene. There was also evidence for slightly higher evolutionary rate for HCV subtype 1a compared to subtype 1b.ConclusionsUsing new statistical methods and comparable whole genome datasets we have quantified, for the first time, the variation in HCV evolutionary dynamics at different scales of organisation. This confirms that differences in molecular evolution between biological scales are not restricted to HIV and may represent a common feature of chronic RNA viral infection. We conclude that the elevated rate observed in the E1/E2 region during within-host evolution more likely results from the reversion of host-specific adaptations (resulting in slower long-term among-host evolution) than from the preferential transmission of slowly-evolving lineages.

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Section: Methodsmentioning

confidence: 99%

The mode and tempo of hepatitis C virus evolution within and among hosts

Parker²,

et al. 2011

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“…Another example is the recently reported F protein of hepatitis C virus. The function of this internal +1 frameshifted protein is unknown and it is not essential for viral replication (Baril and Brakier-Gingras 2005); analysis of its sequence suggests that molecular change in the gene is dominated by purifying selection on the primary gene which overlaps it-an essential polyprotein (Cristina et al 2005). If, as seems likely, the F protein does not yet have a function but its ORF has a tendency to be expressed in error, then this opens the opportunity for it to acquire a function in the future.…”

Section: Discussionmentioning

confidence: 99%

The evolution of genome compression and genomic novelty in RNA viruses

Belshaw

Pybus²,

Rambaut³

2007

Genome Res.

147

170

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The genomes of RNA viruses are characterized by their extremely small size and extremely high mutation rates (typically 10 kb and 10 −4 /base/replication cycle, respectively), traits that are thought to be causally linked. One aspect of their small size is the genome compression caused by the use of overlapping genes (where some nucleotides code for two genes). Using a comparative analysis of all known RNA viral species, we show that viruses with larger genomes tend to have less gene overlap. We provide a numerical model to show how a high mutation rate could lead to gene overlap, and we discuss the factors that might explain the observed relationship between gene overlap and genome size. We also propose a model for the evolution of gene overlap based on the co-opting of previously unused ORFs, which gives rise to two types of overlap: (1) the creation of novel genes inside older genes, predominantly via +1 frameshifts, and (2) the incremental increase in overlap between originally contiguous genes, with no frameshift preference. Both types of overlap are viewed as the creation of genomic novelty under pressure for genome compression. Simulations based on our model generate the empirical size distributions of overlaps and explain the observed frameshift preferences. We suggest that RNA viruses are a good model system for the investigation of general evolutionary relationship between genome attributes such as mutational robustness, mutation rate, and size.

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“…The ARFP/C coding sequence also includes several predicted RNA stem-loop structures (SLV and SLVI) (23,218,219,227). Although serologic and T-cell responses against ARFP have been detected in HCV patients (214), a comparison of ARFP codon usage and sequences among HCV genotypes suggests a lack of evolutionary constraints (35), and its function, if any, remains unclear. Recently, the ARF/C SLVI RNA element, rather than ARFP expression, was shown to be important for HCV replication in cell culture and a chimpanzee infection (148).…”

mentioning

confidence: 99%

Studying Hepatitis C Virus: Making the Best of a Bad Virus

Tellinghuisen

Evans

Hahn

et al. 2007

J Virol

118

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2An estimated 3% of the world population is infected with hepatitis C virus (HCV) (5,232). In most infected individuals, this remarkable RNA virus evades the immune system and establishes a chronic infection that can lead to cirrhosis, liver cancer, and death. While advances have been made in treating HCV, the current therapy, a combination of pegylated alpha interferon and ribavirin, is poorly tolerated and is effective in only 50% of genotype 1-infected patients (reviewed in reference 53). The quest for new HCV therapies has driven research in academia and industry, which has led to significant progress in understanding basic virus replication mechanisms and in developing specific candidate antiviral compounds. In this minireview, we highlight recent advances in cell culture model systems used to study HCV and describe new insights into the virus life cycle that have been gleaned from these and other recent studies. This review is limited in scope to recent developments in HCV biology and is by no means comprehensive. Throughout the article, we have attempted to direct the reader to a number of high-quality review articles covering various aspects of HCV biology in greater detail.

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Hepatitis C virus F protein sequence reveals a lack of functional constraints and a variable pattern of amino acid substitution

Cited by 15 publications

References 22 publications

The mode and tempo of hepatitis C virus evolution within and among hosts

The mode and tempo of hepatitis C virus evolution within and among hosts

The evolution of genome compression and genomic novelty in RNA viruses

Studying Hepatitis C Virus: Making the Best of a Bad Virus

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