Why genes overlap in viruses

Chirico, Nicola; Vianelli, Alberto; Belshaw, Robert

doi:10.1098/rspb.2010.1052

Cited by 127 publications

(144 citation statements)

References 75 publications

(152 reference statements)

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“…We therefore postulate that the signal of positive selection in those genomic regions that interact with the host (ORF2 and ORF3 [ORF1 contains housekeeping genes]) represents a cyclical but ultimately futile selection process in each species, resulting in a phenotype that is suboptimally fit in both, although, interestingly, our host-specific analysis provides evidence that the scales are currently tipped toward optimizing for the human host. Overlapping reading frames are not uncommon in RNA viruses (37) and have been suggested as a mechanism of packing more genes into a limited genomic space (38). While other studies have found a scattering of positively selected codons in this region (26), none have investigated the overlap region as a locus for positive selection.…”

Section: Discussionmentioning

confidence: 95%

Genotype-Specific Evolution of Hepatitis E Virus

Brayne

Dearlove

Lester

et al. 2017

J Virol

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Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis globally. HEV comprises four genotypes with different geographic distributions and host ranges. We utilize this natural case-control study for investigating the evolution of zoonotic viruses compared to single-host viruses, using 244 near-full-length HEV genomes. Genome-wide estimates of the ratio of nonsynonymous to synonymous evolutionary changes (dN/dS ratio) located a region of overlapping reading frames, which is subject to positive selection in genotypes 3 and 4. The open reading frames (ORFs) involved have functions related to host-pathogen interaction, so genotype-specific evolution of these regions may reflect their fitness. Bayesian inference of evolutionary rates shows that genotypes 3 and 4 have significantly higher rates than genotype 1 across all ORFs. Reconstruction of the phylogenies of zoonotic genotypes demonstrates significant intermingling of isolates between hosts. We speculate that the genotype-specific differences may result from cyclical adaptation to different hosts in genotypes 3 and 4.IMPORTANCE Hepatitis E virus (HEV) is increasingly recognized as a pathogen that affects both the developing and the developed world. While most often clinically mild, HEV can be severe or fatal in certain demographics, such as expectant mothers. Like many other viral pathogens, HEV has been classified into several distinct genotypes. We show that most of the HEV genome is evolutionarily constrained. One locus of positive selection is unusual in that it encodes two distinct protein products. We are the first to detect positive selection in this overlap region. Genotype 1, which infects humans only, appears to be evolving differently from genotypes 3 and 4, which infect multiple species, possibly because genotypes 3 and 4 are unable to achieve the same fitness due to repeated host jumps. KEYWORDS evolution, evolutionary biology, genotypic identification, hepatitis E virus, positive selection H epatitis E virus (HEV) is a nonenveloped single-stranded positive-sense RNA virus that infects approximately 20 million people globally each year (1). It causes large propagated epidemics of acute hepatitis in Asia and Africa, as well as low-level, sporadic, food-associated infections in the developed world (2, 3). Its pathogenicity ranges from acute liver failure and mortality rates as high as 20% in some subpopulations (for example, in pregnant women) to apparently asymptomatic infections in others (4). Acquired via the fecal-oral route, HEV is associated with poor hygiene and living conditions. It can also be acquired by eating contaminated food, including infected artiodactyls (swine, deer, and boar) and shellfish (4-6).Mammalian HEV exists in four internationally recognized genotypes (7). Genotyping is based on nucleotide divergence in the capsid open reading frame (ORF) (8) and on whole-genome phylogenetic analysis (9). Genotypes differ at the epidemiological (distribution, hosts) and virological (pathogenicity, translation mecha...

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Section: Discussionmentioning

confidence: 95%

Genotype-Specific Evolution of Hepatitis E Virus

Brayne

Dearlove

Lester

et al. 2017

J Virol

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“…The discovery that the alphaviruses employ a frameshifting technique to encode separate proteins in overlapping reading frames is quite intriguing, but not surprising, given that multiple viruses employ this strategy to minimize the size of their genome (36). Historically, electrophoretic analyses of purified alphavirus preparations have consistently revealed two closely migrating bands in the 4-to 8-kDa range, and it was presumed that these bands rep- resented alternative acylation states of 6K (18).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of the Alphavirus TF Protein

Snyder

Kulcsar

Schultz

et al. 2013

J Virol

128

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Here, we validate the findings of Firth and colleagues with respect to the production of the TF protein and begin to characterize the function of TF. Using a mass spectrometry-based approach, we identified TF in purified preparations of both Sindbis and Chikungunya virus particles. We next constructed a panel of Sindbis virus mutants with mutations which alter the production, size, or sequence of TF. We demonstrate that TF is not absolutely required in culture, although disrupting TF production leads to a decrease in virus particle release in both mammalian and insect cells. In a mouse neuropathogenesis model, mortality was <15% in animals infected with the TF mutants, whereas mortality was 95% in animals infected with the wild-type virus. Using a variety of additional assays, we demonstrate that TF retains ion-channel activity analogous to that of 6K and that lack of production of TF does not affect genome replication, particle infectivity, or envelope protein transit to the cell surface. The TF protein therefore represents a previously uncharacterized factor important for alphavirus assembly.

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“…Overlapping genes are a common feature of viruses to "compress" their genome (15). However, as the same portion of DNA encodes for several proteins, their adaptability is strongly lowered (16).…”

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confidence: 99%

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

Cassan

Arigon-Chifolleau

Mesnard

et al. 2016

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

114

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Recent experiments provide sound arguments in favor of the in vivo expression of the AntiSense Protein (ASP) of HIV-1. This putative protein is encoded on the antisense strand of the provirus genome and entirely overlapped by the env gene with reading frame −2. The existence of ASP was suggested in 1988, but is still controversial, and its function has yet to be determined. We used a large dataset of ∼23,000 HIV-1 and SIV sequences to study the origin, evolution, and conservation of the asp gene. We found that the ASP ORF is specific to group M of HIV-1, which is responsible for the human pandemic. Moreover, the correlation between the presence of asp and the prevalence of HIV-1 groups and M subtypes appeared to be statistically significant. We then looked for evidence of selection pressure acting on asp. Using computer simulations, we showed that the conservation of the ASP ORF in the group M could not be due to chance. Standard methods were ineffective in disentangling the two selection pressures imposed by both the Env and ASP proteins-an expected outcome with overlaps in frame −2. We thus developed a method based on careful evolutionary analysis of the presence/absence of stop codons, revealing that ASP does impose significant selection pressure. All of these results support the idea that asp is the 10th gene of HIV-1 group M and indicate a correlation with the spread of the pandemic.HIV-1 | asp and env genes | overlapping genes | phylogenetic analyses | selection pressure

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Why genes overlap in viruses

Cited by 127 publications

References 75 publications

Genotype-Specific Evolution of Hepatitis E Virus

Genotype-Specific Evolution of Hepatitis E Virus

Functional Characterization of the Alphavirus TF Protein

Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic

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