Suppressors of RNAi from plant viruses are subject to episodic positive selection

Viral suppressors of RNAi (VSRs) are proteins that actively inhibit the antiviral RNA interference (RNAi) immune response, providing an immune evasion route for viruses. It has been hypothesized that VSRs are engaged in a molecular ‘arms race’ with RNAi pathway genes. Two lines of evidence support this. First, VSRs from plant viruses display high sequence diversity, and are frequently gained and lost over evolutionary time scales. Second, Drosophila antiviral RNAi genes show high rates of adaptive evolution. Here, we investigate whether VSRs diversify faster than other genes and, if so, whether this is a result of positive selection, as might be expected in an arms race. By analysis of 12 plant RNA viruses, we show that the relative rate of protein evolution is higher for VSRs than for other genes, but that this is not attributable to pervasive positive selection. We argue that, because evolutionary time scales are extremely different for viruses and eukaryotes, it is improbable that viral adaptation (as measured by the ratio of non-synonymous to synonymous change) will be dominated by one-to-one coevolution with eukaryotes. Instead, for plant virus VSRs, we find strong evidence of episodic selection—diversifying selection that acts on a subset of lineages—which might be attributable to frequent shifts between different host genotypes or species

Molecular footprint of drug-selective pressure in a human immunodeficiency virus transmission chain

Known human immunodeficiency virus (HIV) transmission histories are invaluable models for investigating the evolutionary and transmission dynamics of the virus and to assess the accuracy of phylogenetic reconstructions. Here we have characterized an HIV-1 transmission chain consisting of nine infected patients, almost all of whom were treated with antiviral drugs at later stages of infection. Partial pol and env gp41 regions of the HIV genome were directly sequenced from plasma viral RNA for at least one sample from each patient. Phylogenetic analyses in pol using likelihood methods inferred an evolutionary history not fully compatible with the known transmission history. This could be attributed to parallel evolution of drug resistance mutations resulting in the incorrect clustering of multidrug-resistant virus. On the other hand, a fully compatible phylogenetic tree was reconstructed from the env sequences. We were able to identify and quantify the molecular footprint of drug-selective pressure in pol using maximum likelihood inference under different codon substitution models. An increased fixation rate of mutations in the HIV population of the multidrug-resistant patient was demonstrated using molecular clock modeling. We show that molecular evolutionary analyses, guided by a known transmission history, can reveal the presence of confounding factors like natural selection and caution should be taken when accurate descriptions of HIV evolution are required.status: publishe

New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels

Over calendar time, HIV-1 evolves considerably faster within individuals than it does at the epidemic level. This is a surprising observation since, from basic population genetic theory, we would expect the genetic substitution rate to be similar across different levels of biological organization. Three different mechanisms could potentially cause the observed mismatch in phylogenetic rates of divergence: temporal changes in selection pressure during the course of infection; frequent reversion of adaptive mutations after transmission; and the storage of the virus in the body followed by the preferential transmission of stored ancestral virus. We evaluate each of these mechanisms to determine whether they are likely to make a major contribution to the mismatch in phylogenetic rates. We conclude that the cycling of the virus through very long-lived memory CD4+ T cells, a process that we call ‘store and retrieve’, is probably the major contributing factor to the rate mismatch. The preferential transmission of ancestral virus needs to be integrated into evolutionary models if we are to accurately predict the evolution of immune escape, drug resistance and virulence in HIV-1 at the population level. Moreover, early infection viruses should be the major target for vaccine design, because these are the viral strains primarily involved in transmission

Evidence for a Complex Mosaic Genome Pattern in a Full-length Hepatitis C Virus Sequence

The genome of the hepatitis C virus (HCV) exhibits a high genetic variability. This remarkable heterogeneity is mainly attributed to the gradual accumulation of mutational changes, whereas the contribution of recombination events to the evolution of HCV remains controversial so far. While performing phylogenetic analyses including a large number of sequences deposited in the GenBank, we encountered a full-length HCV sequence (AY651061) that showed evidence for inter-subtype recombination and was, therefore, subjected to a detailed analysis of its molecular structure. The obtained results indicated that AY651061 does not represent a “simple” HCV 1c isolate, but a complex 1a/1c mosaic genome, showing five putative breakpoints in the core to NS3 regions. To our knowledge, this is the first report on a mosaic HCV full-length sequence with multiple breakpoints. The molecular structure of AY651061 is reminiscent of complex homologous recombinant variants occurring among other members of the flaviviridae family, e.g. GB virus C, dengue virus, and Japanese encephalitis virus. Our finding of a mosaic HCV sequence may have important implications for many fields of current HCV research which merit careful consideration

High GUD Incidence in the Early 20th Century Created a Particularly Permissive Time Window for the Origin and Initial Spread of Epidemic HIV Strains

The processes that permitted a few SIV strains to emerge epidemically as HIV groups remain elusive. Paradigmatic theories propose factors that may have facilitated adaptation to the human host (e.g., unsafe injections), none of which provide a coherent explanation for the timing, geographical origin, and scarcity of epidemic HIV strains. Our updated molecular clock analyses established relatively narrow time intervals (roughly 1880–1940) for major SIV transfers to humans. Factors that could favor HIV emergence in this time frame may have been genital ulcer disease (GUD), resulting in high HIV-1 transmissibility (4–43%), largely exceeding parenteral transmissibility; lack of male circumcision increasing male HIV infection risk; and gender-skewed city growth increasing sexual promiscuity. We surveyed colonial medical literature reporting incidences of GUD for the relevant regions, concentrating on cities, suffering less reporting biases than rural areas. Coinciding in time with the origin of the major HIV groups, colonial cities showed intense GUD outbreaks with incidences 1.5–2.5 orders of magnitude higher than in mid 20th century. We surveyed ethnographic literature, and concluded that male circumcision frequencies were lower in early 20th century than nowadays, with low rates correlating spatially with the emergence of HIV groups. We developed computer simulations to model the early spread of HIV-1 group M in Kinshasa before, during and after the estimated origin of the virus, using parameters derived from the colonial literature. These confirmed that the early 20th century was particularly permissive for the emergence of HIV by heterosexual transmission. The strongest potential facilitating factor was high GUD levels. Remarkably, the direct effects of city population size and circumcision frequency seemed relatively small. Our results suggest that intense GUD in promiscuous urban communities was the main factor driving HIV emergence. Low circumcision rates may have played a role, probably by their indirect effects on GUD

Inferring pandemic growth rates from sequence data

Using sequence data to infer population dynamics is playing an increasing role in the analysis of outbreaks. The most common methods in use, based on coalescent inference, have been widely used but not extensively tested against simulated epidemics. Here, we use simulated data to test the ability of both parametric and non-parametric methods for inference of effective population size (coded in the popular BEAST package) to reconstruct epidemic dynamics. We consider a range of simulations centred on scenarios considered plausible for pandemic influenza, but our conclusions are generic for any exponentially growing epidemic. We highlight systematic biases in non-parametric effective population size estimation. The most prominent such bias leads to the false inference of slowing of epidemic spread in the recent past even when the real epidemic is growing exponentially. We suggest some sampling strategies that could reduce (but not eliminate) some of the biases. Parametric methods can correct for these biases if the infected population size is large. We also explore how some poor sampling strategies (e.g. that over-represent epidemiologically linked clusters of cases) could dramatically exacerbate bias in an uncontrolled manner. Finally, we present a simple diagnostic indicator, based on coalescent density and which can easily be applied to reconstructed phylogenies, that identifies time-periods for which effective population size estimates are less likely to be biased. We illustrate this with an application to the 2009 H1N1 pandemic

Sorting signed circular permutations by super short reversals

We consider the problem of sorting a circular permutation by reversals of length at most 2, a problem that finds application in comparative genomics. Polynomial-time solutions for the unsigned version of this problem are known, but the signed version remained open. In this paper, we present the first polynomial-time solution for the signed version of this problem. Moreover, we perform an experiment for inferring distances and phylogenies for published Yersinia genomes and compare the results with the phylogenies presented in previous works.We consider the problem of sorting a circular permutation by reversals of length at most 2, a problem that finds application in comparative genomics. Polynomial-time solutions for the unsigned version of this problem are known, but the signed version rema9096272283FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2013/08293-72014/04718-6306730/2012-0; 477692/2012-5; 483370/2013-411th International Symposium on Bioinformatics Research and Application

Dynamic features of the selective pressure on the human immunodeficiency virus type 1 (HIV-1) gp120 CD4-binding site in a group of long term non progressor (LTNP) subjects.

Abstract The characteristics of intra-host human immunodeficiency virus type 1 (HIV-1) env evolution were evaluated in untreated HIV-1-infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term non-progressor [LTNP] patients. High-resolution phylogenetic analysis of the C2-C5 env gene sequences of the replicating HIV-1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV-1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3rd codon mutation rate was equal or even lower than that observed at the 1st and 2nd positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximum-likelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of N-linked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4-binding site (CD4bs). In addition, localized pressure in the area of the IgG-b12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3-dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV-1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV-1 infection.</p

Whole genome analysis of local Kenyan and global sequences unravels the epidemiological and molecular evolutionary dynamics of RSV genotype ON1 strains

The respiratory syncytial virus (RSV) group A variant with the 72-nucleotide duplication in the G gene, genotype ON1, was first detected in Kilifi in 2012 and has almost completely replaced previously circulating genotype GA2 strains. This replacement suggests some fitness advantage of ON1 over the GA2 viruses, and might be accompanied by important genomic substitutions in ON1 viruses. Close observation of such a new virus introduction over time provides an opportunity to better understand the transmission and evolutionary dynamics of the pathogen. We have generated and analyzed 184 RSV-A whole genome sequences (WGS) from Kilifi (Kenya) collected between 2011 and 2016, the first ON1 genomes from Africa and the largest collection globally from a single location. Phylogenetic analysis indicates that RSV-A transmission into this coastal Kenya location is characterized by multiple introductions of viral lineages from diverse origins but with varied success in local transmission. We identify signature amino acid substitutions between ON1 and GA2 viruses within genes encoding the surface proteins (G, F), polymerase (L) and matrix M2-1 proteins, some of which were identified as positively selected, and thereby provide an enhanced picture of RSV-A diversity. Furthermore, five of the eleven RSV open reading frames (ORF) (i.e. G, F, L, N and P), analyzed separately, formed distinct phylogenetic clusters for the two genotypes. This might suggest that coding regions outside of the most frequently studied G ORF play a role in the adaptation of RSV to host populations with the alternative possibility that some of the substitutions are nothing more than genetic hitchhikers. Our analysis provides insight into the epidemiological processes that define RSV spread, highlights the genetic substitutions that characterize emerging strains, and demonstrates the utility of large-scale WGS in molecular epidemiological studies