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  • Complete genome sequencing and phylogenetic analysis of HCV isolates from China reveals a new subtype, designated 6u.

    16 October 2018

    Full length genome sequences were characterized for three novel hepatitis C virus (HCV) isolates (here named DH012, DH014, and DH028). The complete genomes were all isolated from injecting drug users (IDUs) who were co-infected with HIV-1 and lived in Dehong prefecture, Yunnan Province, China, which neighbors Myanmar. The three genomes are 9,443-9,470 nt in length and each contains a single open reading frame (ORF) of 9,069 nt long. Pairwise comparisons indicated nucleotide similarities of 97.9-98.6% among the three isolates, and similarities of 72.4-75.0% between the three isolates and 20 reference strains (representing HCV subtypes 6a-6q and 6t plus two unassigned genotype 6 isolates km41 and gz52557). Phylogenetic analyses demostrated that the three isolates formed a tight and well-supported monophyletic cluster in the genotype 6 clade. No evidence of viral recombination was found using similarity plots and bootscanning analyses. Based on the current HCV classification criteria, we have assigned the three isolates to a new subtype, 6u. Although another "6u" isolate D83 has been reported very recently, it is subtypically distinct from the three isolates we described here. Because its designation does not meet the criteria described in the updated HCV nomenclature proposal, this "6u" isolate should be reclassified.

  • The evolution of genome compression and genomic novelty in RNA viruses.

    16 October 2018

    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.

  • JC virus evolution and its association with human populations.

    16 October 2018

    The ubiquitous human polyomavirus JC (JCV) is a small double-stranded DNA virus that establishes a persistent infection, and it is often transmitted from parents to children. There are at least 14 subtypes of the virus associated with different human populations. Because of its presumed codivergence with humans, JCV has been used as a genetic marker for human evolution and migration. Codivergence has also been used as a basis for estimating the rate of nucleotide substitution in JCV. We tested the hypothesis of host-virus codivergence by (i) performing a reconciliation analysis of phylogenetic trees of human and JCV populations and (ii) providing the first estimate of the evolutionary rate of JCV that is independent from the assumption of codivergence. Strikingly, our comparisons of JCV and human phylogenies provided no evidence for codivergence, suggesting that this virus should not be used as a marker for human population history. Further, while the estimated nucleotide substitution rate of JCV has large confidence intervals due to limited sampling, our analysis suggests that this virus may evolve nearly two orders of magnitude faster than predicted under the codivergence hypothesis.

  • The evolutionary dynamics of endogenous retroviruses.

    16 October 2018

    Endogenous retroviruses (ERVs) are vertically transmitted intragenomic elements derived from integrated retroviruses. ERVs can proliferate within the genome of their host until they either acquire inactivating mutations or are lost by recombinational deletion. We present a model that unifies current knowledge of ERV biology into a single evolutionary framework. The model predicts the possible long-term outcomes of retroviral germline infection and can account for the variable patterns of observed ERV genetic diversity. We hope the model will provide a useful framework for understanding ERV evolution, enabling the testing of evolutionary hypotheses and the estimation of parameters governing ERV proliferation.

  • GENIE: estimating demographic history from molecular phylogenies.

    16 October 2018

    UNLABELLED: GENIE implements a statistical framework for inferring the demographic history of a population from phylogenies that have been reconstructed from sampled DNA sequences. The methods are based on population genetic models known collectively as coalescent theory. AVAILABILITY: GENIE is available from http://evolve.zoo.ox.ac.uk. All popular operating systems are supported.

  • Phylogeography and epidemic history of hepatitis C virus genotype 4 in Africa.

    16 October 2018

    HCV genotype 4 is prevalent in many African countries, yet little is known about the genotype׳s epidemic history on the continent. We present a comprehensive study of the molecular epidemiology of genotype 4. To address the deficit of data from the Democratic Republic of the Congo (DRC) we PCR amplified 60 new HCV isolates from the DRC, resulting in 33 core- and 48 NS5B-region sequences. Our data, together with genotype 4 database sequences, were analysed using Bayesian phylogenetic approaches. We find three well-supported intra-genotypic lineages and estimate that the genotype 4 common ancestor existed around 1733 (1650-1805). We show that genotype 4 originated in central Africa and that multiple lineages have been exported to north Africa since ~1850, including subtype 4a which dominates the epidemic in Egypt. We speculate on the causes of the historical intra-continental spread of genotype 4, including population movements during World War 2.

  • The genomic rate of molecular adaptation of the human influenza A virus.

    16 October 2018

    Quantifying adaptive evolution at the genomic scale is an essential yet challenging aspect of evolutionary biology. Here, we develop a method that extends and generalizes previous approaches to estimate the rate of genomic adaptation in rapidly evolving populations and apply it to a large data set of complete human influenza A virus genome sequences. In accord with previous studies, we observe particularly high rates of adaptive evolution in domain 1 of the viral hemagglutinin (HA1). However, our novel approach also reveals previously unseen adaptation in other viral genes. Notably, we find that the rate of adaptation (per codon per year) is higher in surface residues of the viral neuraminidase than in HA1, indicating strong antibody-mediated selection on the former. We also observed high rates of adaptive evolution in several nonstructural proteins, which may relate to viral evasion of T-cell and innate immune responses. Furthermore, our analysis provides strong quantitative support for the hypothesis that human H1N1 influenza experiences weaker antigenic selection than H3N2. As well as shedding new light on the dynamics and determinants of positive Darwinian selection in influenza viruses, the approach introduced here is applicable to other pathogens for which densely sampled genome sequences are available, and hence is ideally suited to the interpretation of next-generation genome sequencing data.

  • Phylogeography and molecular epidemiology of hepatitis C virus genotype 2 in Africa.

    16 October 2018

    Understanding the origin and nature of hepatitis C virus (HCV) genetic diversity is critical for improving treatment and vaccine design, and such diversity is the sole source of information about the virus' epidemic history prior to its identification 20 years ago. In this paper, we study the molecular epidemiology of HCV genotype 2 in its region of endemic origin, west and central Africa. Our analysis includes 56 new and highly diverse HCV isolates sampled from infected individuals in Guinea-Bissau. By combining phylogenetic, geographical and epidemiological information, we find a previously unappreciated geographical structure in the diversity of HCV genotype 2, pointing to a history of eastwards spatial spread from the west African coast to Cameroon that took place over several centuries. Molecular clock analysis dates the common ancestor of HCV in Guinea-Bissau to 1470 (1414-1582). The phylogenetic position of isolates from Madagascar and Martinique suggests a role for the historical slave trade in the global dissemination of HCV and of the epidemic subtypes 2a and 2c. Coalescent-based estimates of epidemic growth indicate a rapid 20th-century spread of HCV genotype 2 in Cameroon that is absent in Guinea-Bissau. We discuss this contrast in the context of possible parenteral HCV exposure during public-health campaigns undertaken during the colonial era.

  • Variable epidemic histories of hepatitis C virus genotype 2 infection in West Africa and Cameroon.

    16 October 2018

    It has recently been suggested that HCV genotype 2 (HCV-2) was more recently introduced to Cameroon (Middle Africa) than West African countries. In order to explore the relationships among HCV-2 strains from Cameroon and West Africa, and to estimate the epidemic history of each lineage, a recently-developed Bayesian evolutionary analysis approach was used. The estimated date of the most recent common ancestor (MRCA) of the Cameroon HCV-2 strains, 1630 (95% highest posterior density interval: 1470-1760) was slightly more recent than that of West Africa, 1540 (95% highest posterior density interval: 1380-1680). Estimates of epidemic history indicate significant differences between the two strains. HCV-2 appears to have spread relatively slowly within the West African population from 1630 to 1900, whilst the Cameroon lineages exhibit rapid, exponential spread from 1920 to 1960. This comparative genetic analysis indicates that Cameroon HCV-2 strains are derived from West African strains and that HCV-2 has undergone radically different epidemiological histories in the two regions.

  • Temporal and spatial dynamics of human immunodeficiency virus type 1 circulating recombinant forms 08_BC and 07_BC in Asia.

    16 October 2018

    Human immunodeficiency virus type 1 (HIV-1) CRF08_BC and CRF07_BC are two major recombinants descended from subtypes B' and C. Despite their massive epidemic impact in China, their migration patterns and divergence times remain unknown. Phylogenetic and population genetic analyses were performed on 228 HIV-1 sequences representing CRF08_BC, CRF07_BC, and subtype C strains from different locations across China, India, and Myanmar. Genome-specific rates of evolution and divergence times were estimated using a Bayesian Markov chain Monte Carlo framework under various evolutionary models. CRF08_BC originated in 1990.3 (95% credible region [CR], 1988.6 to 1991.9) in Yunnan province before spreading to Guangxi (south) and Liaoning (northeast) around 1995. Inside Guangxi region, the eastward expansion of CRF08_BC continued from Baise city (west) to Binyang (central) between 1997 and 1998 and later spread into Pingxiang around 1999 in the south, mainly through injecting drug users. Additionally, CRF07_BC diverged from its common ancestor in 1993.3 (95% CR, 1991.2 to 1995.2) before crossing the border into southern Taiwan in late 1990s. Phylogenetic analysis indicates that both CRF08_BC and CRF07_BC can trace their origins to Yunnan. The parental Indian subtype C lineage likely entered China around 1981.2 (95% CR, 1976.7 to 1985.9). Using a multiple unlinked locus model, we also showed that the dates of divergence calculated in this study may not be significantly affected by intrasubtype recombination among different lineages. This is the first phylodynamic study depicting the spatiotemporal dynamics of HIV/AIDS in East Asia.