Dataset Information

Dissimilar Conservation Pattern in Hepatitis C Virus Mutant Spectra, Consensus Sequences, and Data Banks.

ABSTRACT: The influence of quasispecies dynamics on long-term virus diversification in nature is a largely unexplored question. Specifically, whether intra-host nucleotide and amino acid variation in quasispecies fit the variation observed in consensus sequences or data bank alignments is unknown. Genome conservation and dynamics simulations are used for the computational design of universal vaccines, therapeutic antibodies and pan-genomic antiviral agents. The expectation is that selection of escape mutants will be limited when mutations at conserved residues are required. This strategy assumes long-term (epidemiologically relevant) conservation but, critically, does not consider short-term (quasispecies-dictated) residue conservation. We calculated mutant frequencies of individual loci from mutant spectra of hepatitis C virus (HCV) populations passaged in cell culture and from infected patients. Nucleotide or amino acid conservation in consensus sequences of the same populations, or in the Los Alamos HCV data bank did not match residue conservation in mutant spectra. The results relativize the concept of sequence conservation in viral genetics and suggest that residue invariance in data banks is an insufficient basis for the design of universal viral ligands for clinical purposes. Our calculations suggest relaxed mutational restrictions during quasispecies dynamics, which may contribute to higher calculated short-term than long-term viral evolutionary rates.

SUBMITTER: Garcia-Crespo C

PROVIDER: S-EPMC7692060 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Dissimilar Conservation Pattern in Hepatitis C Virus Mutant Spectra, Consensus Sequences, and Data Banks.

García-Crespo Carlos C Soria María Eugenia ME Gallego Isabel I Ávila Ana Isabel de AI Martínez-González Brenda B Vázquez-Sirvent Lucía L Gómez Jordi J Briones Carlos C Gregori Josep J Quer Josep J Perales Celia C Domingo Esteban E

Journal of clinical medicine 20201027 11

The influence of quasispecies dynamics on long-term virus diversification in nature is a largely unexplored question. Specifically, whether intra-host nucleotide and amino acid variation in quasispecies fit the variation observed in consensus sequences or data bank alignments is unknown. Genome conservation and dynamics simulations are used for the computational design of universal vaccines, therapeutic antibodies and pan-genomic antiviral agents. The expectation is that selection of escape muta ...[more]

PMID: 33121037

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Project description:Geminiviruses (family Geminiviridae) possess single-stranded circular DNA genomes that are replicated by cellular polymerases in plant host cell nuclei. In their hosts, geminivirus populations behave as ensembles of mutant and recombinant genomes, known as viral quasispecies. This favors the emergence of new geminiviruses with altered host range, facilitating new or more severe diseases or overcoming resistance traits. In warm and temperate areas several whitefly-transmitted geminiviruses of the genus Begomovirus cause the tomato yellow leaf curl disease (TYLCD) with significant economic consequences. TYLCD is frequently controlled in commercial tomatoes by using the dominant Ty-1 resistance gene. Over a 45 day period we have studied the diversification of three begomoviruses causing TYLCD: tomato yellow leaf curl virus (TYLCV), tomato yellow leaf curl Sardinia virus (TYLCSV) and tomato yellow leaf curl Malaga virus (TYLCMaV, a natural recombinant between TYLCV and TYLCSV). Viral quasispecies resulting from inoculation of geminivirus infectious clones were examined in plants of susceptible tomato (ty-1/ty-1), heterozygous resistant tomato (Ty-1/ty-1), common bean, and the wild reservoir Solanum nigrum. Differences in virus fitness across hosts were observed while viral consensus sequences remained invariant. However, the complexity and heterogeneity of the quasispecies were high, especially in common bean and the wild host. Interestingly, the presence or absence of the Ty-1 allele in tomato did not lead to differences in begomovirus mutant spectra. However, the fitness decrease of TYLCSV and TYLCV in tomato at 45 dpi might be related to an increase in CP (Coat protein) mutation frequency. In Solanum nigrum the recombinant TYLCMaV, which showed lower fitness than TYLCSV, at 45 dpi actively explored Rep (Replication associated protein) ORF but not the overlapping C4. Our results underline the importance of begomovirus mutant spectra during infections. This is especially relevant in the wild reservoir of the viruses, which has the potential to maintain highly diverse mutant spectra without modifying their consensus sequences.

Project description:BackgroundNuclear magnetic resonance spectroscopy is one of the primary tools in metabolomics analyses, where it is used to track and quantify changes in metabolite concentrations or profiles in response to perturbation through disease, toxicants or drugs. The spectra generated through such analyses are typically confounded by noise of various types, obscuring the signals and hindering downstream statistical analysis. Such issues are becoming increasingly significant as greater numbers of large-scale systems or longitudinal studies are being performed, in which many spectra from different conditions need to be compared simultaneously.ResultsWe describe a novel approach, termed Progressive Consensus Alignment of Nmr Spectra (PCANS), for the alignment of NMR spectra. Through the progressive integration of many pairwise comparisons, this approach generates a single consensus spectrum as an output that is then used to adjust the chemical shift positions of the peaks from the original input spectra to their final aligned positions. We characterize the performance of PCANS by aligning simulated NMR spectra, which have been provided with user-defined amounts of chemical shift variation as well as inter-group differences as would be observed in control-treatment applications. Moreover, we demonstrate how our method provides better performance than either template-based alignment or binning. Finally, we further evaluate this approach in the alignment of real mouse urine spectra and demonstrate its ability to improve downstream PCA and PLS analyses.ConclusionsBy avoiding the use of a template or reference spectrum, PCANS allows for the creation of a consensus spectrum that enhances the signals within the spectra while maintaining sample-specific features. This approach is of greatest benefit when complex samples are being analyzed and where it is expected that there will be spectral features unique and/or strongly different between subgroups within the samples. Furthermore, this approach can be potentially applied to the alignment of any data having spectra-like properties.

Project description:AimConservation planning exercises increasingly rely on species distributions predicted either from one particular statistical model or, more recently, from an ensemble of models (i.e. ensemble forecasting). However, it has not yet been explored how different ways of summarizing ensemble predictions affect conservation planning outcomes. We evaluate these effects and compare commonplace consensus methods, applied before the conservation prioritization phase, to a novel method that applies consensus after reserve selection.LocationEurope.MethodsWe used an ensemble of predicted distributions of 146 Western Palaearctic bird species in alternative ways: four different consensus methods, as well as distributions discounted with variability, were used to produce inputs for spatial conservation prioritization. In addition, we developed and tested a novel method, in which we built 100 datasets by sampling the ensemble of predicted distributions, ran a conservation prioritization analysis on each of them and averaged the resulting priority ranks. We evaluated the conservation outcome against three controls: (i) a null control, based on random ranking of cells; (2) the reference solution, based on an expert-refined dataset; and (3) the independent solution, based on an independent dataset.ResultsNetworks based on predicted distributions were more representative of rare species than randomly selected networks. Alternative methods to summarize ensemble predictions differed in representativeness of resulting reserve networks. Our novel method resulted in better representation of rare species than pre-selection consensus methods.Main conclusionsRetaining information about the variation in the predicted distributions throughout the conservation prioritization seems to provide better results than summarizing the predictions before conservation prioritization. Our results highlight the need to understand and consider model-based uncertainty when using predicted distribution data in conservation prioritization.

Dataset Information

Dissimilar Conservation Pattern in Hepatitis C Virus Mutant Spectra, Consensus Sequences, and Data Banks.

Publications

Dissimilar Conservation Pattern in Hepatitis C Virus Mutant Spectra, Consensus Sequences, and Data Banks.

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