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Esteban Domingo - One of the best experts on this subject based on the ideXlab platform.
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Viral Quasispecies complexity measures
Virology, 2016Co-Authors: Josep Gregori, Celia Perales, Francisco Rodriguez-frias, Juan Ignacio Esteban, Josep Quer, Esteban DomingoAbstract:Mutant spectrum dynamics (changes in the related mutants that compose Viral populations) has a decisive impact on virus behavior. The several platforms of next generation sequencing (NGS) to study Viral Quasispecies offer a magnifying glass to study Viral Quasispecies complexity. Several parameters are available to quantify the complexity of mutant spectra, but they have limitations. Here we critically evaluate the information provided by several population diversity indices, and we propose the introduction of some new ones used in ecology. In particular we make a distinction between incidence, abundance and function measures of Viral Quasispecies composition. We suggest a multidimensional approach (complementary information contributed by adequately chosen indices), propose some guidelines, and illustrate the use of indices with a simple example. We apply the indices to three clinical samples of hepatitis C virus that display different population heterogeneity. Areas of virus biology in which population complexity plays a role are discussed.
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Viral Quasispecies and Lethal Mutagenesis
European Review, 2016Co-Authors: Esteban Domingo, Celia PeralesAbstract:Virology has undergone a profound transformation with the incorporation of Quasispecies theory to the understanding of the composition and dynamics of Viral populations as they cause disease. RNA Viral populations do not consist of a genome class with a defined nucleotide sequence but of a cloud or swarm or related mutants due to high mutation rates (number of incorrect nucleotides introduced per nucleotide copied) during replication. DNA and RNA viruses whose multiplication is catalysed by a low fidelity polymerase replicate close to an error threshold for maintenance of their genetic information. This means that modest increases in mutation rate jeopardize their genetic stability. Realization of this important corollary of Quasispecies theory has opened new approaches to combating Viral disease. One of these approaches is lethal mutagenesis that consists of forcing virus extinction by an excess of mutations evoked by virus-specific mutagenic agents. This article summarizes the origin and current status of this new antiViral approach.
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Species Concepts: Viral Quasispecies
Encyclopedia of Evolutionary Biology, 2016Co-Authors: Esteban Domingo, Celia PeralesAbstract:RNA viruses replicate as complex and dynamic collections of related mutants (also termed mutant spectra, distributions, clouds, or swarms), termed Viral Quasispecies. A Viral isolate is not characterized by a defined genomic sequence but by a weighted average of multitudes of related sequences. This population structure was documented by cloning-sequencing techniques, and has been confirmed by the new deep sequencing methodologies. Quasispecies dynamics explains the adaptive potential of viruses, including the response to antiViral treatments. Here we explain the Quasispecies concept, and review some of its biological implications.
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Quasispecies and Drug Resistance
2015Co-Authors: Celia Perales, Julie Sheldon, Luis Menéndez-arias, Ana M. Ortega-prieto, Nathan M. Beach, Esteban DomingoAbstract:Mutant spectra of Viral Quasispecies are complex reservoirs of genetic and phenotypic variants, including drug-resistant mutants. Here we review basic features of RNA Viral Quasispecies such as internal interactions within mutant spectra and the effect of population size and bottleneck events as they affect the frequency of inhibitor-escape mutants. Genetic barriers to resistance and fitness cost of specific amino acid substitutions involved in resistance are discussed, with specific examples for human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). Prospects for new antiViral designs aimed at counteracting the adaptive potential of Viral Quasispecies are presented. Introduction: Relevance of Quasispecies in Virus Biology Viral Quasispecies are mutant distributions (also termed mutant spectra, clouds, or swarms) that characterize genome populations of RNA viruses and at least some DNA viruses (Fig. 1). Both clonal analyses by classic nucleotide sequencing techniques and bulk population analyses by ultradeep sequencing have documented that mutant distributions are extremely complex with many minority mutations occurring at low frequency (1 % which is the present standard cutoff value for reliable mutant frequency determination and probably lower according to studies that achieved lower cutoff values). From all evidence, mutant spectra originate from high mutation rates in RNA (and some DNA) viruses, which have been estimated in 10 3 to 10 5 mutations introduced per nucleotide copied, together with competition and intrapopulation interactions among genomes [reviewed in (Domingo et al. 2012)]. Viral Quasispecies took its name from a theory of the origin of life developed by M. Eigen, P. Schuster, and their colleagues (Eigen and Schuster 1979). Theoretical studies on Quasispecies have paralleled experimental investigations with RNA viruses, reaching a considerable degree of conceptual cross-fertilization (Eigen 2013; Holland 2006; Mas et al. 2010; Ojosnegros et al. 2011). The biological behavior of Viral Quasispecies is not equivalent to that of sets of identical genomes undergoing only occasional mutations for two main reasons. One is that mutant spectra constitute vast reservoirs of genetic and phenotypic variants, including, notably, drug-, antibody-, or cytotoxic T-cell (CTL)-escape mutants. The second reason is that the variant genomes which dynamically arise, persist, increase, or decrease in frequency or are eliminated (transiently or irreversibly) do not act independently. Variants can complement each other to give rise to a new phenotype (Cao et al. 2014; Shirogane et al. 2012), to trigger large evolutionary transitions such as genome *Email: cperales@cbm.csic.es Handbook of Antimicrobial Resistance DOI 10.1007/978-1-4939-0667-3_1-1 # Springer Science+Business Media New York 2014
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Inference with Viral Quasispecies diversity indices: clonal and NGS approaches
Bioinformatics (Oxford England), 2014Co-Authors: Josep Gregori, Esteban Domingo, Francisco Rodriguez-frias, Juan Ignacio Esteban, Miquel Salicrú, Alex Sánchez, Josep QuerAbstract:Given the inherent dynamics of a Viral Quasispecies, we are often interested in the comparison of diversity indices of sequential samples of a patient, or in the comparison of diversity indices of virus in groups of patients in a treated versus control design. It is then important to make sure that the diversity measures from each sample may be compared with no bias and within a consistent statistical framework. In the present report, we review some indices often used as measures for Viral Quasispecies complexity and provide means for statistical inference, applying procedures taken from the ecology field. In particular, we examine the Shannon entropy and the mutation frequency, and we discuss the appropriateness of different normalization methods of the Shannon entropy found in the literature. By taking amplicons ultradeep pyrosequencing (UDPS) raw data as a surrogate of a real hepatitis C virus Viral population, we study through in-silico sampling the statistical properties of these indices under two methods of Viral Quasispecies sampling, classical cloning followed by Sanger sequencing (CCSS) and next-generation sequencing (NGS) such as UDPS. We propose solutions specific to each of the two sampling methods— CCSS and NGS—to guarantee statistically conforming conclusions as free of bias as possible.
Josep Gregori - One of the best experts on this subject based on the ideXlab platform.
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Sophisticated Viral Quasispecies with a genotype-related pattern of mutations in the hepatitis B X gene of HBeAg-ve chronically infected patients.
Scientific reports, 2021Co-Authors: Maria Francesca Cortese, Josep Gregori, Carolina González, Rosario Casillas, L. Carioti, Mercedes Guerrero-murillo, Mar Riveiro-barciela, Cristina Godoy, Sara Sopena, Marçal YllAbstract:Patients with HBeAg-negative chronic infection (CI) have not been extensively studied because of low viremia. The HBx protein, encoded by HBX, has a key role in Viral replication. Here, we analyzed the Viral Quasispecies at the 5' end of HBX in CI patients and compared it with that of patients in other clinical stages. Fifty-eight HBeAg-negative patients were included: 16 CI, 19 chronic hepatitis B, 16 hepatocellular carcinoma and 6 liver cirrhosis. Quasispecies complexity and conservation were determined in the region between nucleotides 1255 and 1611. Amino acid changes detected were tested in vitro. CI patients showed higher complexity in terms of mutation frequency and nucleotide diversity and higher Quasispecies conservation (p < 0.05). A genotype D-specific pattern of mutations (A12S/P33S/P46S/T36D-G) was identified in CI (median frequency, 81.7%), which determined a reduction in HBV DNA release of up to 1.5 log in vitro. CI patients showed a more complex and conserved Viral Quasispecies than the other groups. The genotype-specific pattern of mutations could partially explain the low viremia observed in these patients.
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naturally occurring sars cov 2 gene deletions close to the spike s1 s2 cleavage site in the Viral Quasispecies of covid19 patients
Emerging microbes & infections, 2020Co-Authors: Cristina Andrés, Josep Gregori, Maria Piñana, Juliana Esperalba, Ariadna Rando, Damir Garciacehic, Francisco Rodriguezfrias, Mercedes Guerreromurillo, Lidia GoterrisAbstract:The SARS-CoV-2 spike (S) protein, the Viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site (PRRAR/S), generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the Viral Quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We suggest that natural selection has favoured a "Don't burn down the house" strategy, in which free S1 protein may compete with Viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.
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Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the Viral Quasispecies of COVID19 patients
2020Co-Authors: Cristina Andrés, Josep Gregori, Francisco Rodriguez-frias, Mercedes Guerrero-murillo, Damir Garcia-cehic, Maria Piñana, Juliana Esperalba, Ariadna Rando, Lidia Goterris, Maria Gema CodinaAbstract:The SARS-CoV-2 spike (S) protein, the Viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the Viral Quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a Do not burn down the house strategy, in which free S1 protein may compete with Viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.
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Viral Quasispecies complexity measures
Virology, 2016Co-Authors: Josep Gregori, Celia Perales, Francisco Rodriguez-frias, Juan Ignacio Esteban, Josep Quer, Esteban DomingoAbstract:Mutant spectrum dynamics (changes in the related mutants that compose Viral populations) has a decisive impact on virus behavior. The several platforms of next generation sequencing (NGS) to study Viral Quasispecies offer a magnifying glass to study Viral Quasispecies complexity. Several parameters are available to quantify the complexity of mutant spectra, but they have limitations. Here we critically evaluate the information provided by several population diversity indices, and we propose the introduction of some new ones used in ecology. In particular we make a distinction between incidence, abundance and function measures of Viral Quasispecies composition. We suggest a multidimensional approach (complementary information contributed by adequately chosen indices), propose some guidelines, and illustrate the use of indices with a simple example. We apply the indices to three clinical samples of hepatitis C virus that display different population heterogeneity. Areas of virus biology in which population complexity plays a role are discussed.
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Inference with Viral Quasispecies diversity indices: clonal and NGS approaches
Bioinformatics (Oxford England), 2014Co-Authors: Josep Gregori, Esteban Domingo, Francisco Rodriguez-frias, Juan Ignacio Esteban, Miquel Salicrú, Alex Sánchez, Josep QuerAbstract:Given the inherent dynamics of a Viral Quasispecies, we are often interested in the comparison of diversity indices of sequential samples of a patient, or in the comparison of diversity indices of virus in groups of patients in a treated versus control design. It is then important to make sure that the diversity measures from each sample may be compared with no bias and within a consistent statistical framework. In the present report, we review some indices often used as measures for Viral Quasispecies complexity and provide means for statistical inference, applying procedures taken from the ecology field. In particular, we examine the Shannon entropy and the mutation frequency, and we discuss the appropriateness of different normalization methods of the Shannon entropy found in the literature. By taking amplicons ultradeep pyrosequencing (UDPS) raw data as a surrogate of a real hepatitis C virus Viral population, we study through in-silico sampling the statistical properties of these indices under two methods of Viral Quasispecies sampling, classical cloning followed by Sanger sequencing (CCSS) and next-generation sequencing (NGS) such as UDPS. We propose solutions specific to each of the two sampling methods— CCSS and NGS—to guarantee statistically conforming conclusions as free of bias as possible.
Cristina Escarmís - One of the best experts on this subject based on the ideXlab platform.
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Viral Quasispecies: Dynamics, Interactions, and Pathogenesis
Origin and Evolution of Viruses, 2008Co-Authors: Esteban Domingo, Celia Perales, Cristina Escarmís, Luis Menéndez-arias, Mónica Herrera, Isabel S. Novella, John J. HollandAbstract:ABSTRACT Quasispecies theory is providing a solid, evolving conceptual framework for insights into virus population dynamics, adaptive potential, and response to lethal mutagenesis. The complexity of mutant spectra can influence disease progression and Viral pathogenesis, as demonstrated using virus variants selected for increased replicative fidelity. Complementation and interference exerted among components of a Viral Quasispecies can either reinforce or limit the replicative capacity and disease potential of the ensemble. In particular, a progressive enrichment of a replicating mutant spectrum with interfering mutant genomes prompted by enhanced mutagenesis may be a key event in the sharp transition of virus populations into error catastrophe that leads to virus extinction. Fitness variations are influenced by the passage regimes to which Viral populations are subjected, notably average fitness decreases upon repeated bottleneck events and fitness gains upon competitive optimization of large Viral populations. Evolving Viral Quasispecies respond to selective constraints by replication of subpopulations of variant genomes that display higher fitness than the parental population in the presence of the selective constraint. This has been profusely documented with fitness effects of mutations associated with resistance of pathogenic viruses to antiViral agents. In particular, selection of HIV-1 mutants resistant to one or multiple antiretroViral inhibitors, and the compensatory effect of mutations in the same genome, offers a compendium of the molecular intricacies that a virus can exploit for its survival. This chapter reviews the basic principles of Quasispecies dynamics as they can serve to explain the behavior of viruses.
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Fitness increase of memory genomes in a Viral Quasispecies.
Journal of molecular biology, 2004Co-Authors: Armando Arias, Carmen M. Ruiz-jarabo, Cristina Escarmís, Esteban DomingoAbstract:Viral Quasispecies may contain a subset of minority genomes that reflect those genomic sequences that were dominant at an early phase of Quasispecies evolution. Such minority genomes are referred to as memory in Viral Quasispecies. A memory marker previously characterized in foot-and-mouth disease virus (FMDV) is an internal oligoadenylate tract of variable length that became dominant upon serial plaque-to-plaque transfers of FMDV clones. During large population passages, genomes with internal oligoadenylate were outcompeted by wild-type revertants but remained in the mutant spectra as memory genomes. Here, we report a quantification of relative fitness of several FMDV clones, harboring internal oligoadenylate tracts of different length, and that were retrieved at early or late times (passage number) after implementation of memory. The results show that for any given length range of the oligoadenylate, maintenance in memory resulted in an increase in relative fitness, comparable to the increase undergone by the entire population. The fitness increase is in agreement with the Red Queen hypothesis, and implies a replicative memory mechanism. Thus, permanence of memory genomes may be a source of high fitness variants despite their initial low fitness, and despite having remained hidden in mutant spectra. This reinforces the interest of diagnosing minority genomes during chronic human and animal Viral infections.
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Emergence and selection of RNA virus variants: memory and extinction.
Virus Research, 2002Co-Authors: Esteban Domingo, Carmen M. Ruiz-jarabo, Armando Arias, Eric Baranowski, Saleta Sierra, Nonia Pariente, Cristina EscarmísAbstract:Two features of Viral Quasispecies are reviewed: the presence of memory genomes as minority components of their mutant spectra, and Viral extinction due to enhanced mutagenesis. Memory has been documented with several genetic markers of the important animal picornavirus foot-and-mouth disease virus (FMDV). The presence of memory genomes in Viral Quasispecies may accelerate their adaptive response whenever a selective constraint has already been experienced by a Viral population during previous stages of its evolution. Enhanced mutagenesis has been shown to lead to losses of infectivity of a number of RNA viruses: poliovirus, vesicular stomatitis virus, human immunodeficiency virus type 1 and FMDV. These observations, based on the theoretical prediction of the existence of a copying error-threshold for maintenance of genetic information, may contribute to the development of a new antiViral strategy.
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Memory in Viral Quasispecies
Journal of Virology, 2000Co-Authors: Carmen M. Ruiz-jarabo, Armando Arias, Eric Baranowski, Cristina Escarmís, Esteban DomingoAbstract:Biological adaptive systems share some common features: variation among their constituent elements and continuity of core information. Some of them, such as the immune system, are endowed with memory of past events. In this study we provide direct evidence that evolving Viral Quasispecies possess a molecular memory in the form of minority components that populate their mutant spectra. The experiments have involved foot-and-mouth disease virus populations with known evolutionary histories. The composition and behavior of the Viral population in response to a selective constraint were influenced by past evolutionary history in a way that could not be predicted from examination of consensus nucleotide sequences of the Viral populations. The molecular memory of the Viral Quasispecies influenced both the nature and the intensity of the response of the virus to a selective constraint.
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Viral Quasispecies and Fitness Variations
Origin and Evolution of Viruses, 1999Co-Authors: Esteban Domingo, Cristina Escarmís, Luis Menéndez-arias, John J. HollandAbstract:Publisher Summary The Quasispecies model of molecular evolution was initially proposed to describe the error-prone replication, self-organization, and adaptability of primitive replicons such as those thought to have populated the earth some 4000 million years ago. Error-prone replication has been maintained as a stable trait in present-day RNA viruses. One of the critical features that distinguish cells from viruses is the extreme difference in the complexity of their genetic material, even after accounting for repeated DNA in animal and plant cells. The dynamic mutant distributions that compose replicating RNA viruses are termed Viral Quasispecies. When the relative fitness of the evolving Quasispecies reaches a high value, even quite large population sizes can constitute an effective bottleneck and prevent continuing fitness increase. The experiments on fitness variation of viruses in cell culture have been instrumental in defining some basic influences presaging fitness evolution of Viral Quasispecies. However, in their replication in a natural setting, viruses encounter multiple changing environments and often have to cope with conflicting selective constraints. Even in a relatively constant biological and physical environment, such as vitro cell culture systems, the degree of adaptation of Viral Quasispecies may undergo remarkable quantitative variations.
Haris Vikalo - One of the best experts on this subject based on the ideXlab platform.
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A Convolutional Auto-Encoder for Haplotype Assembly and Viral Quasispecies Reconstruction
2020Co-Authors: Haris VikaloAbstract:Haplotype assembly and Viral Quasispecies reconstruction are challenging tasks concerned with analysis of genomic mixtures using sequencing data. High-throughput sequencing technologies generate enormous amounts of short fragments (reads) which essentially oversample components of a mixture; the representation redundancy enables reconstruction of the components (haplotypes, Viral strains). The reconstruction problem, known to be NP-hard, boils down to grouping together reads originating from the same component in a mixture. Existing methods struggle to solve this problem with required level of accuracy and low runtimes; the problem is becoming increasingly more challenging as the number and length of the components increase. This paper proposes a read clustering method based on a convolutional auto-encoder designed to first project sequenced fragments to a low-dimensional space and then estimate the probability of the read origin using learned embedded features. The components are reconstructed by finding consensus sequences that agglomerate reads from the same origin. Mini-batch stochastic gradient descent and dimension reduction of reads allow the proposed method to efficiently deal with massive numbers of long reads. Experiments on simulated, semi-experimental and experimental data demonstrate the ability of the proposed method to accurately reconstruct haplotypes and Viral Quasispecies, often demonstrating superior performance compared to state-of-the-art methods.
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Viral Quasispecies reconstruction via tensor factorization with successive read removal.
Bioinformatics (Oxford England), 2018Co-Authors: Soyeon Ahn, Haris VikaloAbstract:Motivation As RNA viruses mutate and adapt to environmental changes, often developing resistance to anti-Viral vaccines and drugs, they form an ensemble of Viral strains--a Viral Quasispecies. While high-throughput sequencing (HTS) has enabled in-depth studies of Viral Quasispecies, sequencing errors and limited read lengths render the problem of reconstructing the strains and estimating their spectrum challenging. Inference of Viral Quasispecies is difficult due to generally non-uniform frequencies of the strains, and is further exacerbated when the genetic distances between the strains are small. Results This paper presents TenSQR, an algorithm that utilizes tensor factorization framework to analyze HTS data and reconstruct Viral Quasispecies characterized by highly uneven frequencies of its components. Fundamentally, TenSQR performs clustering with successive data removal to infer strains in a Quasispecies in order from the most to the least abundant one; every time a strain is inferred, sequencing reads generated from that strain are removed from the dataset. The proposed successive strain reconstruction and data removal enables discovery of rare strains in a population and facilitates detection of deletions in such strains. Results on simulated datasets demonstrate that TenSQR can reconstruct full-length strains having widely different abundances, generally outperforming state-of-the-art methods at diversities 1-10% and detecting long deletions even in rare strains. A study on a real HIV-1 dataset demonstrates that TenSQR outperforms competing methods in experimental settings as well. Finally, we apply TenSQR to analyze a Zika virus sample and reconstruct the full-length strains it contains. Availability and implementation TenSQR is available at https://github.com/SoYeonA/TenSQR. Supplementary information Supplementary data are available at Bioinformatics online.
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RECOMB - aBayesQR: A Bayesian Method for Reconstruction of Viral Populations Characterized by Low Diversity.
Journal of computational biology : a journal of computational molecular cell biology, 2018Co-Authors: Soyeon Ahn, Haris VikaloAbstract:RNA viruses replicate with high mutation rates, creating closely related Viral populations. The heterogeneous virus populations, referred to as Viral Quasispecies, rapidly adapt to environmental changes thus adversely affecting efficiency of antiViral drugs and vaccines. Therefore, studying the underlying genetic heterogeneity of Viral populations plays a significant role in the development of effective therapeutic treatments. Recent high-throughput sequencing technologies have provided invaluable opportunity for uncovering the structure of Quasispecies populations. However, accurate reconstruction of Viral Quasispecies remains difficult due to limited read-lengths and presence of sequencing errors. The problem is particularly challenging when the strains in a population are highly similar, i.e., the sequences are characterized by low mutual genetic distances, and further exacerbated if some of those strains are relatively rare; this is the setting where state-of-the-art methods struggle. In this paper, we present a novel Viral Quasispecies reconstruction algorithm, aBayesQR, that employs a maximum-likelihood framework to infer individual sequences in a mixture from high-throughput sequencing data. The search for the most likely Quasispecies is conducted on long contigs that our method constructs from the set of short reads via agglomerative hierarchical clustering; operating on contigs rather than short reads enables identification of close strains in a population and provides computational tractability of the Bayesian method. Results on both simulated and real HIV-1 data demonstrate that the proposed algorithm generally outperforms state-of-the-art methods; aBayesQR particularly stands out when reconstructing a set of closely related Viral strains (e.g., Quasispecies characterized by low diversity).
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QSdpR: Viral Quasispecies reconstruction via correlation clustering.
Genomics, 2017Co-Authors: Somsubhra Barik, Shreepriya Das, Haris VikaloAbstract:RNA viruses are characterized by high mutation rates that give rise to populations of closely related genomes, known as Viral Quasispecies. Underlying heterogeneity enables the Quasispecies to adapt to changing conditions and proliferate over the course of an infection. Determining genetic diversity of a virus (i.e., inferring haplotypes and their proportions in the population) is essential for understanding its mutation patterns, and for effective drug developments. Here, we present QSdpR, a method and software for the reconstruction of Quasispecies from short sequencing reads. The reconstruction is achieved by solving a correlation clustering problem on a read-similarity graph and the results of the clustering are used to estimate frequencies of sub-species; the number of sub-species is determined using pseudo F index. Extensive tests on both synthetic datasets and experimental HIV-1 and Zika virus data demonstrate that QSdpR compares favorably to existing methods in terms of various performance metrics.
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Viral Quasispecies reconstruction via tensor factorization
Allerton Conference on Communication Control and Computing, 2017Co-Authors: Soyeon Ahn, Haris VikaloAbstract:Viral Quasispecies are heterogenous mixtures of Viral strains generated as RNA viruses mutate and adapt to environmental changes. High-throughput DNA sequencing enables reconstruction of Viral Quasispecies and estimation of their abundances, thus providing information that assists in the development of effective antiViral drugs and vaccines. In this paper, sequencing data is represented by means of a binary tensor and the Viral strains discovery is formulated as the tensor factorization problem. Performance of the proposed scheme is discussed. Results demonstrate effectiveness of the proposed algorithm.
Celia Perales - One of the best experts on this subject based on the ideXlab platform.
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Viral Quasispecies complexity measures
Virology, 2016Co-Authors: Josep Gregori, Celia Perales, Francisco Rodriguez-frias, Juan Ignacio Esteban, Josep Quer, Esteban DomingoAbstract:Mutant spectrum dynamics (changes in the related mutants that compose Viral populations) has a decisive impact on virus behavior. The several platforms of next generation sequencing (NGS) to study Viral Quasispecies offer a magnifying glass to study Viral Quasispecies complexity. Several parameters are available to quantify the complexity of mutant spectra, but they have limitations. Here we critically evaluate the information provided by several population diversity indices, and we propose the introduction of some new ones used in ecology. In particular we make a distinction between incidence, abundance and function measures of Viral Quasispecies composition. We suggest a multidimensional approach (complementary information contributed by adequately chosen indices), propose some guidelines, and illustrate the use of indices with a simple example. We apply the indices to three clinical samples of hepatitis C virus that display different population heterogeneity. Areas of virus biology in which population complexity plays a role are discussed.
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Viral Quasispecies and Lethal Mutagenesis
European Review, 2016Co-Authors: Esteban Domingo, Celia PeralesAbstract:Virology has undergone a profound transformation with the incorporation of Quasispecies theory to the understanding of the composition and dynamics of Viral populations as they cause disease. RNA Viral populations do not consist of a genome class with a defined nucleotide sequence but of a cloud or swarm or related mutants due to high mutation rates (number of incorrect nucleotides introduced per nucleotide copied) during replication. DNA and RNA viruses whose multiplication is catalysed by a low fidelity polymerase replicate close to an error threshold for maintenance of their genetic information. This means that modest increases in mutation rate jeopardize their genetic stability. Realization of this important corollary of Quasispecies theory has opened new approaches to combating Viral disease. One of these approaches is lethal mutagenesis that consists of forcing virus extinction by an excess of mutations evoked by virus-specific mutagenic agents. This article summarizes the origin and current status of this new antiViral approach.
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Species Concepts: Viral Quasispecies
Encyclopedia of Evolutionary Biology, 2016Co-Authors: Esteban Domingo, Celia PeralesAbstract:RNA viruses replicate as complex and dynamic collections of related mutants (also termed mutant spectra, distributions, clouds, or swarms), termed Viral Quasispecies. A Viral isolate is not characterized by a defined genomic sequence but by a weighted average of multitudes of related sequences. This population structure was documented by cloning-sequencing techniques, and has been confirmed by the new deep sequencing methodologies. Quasispecies dynamics explains the adaptive potential of viruses, including the response to antiViral treatments. Here we explain the Quasispecies concept, and review some of its biological implications.
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Quasispecies and Drug Resistance
2015Co-Authors: Celia Perales, Julie Sheldon, Luis Menéndez-arias, Ana M. Ortega-prieto, Nathan M. Beach, Esteban DomingoAbstract:Mutant spectra of Viral Quasispecies are complex reservoirs of genetic and phenotypic variants, including drug-resistant mutants. Here we review basic features of RNA Viral Quasispecies such as internal interactions within mutant spectra and the effect of population size and bottleneck events as they affect the frequency of inhibitor-escape mutants. Genetic barriers to resistance and fitness cost of specific amino acid substitutions involved in resistance are discussed, with specific examples for human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). Prospects for new antiViral designs aimed at counteracting the adaptive potential of Viral Quasispecies are presented. Introduction: Relevance of Quasispecies in Virus Biology Viral Quasispecies are mutant distributions (also termed mutant spectra, clouds, or swarms) that characterize genome populations of RNA viruses and at least some DNA viruses (Fig. 1). Both clonal analyses by classic nucleotide sequencing techniques and bulk population analyses by ultradeep sequencing have documented that mutant distributions are extremely complex with many minority mutations occurring at low frequency (1 % which is the present standard cutoff value for reliable mutant frequency determination and probably lower according to studies that achieved lower cutoff values). From all evidence, mutant spectra originate from high mutation rates in RNA (and some DNA) viruses, which have been estimated in 10 3 to 10 5 mutations introduced per nucleotide copied, together with competition and intrapopulation interactions among genomes [reviewed in (Domingo et al. 2012)]. Viral Quasispecies took its name from a theory of the origin of life developed by M. Eigen, P. Schuster, and their colleagues (Eigen and Schuster 1979). Theoretical studies on Quasispecies have paralleled experimental investigations with RNA viruses, reaching a considerable degree of conceptual cross-fertilization (Eigen 2013; Holland 2006; Mas et al. 2010; Ojosnegros et al. 2011). The biological behavior of Viral Quasispecies is not equivalent to that of sets of identical genomes undergoing only occasional mutations for two main reasons. One is that mutant spectra constitute vast reservoirs of genetic and phenotypic variants, including, notably, drug-, antibody-, or cytotoxic T-cell (CTL)-escape mutants. The second reason is that the variant genomes which dynamically arise, persist, increase, or decrease in frequency or are eliminated (transiently or irreversibly) do not act independently. Variants can complement each other to give rise to a new phenotype (Cao et al. 2014; Shirogane et al. 2012), to trigger large evolutionary transitions such as genome *Email: cperales@cbm.csic.es Handbook of Antimicrobial Resistance DOI 10.1007/978-1-4939-0667-3_1-1 # Springer Science+Business Media New York 2014
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From Quasispecies Theory to Viral Quasispecies: How Complexity has Permeated Virology
Mathematical Modelling of Natural Phenomena, 2012Co-Authors: Esteban Domingo, Celia PeralesAbstract:RNA viruses replicate as complex and dynamic mutant distributions. They are termed Viral Quasispecies, in recognition of the fundamental contribution of Quasispecies theory in our understanding of error-prone replicative entities. Viral Quasispecies have launched a fertile field of transdiciplinary research, both experimental and theoretical. Here we review the origin and some implications of the Quasispecies concept, with emphasis on internal interactions among components of the same mutant virus ensemble, a critical fact to design new antiViral strategies. We make the distinction between “intrinsic” and “extrinsic” properties of mutant distributions, and emphasize that there are several levels of complexity that can influence Viral Quasispecies behavior.
