The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Esteban Domingo - One of the best experts on this subject based on the ideXlab platform.
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Future prospects for the treatment of rapidly evolving viral pathogens: insights from evolutionary biology.
Expert opinion on biological therapy, 2008Co-Authors: Esteban Domingo, Ana Grande-pérez, Verónica MartínAbstract:The evolutionary dynamics of viruses must be taken into consideration in designing preventive and therapeutic treatments. Here we review mechanisms by which viruses adapt in response to antiviral interventions. We propose combination therapy and multiepitopic vaccines as adequate to circumvent virus adaptability. An alternative design, termed lethal mutagenesis or virus entry into Error Catastrophe is presented. It exploits the high Error rates inherent in RNA virus replication, to provoke virus extinction through excess of mutations.
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foot and mouth disease virus mutant with decreased sensitivity to ribavirin implications for Error Catastrophe
Journal of Virology, 2007Co-Authors: Macarena Sierra, Antero Airaksinen, Claudia Gonzalezlopez, Ruben Agudo, Armando Arias, Esteban DomingoAbstract:The nucleoside analogue ribavirin (R) is mutagenic for foot-and-mouth disease virus (FMDV). Passage of FMDV in the presence of increasing concentrations of R resulted in the selection of FMDV with the amino acid substitution M296I in the viral polymerase (3D). Measurements of progeny production and viral fitness with chimeric viruses in the presence and absence of R documented that the 3D substitution M296I conferred on FMDV a selective replicative advantage in the presence of R but not in the absence of R. In polymerization assays, a purified mutant polymerase with I296 showed a decreased capacity to use ribavirin triphosphate as a substrate in the place of GTP and ATP, compared with the wild-type enzyme. The results suggest that M296I has been selected because it attenuates the mutagenic activity of R with FMDV. Replacement M296I is located within a highly conserved stretch in picornaviral polymerases which includes residues that interact with the template-primer complex and probably also with the incoming nucleotide, according to the three-dimensional structure of FMDV 3D. Given that a 3D substitution, distant from M296I, was associated with resistance to R in poliovirus, the results indicate that picornaviral polymerases include different domains that can alter the interaction of the enzyme with mutagenic nucleoside analogues. Implications for lethal mutagenesis are discussed.
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invariant aphthovirus consensus nucleotide sequence in the transition to Error Catastrophe
Infection Genetics and Evolution, 2005Co-Authors: Claudia Gonzalezlopez, Gema Gomezmariano, Cristina Escarmis, Esteban DomingoAbstract:RNA viruses replicate as complex distributions of non-identical but closely related variant genomes termed viral quasispecies. When the Error rate during genome replication exceeds a threshold value, the genetic information cannot be maintained and the system enters Error Catastrophe. This violation of the Error threshold results in virus extinction and it is currently being investigated as a new antiviral strategy, based on antiviral activity of some mutagenic agents. Previous studies with the important animal pathogen foot-and-mouth disease virus (FMDV) have shown that FMDV entry into Error Catastrophe is associated with an increase of complexity (mutation frequency and Shannon entropy) of the mutant spectrum of the quasispecies and that mutated, pre-extinction RNA interferes with the infectivity of standard RNA. Here, we report that despite the increase of complexity, the genomic consensus nucleotide sequence of pre-extinction FMDV RNA remains invariant, and that the fitness of pre-extinction FMDV is at least six-fold lower than the fitness of the parental viral clone, prior to mutagenic treatments. Thus, a low fitness genome ensemble can suppress replication of high fitness virus. Furthermore, the results show that profound genetic modifications associated with fitness decrease of a virus population can take place without any manifestation in the consensus genomic sequence. Thus, increase in mutant spectrum complexity and invariance of the consensus sequence characterizes FMDV extinction through Error Catastrophe.
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Mutant Viral Polymerase in the Transition of Virus to Error Catastrophe Identifies a Critical Site for RNA Binding
Journal of molecular biology, 2005Co-Authors: Armando Arias, Antero Airaksinen, Ruben Agudo, Esteban Domingo, Cristina Ferrer-orta, Rosa Pérez-luque, Emiliana Brocchi, Núria Verdaguer, Cristina EscarmisAbstract:A foot-and-mouth disease virus (FMDV) polymerase (3D) with amino acid replacements G118D, V239M and G373D (triple DMD mutant) was obtained from a molecular clone derived from a virus population treated with ribavirin, in the transition to Error Catastrophe (virus extinction through lethal mutagenesis). DMD 3D was expressed in Escherichia coli , purified, and its activity compared with that of wild-type enzyme and mutant enzymes with either replacement G118D, G118A or D338A (the latter affecting the catalytic motif YGDD), generated by site-directed mutagenesis. No differences among the enzymes were noted in their interaction with monoclonal antibodies specific for the FMDV polymerase. Mutant enzymes with G118D or G118A showed a 100-fold decrease in polymerization activity relative to wild-type 3D, using poly(A)/oligo(dT) 15 and poly(A)/VPg as template-primers, under several reaction conditions. As expected, the activity of 3D with D338A was undetectable (
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Quasispecies dynamics and RNA virus extinction
Virus research, 2005Co-Authors: Esteban Domingo, Cristina Escarmis, Ester Lázaro, Susanna C. ManrubiaAbstract:The extinction of foot-and-mouth disease virus (FMDV) is strongly influenced by mutation rates, types of mutations, relative viral fitness and virus population regimens during infection. Here we review experimental results and theoretical models that describe a contrast between the effective extinction of FMDV subjected to increased mutagenesis, and the remarkable resistance to extinction of the same and related FMDV clones subjected to serial bottleneck events. The results suggest procedures to master key parameters to develop effective antiviral strategies based on virus entry into Error Catastrophe.
Eugene I. Shakhnovich - One of the best experts on this subject based on the ideXlab platform.
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Genetic instability and the quasispecies model.
Journal of theoretical biology, 2006Co-Authors: Yisroel Brumer, Franziska Michor, Eugene I. ShakhnovichAbstract:Genetic instability is a defining characteristic of cancers. Microsatellite instability (MIN) leads to by elevated point mutation rates, whereas chromosomal instability (CIN) refers to increased rates of losing or gaining whole chromosomes or parts of chromosomes during cell division. CIN and MIN are, in general, mutually exclusive. The quasispecies model is a very successful theoretical framework for the study of evolution at high mutation rates. It predicts the existence of an experimentally verified Error Catastrophe. This Catastrophe occurs when the mutation rates exceed a threshold value, the Error threshold, above which replicative infidelity is incompatible with cell survival. We analyse the semiconservative quasispecies model of both MIN and CIN tumors. We consider the role of post-methylation DNA repair in tumor cells and demonstrate that DNA repair is fundamental to the nature of the Error Catastrophe in both types of tumors. We find that CIN introduces a plateau in the maximum viable mutation rate for a repair-free model, which does not exist in the case of MIN. This provides a plausible explanation for the mutual exclusivity of CIN and MIN.
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solution of the quasispecies model for an arbitrary gene network
Physical Review E, 2004Co-Authors: Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this paper, we study the equilibrium behavior of Eigen's quasispecies equations for an arbitrary gene network. We consider a genome consisting of $N$ genes, so that the full genome sequence $\ensuremath{\sigma}$ may be written as $\ensuremath{\sigma}={\ensuremath{\sigma}}_{1}{\ensuremath{\sigma}}_{2}\ensuremath{\cdots}{\ensuremath{\sigma}}_{N}$, where ${\ensuremath{\sigma}}_{i}$ are sequences of individual genes. We assume a single fitness peak model for each gene, so that gene $i$ has some ``master'' sequence ${\ensuremath{\sigma}}_{i,0}$ for which it is functioning. The fitness landscape is then determined by which genes in the genome are functioning and which are not. The equilibrium behavior of this model may be solved in the limit of infinite sequence length. The central result is that, instead of a single Error Catastrophe, the model exhibits a series of localization to delocalization transitions, which we term an ``Error cascade.'' As the mutation rate is increased, the selective advantage for maintaining functional copies of certain genes in the network disappears, and the population distribution delocalizes over the corresponding sequence spaces. The network goes through a series of such transitions, as more and more genes become inactivated, until eventually delocalization occurs over the entire genome space, resulting in a final Error Catastrophe. This model provides a criterion for determining the conditions under which certain genes in a genome will lose functionality due to genetic drift. It also provides insight into the response of gene networks to mutagens. In particular, it suggests an approach for determining the relative importance of various genes to the fitness of an organism, in a more accurate manner than the standard ``deletion set'' method. The results in this paper also have implications for mutational robustness and what C.O. Wilke termed ``survival of the flattest.''
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Solution of the quasispecies model for an arbitrary gene network.
Physical review. E Statistical nonlinear and soft matter physics, 2004Co-Authors: Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this paper, we study the equilibrium behavior of Eigen's quasispecies equations for an arbitrary gene network. We consider a genome consisting of N genes, so that the full genome sequence sigma may be written as sigma= sigma1sigma2...sigmaN, where sigma(i) are sequences of individual genes. We assume a single fitness peak model for each gene, so that gene i has some "master" sequence sigma(i,0) for which it is functioning. The fitness landscape is then determined by which genes in the genome are functioning and which are not. The equilibrium behavior of this model may be solved in the limit of infinite sequence length. The central result is that, instead of a single Error Catastrophe, the model exhibits a series of localization to delocalization transitions, which we term an "Error cascade." As the mutation rate is increased, the selective advantage for maintaining functional copies of certain genes in the network disappears, and the population distribution delocalizes over the corresponding sequence spaces. The network goes through a series of such transitions, as more and more genes become inactivated, until eventually delocalization occurs over the entire genome space, resulting in a final Error Catastrophe. This model provides a criterion for determining the conditions under which certain genes in a genome will lose functionality due to genetic drift. It also provides insight into the response of gene networks to mutagens. In particular, it suggests an approach for determining the relative importance of various genes to the fitness of an organism, in a more accurate manner than the standard "deletion set" method. The results in this paper also have implications for mutational robustness and what C.O. Wilke termed "survival of the flattest."
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Semiconservative replication in the quasispecies model.
Physical review. E Statistical nonlinear and soft matter physics, 2004Co-Authors: Emmanuel Tannenbaum, Eric J Deeds, Eugene I. ShakhnovichAbstract:This paper extends Eigen's quasispecies equations to account for the semiconservative nature of DNA replication. We solve the equations in the limit of infinite sequence length for the simplest case of a static, sharply peaked fitness landscape. We show that the Error Catastrophe occurs when micro, the product of sequence length and per base pair mismatch probability, exceeds 2 ln [2/ ( 1+1/k ) ], where k>1 is the first-order growth rate constant of the viable "master" sequence (with all other sequences having a first-order growth rate constant of 1 ). This is in contrast to the result of ln k for conservative replication. In particular, as k--> infinity, the Error Catastrophe is never reached for conservative replication, while for semiconservative replication the critical micro approaches 2 ln 2. Semiconservative replication is therefore considerably less robust than conservative replication to the effect of replication Errors. We also show that the mean equilibrium fitness of a semiconservatively replicating system is given by k ( 2 e(-micro/2) -1 ) below the Error Catastrophe, in contrast to the standard result of k e(-micro) for conservative replication (derived by Kimura and Maruyama in 1966). From this result it is readily shown that semiconservative replication is necessary to account for the observation that, at sufficiently high mutagen concentrations, faster replicating cells will die more quickly than more slowly replicating cells. Thus, in contrast to Eigen's original model, the semiconservative quasispecies equations are able to provide a mathematical basis for explaining the efficacy of mutagens as chemotherapeutic agents.
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Imperfect DNA Repair and the Error Catastrophe
arXiv: Biomolecules, 2004Co-Authors: Yisroel Brumer, Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this Letter, we extend the semiconservative quasispecies equations to incorporate imperfect DNA lesion repair. We study the equilibrium behavior of this model in the limit of infinite sequence length and population size, using a single-fitness-peak landscape for which the master genome can sustain a finite number of lesions and remain viable. We provide a full analytical treatment of the problem, providing a general mathematical framework as well as the full solution for a particular class of fitness landscapes. Stochastic simulations using finite sequence lengths and populations agree well with the analytical results. Applications to biological systems are briefly discussed.
Craig E Cameron - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of a Universal 5-Nitroindole Ribonucleotide and Incorporation into RNA by a Viral RNA-Dependent RNA Polymerase
Chembiochem : a European journal of chemical biology, 2007Co-Authors: Daniel A. Harki, Craig E Cameron, Jason D. Graci, Jocelyn P. Edathil, Christian Castro, Blake R. PetersonAbstract:Small molecules that mimic natural nucleosides and nucleotides comprise a major class of antiviral agents. A new approach to the design of these compounds focuses on the generation of lethal mutagens:[1, 2] compounds that further accelerate the high rate of viral mutagenesis[3, 4] to confer antiviral effects. By incorporating artificial nucleobases with degenerate base-pairing abilities into viral genomes, lethal mutagens increase viral genomic mutagenesis to intolerable levels during replication, a process termed “Error Catastrophe”, which results in the loss of viral viability.[5, 6] The antiviral drug ribavirin (1) is one such lethal mutagen effective against the RNA viruses poliovirus (PV) [7] and hepatitis C virus.[8] Ribavirin is converted intracellularly to the 5′-triphosphate (RTP), which is a substrate for viral RNA-dependent RNA polymerases (RdRP). By mimicking the natural purines, RTP is misincorporated opposite pyrimidines in the enzyme-bound viral RNA template. The incorporated nucleobase of ribavirin promotes genomic mutatagenesis by templating C and U during subsequent rounds of viral replication; this facilitates Error Catastrophe and loss of viral viability.[7, 9–11]
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challenges for the development of ribonucleoside analogues as inducers of Error Catastrophe
Antiviral Chemistry & Chemotherapy, 2004Co-Authors: Jason D. Graci, Craig E CameronAbstract:©2004 International Medical Press 0956-3202/02/$17.00 The term riboviruses encompasses viruses with single- and double-stranded RNA genomes and also retroviruses, which are RNA-based for a portion of their lifecycle. Riboviruses are significant pathogens, causing diseases ranging from the common cold to exotic illnesses such as haemorrhagic fever, and also epidemic diseases such as AIDS and hepatitis C. Riboviruses are also prominent among emerging diseases (recently with SARS-associated coronavirus), and represent potential agents of biotErrorism. As such, developing effective treatments for the diseases caused by riboviruses is both a public health and homeland security priority. Unfortunately, few effective antiviral agents exist to combat these diseases. The development of broadly effective therapeutics has been hampered by the tremendous diversity of riboviruses, as well as the ability of these viruses to rapidly adapt and acquire resistance to treatments. This adaptability is a direct reflection of the extremely high mutation frequency exhibited by riboviruses, resulting in a heterogeneous virus population or quasispecies. Recently, compelling evidence has accumulated in support of a new antiviral strategy called ‘lethal mutagenesis’. This strategy attempts to exploit the high mutation frequency of riboviruses by increasing the mutation frequency even further and driving the virus population into Error Catastrophe. Error Catastrophe is marked by an increase in mutation frequency beyond a threshold that supports viability. Here we review our current understanding of quasispecies, Error Catastrophe and lethal mutagenesis. Additionally, we describe ribavarin’s mechanism of action and discuss problems that need to be overcome in order to design new and more potent lethal mutagens.
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Challenges for the development of ribonucleoside analogues as inducers of Error Catastrophe.
Antiviral chemistry & chemotherapy, 2004Co-Authors: Jason D. Graci, Craig E CameronAbstract:RNA viruses are responsible for numerous human diseases; some of these viruses are also potential agents of biotErrorism. In general, the replication of RNA viruses results in the incorporation of at least one mutation per round of replication, leading to a heterogeneous population, termed a quasispecies. The antiviral nucleoside ribavirin has been shown to cause an increase in the mutation frequency of RNA viruses. This increase in mutation frequency leads to a loss of viability due to Error Catastrophe. In this article, we review lethal mutagenesis as an antiviral strategy, emphasizing the challenges remaining for the development of lethal mutagenesis into a practical clinical approach.
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Lethal mutagens: broad-spectrum antivirals with limited potential for development of resistance?
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2004Co-Authors: Marion S. Freistadt, Glen Meades, Craig E CameronAbstract:RNA virus populations display extreme sequence variation. It is thought that this heterogeneity is advantageous to the population, permitting adaptation to rapidly changing environments that present varying types and degrees of selective pressure. A consequence of this efficient evolution of RNA viruses is the susceptibility of these viruses to compounds that further increase sequence variation as these agents force the virus into Error Catastrophe. Therefore, lethal mutagenesis, induction of Error Catastrophe, represents an important, untapped strategy for development of antiviral agents. This article briefly describes the theoretical and experimental data supporting lethal mutagenesis as an antiviral strategy and discusses host and viral mechanisms for development of resistance to ribavirin, a representative of this class of antiviral agents.
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Quasispecies, Error Catastrophe, and the Antiviral Activity of Ribavirin
Virology, 2002Co-Authors: Jason D. Graci, Craig E CameronAbstract:Ribavirin is the first synthetic, broad-spectrum antiviral nucleoside. Despite its more than 30 year history, the mechanism of action of this compound remains unclear and somewhat controversial. Recent data suggest the possibility that the activity of ribavirin against RNA viruses is a reflection of incorporation of ribavirin into the viral genome. Because ribavirin incorporation is not specific, this event leads to lethal mutagenesis of the virus population. The data supporting this new proposal for the mechanism of action of ribavirin are reviewed herein. In addition, we discuss briefly the challenges that remain for development of lethal mutagenesis as an effective antiviral strategy.
David J. Barton - One of the best experts on this subject based on the ideXlab platform.
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an extended primer grip of picornavirus polymerase facilitates sexual rna replication mechanisms
Journal of Virology, 2020Co-Authors: Brian J. Kempf, Colleen L. Watkins, Olve B. Peersen, David J. BartonAbstract:Picornaviruses have both asexual and sexual RNA replication mechanisms. Asexual RNA replication mechanisms involve one parental template, whereas sexual RNA replication mechanisms involve two or more parental templates. Because sexual RNA replication mechanisms counteract ribavirin-induced Error Catastrophe, we selected for ribavirin-resistant poliovirus to identify polymerase residues that facilitate sexual RNA replication mechanisms. We used serial passage in ribavirin, beginning with a variety of ribavirin-sensitive and ribavirin-resistant parental viruses. Ribavirin-sensitive virus contained an L420A polymerase mutation, while ribavirin-resistant virus contained a G64S polymerase mutation. A G64 codon mutation (G64Fix) was used to inhibit emergence of G64S-mediated ribavirin resistance. Revertants (L420) or pseudorevertants (L420V and L420I) were selected from all independent lineages of L420A, G64Fix L420A, and G64S L420A parental viruses. Ribavirin resistance G64S mutations were selected in two independent lineages, and novel ribavirin resistance mutations were selected in the polymerase in other lineages (M299I, M323I, M392V, and T353I). The structural orientation of M392, immediately adjacent to L420 and the polymerase primer grip region, led us to engineer additional polymerase mutations into poliovirus (M392A, M392L, M392V, K375R, and R376K). L420A revertants and pseudorevertants (L420V and L420I) restored efficient viral RNA recombination, confirming that ribavirin-induced Error Catastrophe coincides with defects in sexual RNA replication mechanisms. Viruses containing M392 mutations (M392A, M392L, and M392V) and primer grip mutations (K375R and R376K) exhibited divergent RNA recombination, ribavirin sensitivity, and biochemical phenotypes, consistent with changes in the fidelity of RNA synthesis. We conclude that an extended primer grip of the polymerase, including L420, M392, K375, and R376, contributes to the fidelity of RNA synthesis and to efficient sexual RNA replication mechanisms.IMPORTANCE Picornaviruses have both asexual and sexual RNA replication mechanisms. Sexual RNA replication shapes picornavirus species groups, contributes to the emergence of vaccine-derived polioviruses, and counteracts Error Catastrophe. Can viruses distinguish between homologous and nonhomologous partners during sexual RNA replication? We implicate an extended primer grip of the viral polymerase in sexual RNA replication mechanisms. By sensing RNA sequence complementarity near the active site, the extended primer grip of the polymerase has the potential to distinguish between homologous and nonhomologous RNA templates during sexual RNA replication.
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an extended primer grip of picornavirus polymerase facilitates sexual rna replication mechanisms
bioRxiv, 2019Co-Authors: Brian J. Kempf, Colleen L. Watkins, Olve B. Peersen, David J. BartonAbstract:Picornaviruses have both asexual and sexual RNA replication mechanisms. Asexual RNA replication mechanisms involve one parental template whereas sexual RNA replication mechanisms involve two or more parental templates. Because sexual RNA replication mechanisms counteract ribavirin-induced Error Catastrophe, we selected for ribavirin-resistant poliovirus to identify polymerase residues that facilitate sexual RNA replication mechanisms. We used serial passage in ribavirin, beginning with a variety of ribavirin-sensitive and ribavirin-resistant parental viruses. Ribavirin-sensitive virus contained an L420A polymerase mutation while ribavirin-resistant virus contained a G64S polymerase mutation. A G64 codon mutation (G64Fix) was used to inhibit emergence of G64S-mediated ribavirin resistance. Revertants (L420) or pseudo-revertants (L420V, L420I) were selected from all independent lineages of L420A, G64Fix L420A and G64S L420A parental viruses. Ribavirin-resistant G64S mutations were selected in two independent lineages and novel ribavirin-resistance mutations were selected in the polymerase in other lineages (M299I, M323I, M392V, T353I). The structural orientation of M392, immediately adjacent to L420 and the polymerase primer grip region, led us to engineer additional polymerase mutations into poliovirus (M392A, M392L & M392V and K375R & R376K). L420A revertants and pseudorevertants (L420V, L420I) restored efficient sexual RNA replication mechanisms, confirming that ribavirin-induced Error Catastrophe coincides with defects in sexual RNA replication mechanisms. Viruses containing M392 mutations (M392A, M392L & M392V) and primer grip mutations (K375R & R376K) exhibited divergent RNA recombination, ribavirin sensitivity and biochemical phenotypes, consistent with changes in the fidelity of RNA synthesis. We conclude that an extended primer grip of the polymerase, including L420, M392, K375 & R376, contributes to the fidelity of RNA synthesis and to efficient sexual RNA replication mechanisms.
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Picornavirus RNA Recombination Counteracts Error Catastrophe.
Journal of virology, 2019Co-Authors: Brian J. Kempf, Colleen L. Watkins, Olve B. Peersen, David J. BartonAbstract:Template-dependent RNA replication mechanisms render picornaviruses susceptible to Error Catastrophe, an overwhelming accumulation of mutations incompatible with viability. Viral RNA recombination, in theory, provides a mechanism for viruses to counteract Error Catastrophe. We tested this theory by exploiting well-defined mutations in the poliovirus RNA-dependent RNA polymerase (RDRP), namely, a G64S mutation and an L420A mutation. Our data reveal two distinct mechanisms by which picornaviral RDRPs influence Error Catastrophe: fidelity of RNA synthesis and RNA recombination. A G64S mutation increased the fidelity of the viral polymerase and rendered the virus resistant to ribavirin-induced Error Catastrophe, but only when RNA recombination was at wild-type levels. An L420A mutation in the viral polymerase inhibited RNA recombination and exacerbated ribavirin-induced Error Catastrophe. Furthermore, when RNA recombination was substantially reduced by an L420A mutation, a high-fidelity G64S polymerase failed to make the virus resistant to ribavirin. These data indicate that viral RNA recombination is required for poliovirus to evade ribavirin-induced Error Catastrophe. The conserved nature of L420 within RDRPs suggests that RNA recombination is a common mechanism for picornaviruses to counteract and avoid Error Catastrophe.IMPORTANCE Positive-strand RNA viruses produce vast amounts of progeny in very short periods of time via template-dependent RNA replication mechanisms. Template-dependent RNA replication, while efficient, can be disadvantageous due to Error-prone viral polymerases. The accumulation of mutations in viral RNA genomes leads to Error Catastrophe. In this study, we substantiate long-held theories regarding the advantages and disadvantages of asexual and sexual replication strategies among RNA viruses. In particular, we show that picornavirus RNA recombination counteracts the negative consequences of asexual template-dependent RNA replication mechanisms, namely, Error Catastrophe.
Emmanuel Tannenbaum - One of the best experts on this subject based on the ideXlab platform.
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Second-Order Catalytic Quasispecies Yields First-Order Phase Transition
arXiv: Populations and Evolution, 2009Co-Authors: Nathaniel Wagner, Emmanuel Tannenbaum, Gonen AshkenasyAbstract:The quasispecies model describes processes related to the origin of life and viral evolutionary dynamics. We discuss how the Error Catastrophe that reflects the transition from localized to delocalized quasispecies population is affected by catalytic replication of different reaction orders. Specifically, we find that 2nd order mechanisms lead to 1st order discontinuous phase transitions in the viable population fraction, and conclude that the "higher" the interaction the "lower" the transition. We discuss potential implications for understanding the replication of highly mutating RNA viruses.
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solution of the quasispecies model for an arbitrary gene network
Physical Review E, 2004Co-Authors: Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this paper, we study the equilibrium behavior of Eigen's quasispecies equations for an arbitrary gene network. We consider a genome consisting of $N$ genes, so that the full genome sequence $\ensuremath{\sigma}$ may be written as $\ensuremath{\sigma}={\ensuremath{\sigma}}_{1}{\ensuremath{\sigma}}_{2}\ensuremath{\cdots}{\ensuremath{\sigma}}_{N}$, where ${\ensuremath{\sigma}}_{i}$ are sequences of individual genes. We assume a single fitness peak model for each gene, so that gene $i$ has some ``master'' sequence ${\ensuremath{\sigma}}_{i,0}$ for which it is functioning. The fitness landscape is then determined by which genes in the genome are functioning and which are not. The equilibrium behavior of this model may be solved in the limit of infinite sequence length. The central result is that, instead of a single Error Catastrophe, the model exhibits a series of localization to delocalization transitions, which we term an ``Error cascade.'' As the mutation rate is increased, the selective advantage for maintaining functional copies of certain genes in the network disappears, and the population distribution delocalizes over the corresponding sequence spaces. The network goes through a series of such transitions, as more and more genes become inactivated, until eventually delocalization occurs over the entire genome space, resulting in a final Error Catastrophe. This model provides a criterion for determining the conditions under which certain genes in a genome will lose functionality due to genetic drift. It also provides insight into the response of gene networks to mutagens. In particular, it suggests an approach for determining the relative importance of various genes to the fitness of an organism, in a more accurate manner than the standard ``deletion set'' method. The results in this paper also have implications for mutational robustness and what C.O. Wilke termed ``survival of the flattest.''
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Solution of the quasispecies model for an arbitrary gene network.
Physical review. E Statistical nonlinear and soft matter physics, 2004Co-Authors: Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this paper, we study the equilibrium behavior of Eigen's quasispecies equations for an arbitrary gene network. We consider a genome consisting of N genes, so that the full genome sequence sigma may be written as sigma= sigma1sigma2...sigmaN, where sigma(i) are sequences of individual genes. We assume a single fitness peak model for each gene, so that gene i has some "master" sequence sigma(i,0) for which it is functioning. The fitness landscape is then determined by which genes in the genome are functioning and which are not. The equilibrium behavior of this model may be solved in the limit of infinite sequence length. The central result is that, instead of a single Error Catastrophe, the model exhibits a series of localization to delocalization transitions, which we term an "Error cascade." As the mutation rate is increased, the selective advantage for maintaining functional copies of certain genes in the network disappears, and the population distribution delocalizes over the corresponding sequence spaces. The network goes through a series of such transitions, as more and more genes become inactivated, until eventually delocalization occurs over the entire genome space, resulting in a final Error Catastrophe. This model provides a criterion for determining the conditions under which certain genes in a genome will lose functionality due to genetic drift. It also provides insight into the response of gene networks to mutagens. In particular, it suggests an approach for determining the relative importance of various genes to the fitness of an organism, in a more accurate manner than the standard "deletion set" method. The results in this paper also have implications for mutational robustness and what C.O. Wilke termed "survival of the flattest."
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Semiconservative replication in the quasispecies model.
Physical review. E Statistical nonlinear and soft matter physics, 2004Co-Authors: Emmanuel Tannenbaum, Eric J Deeds, Eugene I. ShakhnovichAbstract:This paper extends Eigen's quasispecies equations to account for the semiconservative nature of DNA replication. We solve the equations in the limit of infinite sequence length for the simplest case of a static, sharply peaked fitness landscape. We show that the Error Catastrophe occurs when micro, the product of sequence length and per base pair mismatch probability, exceeds 2 ln [2/ ( 1+1/k ) ], where k>1 is the first-order growth rate constant of the viable "master" sequence (with all other sequences having a first-order growth rate constant of 1 ). This is in contrast to the result of ln k for conservative replication. In particular, as k--> infinity, the Error Catastrophe is never reached for conservative replication, while for semiconservative replication the critical micro approaches 2 ln 2. Semiconservative replication is therefore considerably less robust than conservative replication to the effect of replication Errors. We also show that the mean equilibrium fitness of a semiconservatively replicating system is given by k ( 2 e(-micro/2) -1 ) below the Error Catastrophe, in contrast to the standard result of k e(-micro) for conservative replication (derived by Kimura and Maruyama in 1966). From this result it is readily shown that semiconservative replication is necessary to account for the observation that, at sufficiently high mutagen concentrations, faster replicating cells will die more quickly than more slowly replicating cells. Thus, in contrast to Eigen's original model, the semiconservative quasispecies equations are able to provide a mathematical basis for explaining the efficacy of mutagens as chemotherapeutic agents.
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Imperfect DNA Repair and the Error Catastrophe
arXiv: Biomolecules, 2004Co-Authors: Yisroel Brumer, Emmanuel Tannenbaum, Eugene I. ShakhnovichAbstract:In this Letter, we extend the semiconservative quasispecies equations to incorporate imperfect DNA lesion repair. We study the equilibrium behavior of this model in the limit of infinite sequence length and population size, using a single-fitness-peak landscape for which the master genome can sustain a finite number of lesions and remain viable. We provide a full analytical treatment of the problem, providing a general mathematical framework as well as the full solution for a particular class of fitness landscapes. Stochastic simulations using finite sequence lengths and populations agree well with the analytical results. Applications to biological systems are briefly discussed.