A two-valued fitness landscape is introduced for the classical Eigen's quasispecies model. This fitness landscape can be considered as a direct generalization of the so-called single or sharply peaked landscape. A general, non permutation invariant quasispecies model is studied, therefore the dimension of the problem is $2^N\times 2^N$, where $N$ is the sequence length. It is shown that if the fitness function is equal to $w+s$ on a $G$-orbit $A$ and is equal to $w$ elsewhere, then the mean population fitness can be found as the largest root of an algebraic equation of degree at most $N+1$. Here $G$ is an arbitrary isometry group acting on the metric space of sequences of zeroes and ones of the length $N$ with the Hamming distance. An explicit form of this exact algebraic equation is given in terms of the spherical growth function of the $G$-orbit $A$. Sufficient conditions for the so-called error threshold for sequences of orbits are given. Motivated by the analysis of the two-valued fitness landscapes an abstract generalization of Eigen's model is introduced such that the sequences are identified with the points of a finite metric space $X$ together with a group of isometries acting transitively on $X$. In particular, a simplicial analogue of the original quasispecies model is discussed, which can be considered as a mathematical model of the switching of the antigenic variants for some bacteria.
We consider finite population size effects for Crow-Kimura and Eigen quasispecies models with single peak fitness landscape. We formulate accurately the iteration procedure for the finite population models, then derive Hamilton-Jacobi equation (HJE) to describe the dynamic of the probability distribution. The steady state solution of HJE gives the variance of the mean fitness. Our results are useful for understanding population sizes of virus in which the infinite population models can give reliable results for the biological evolution problems.
We investigate the evolutionary dynamics of a finite population of RNA sequences adapting to a neutral fitness landscape. Despite the lack of differential fitness between viable sequences, we observe typical properties of adaptive evolution, such as increase of mean fitness over time and punctuated equilibrium transitions. We discuss the implications of these results for understanding evolution at high mutation rates, and extend the relevance of the quasispecies concept to finite populations and time scales. Our results imply that the quasispecies concept and neutral drift are not complementar…
We study Eigen's quasispecies model in the asymptotic regime where the length of the genotypes goes to infinity and the mutation probability goes to 0. We give several explicit formulas for the stationary solutions of the limiting system of differential equations.
The stochastic Eigen model proposed by Feng et al. (Journal of theoretical biology, 246 (2007) 28) showed that error threshold is no longer a phase transition point but a crossover region whose width depends on the strength of the random fluctuation in an environment. The underlying cause of this phenomenon has not yet been well examined. In this article, we adopt a single peak Gaussian distributed fitness landscape instead of a constant one to investigate and analyze the change of the error threshold and the statistical property of the quasi-species population. We find a roughly linear relati…
We suggest a natural approach that leads to a modification of classical quasispecies models and incorporates the possibility of population extinction in addition to growth. The resulting modified models are called open. Their essential properties, regarding in particular equilibrium behavior, are investigated both analytically and numerically. The hallmarks of the quasispecies dynamics, viz. the heterogeneous quasispecies distribution itself and the error threshold phenomenon, can be observed in our models, along with extinction. In order to demonstrate the flexibility of the introduced framew…
We use a path integral representation to solve the Eigen and Crow-Kimura molecular evolution models for the case of multiple fitness peaks with arbitrary fitness and degradation functions. In the general case, we find that the solution to these molecular evolution models can be written as the optimum of a fitness function, with constraints enforced by Lagrange multipliers and with a term accounting for the entropy of the spreading population in sequence space. The results for the Eigen model are applied to consider virus or cancer proliferation under the control of drugs or the immune system.
We review the major progress in the rigorous analysis of the classical quasispecies model that usually comes in two related but different forms: the Eigen model and the Crow--Kimura model. The model itself was formulated almost 50 years ago, and in its stationary form represents an easy to formulate eigenvalue problem. Notwithstanding the simplicity of the problem statement, we still lack full understanding of the behavior of the mean population fitness and the quasispecies distribution for an arbitrary fitness landscape. Our main goal in this review is two-fold: First, to highlight a number o…
We study the adaptation dynamics of an initially maladapted population evolving via the elementary processes of mutation and selection. The evolution occurs on rugged fitness landscapes which are defined on the multi-dimensional genotypic space and have many local peaks separated by low fitness valleys. We mainly focus on the Eigen's model that describes the deterministic dynamics of an infinite number of self-replicating molecules. In the stationary state, for small mutation rates such a population forms a {\it quasispecies} which consists of the fittest genotype and its closely related mutan…
A particular case of the famous quasispecies model - the Crow-Kimura model with a permutation invariant fitness landscape - is investigated. Using the fact that the mutation matrix in the case of a permutation invariant fitness landscape has a special tridiagonal form, a change of the basis is suggested such that in the new coordinates a number of analytical results can be obtained. In particular, using the eigenvectors of the mutation matrix as the new basis, we show that the quasispecies distribution approaches a binomial one and give simple estimates for the speed of convergence. Another co…
We introduce a generalization of the parallel, or Crow-Kimura, and Eigen models of molecular evolution to represent the exchange of genetic information between individuals in a population. We study the effect of different schemes of genetic recombination on the steady-state mean fitness and distribution of individuals in the population, through an analytic field theoretic mapping. We investigate both horizontal gene transfer from a population and recombination between pairs of individuals. Somewhat surprisingly, these nonlinear generalizations of quasi-species theory to modern biology are anal…
The probability that an advantageous mutant rises to fixation in a viral quasispecies is investigated in the framework of multi-type branching processes. Whether fixation is possible depends on the overall growth rate of the quasispecies that will form if invasion is successful, rather than on the individual fitness of the invading mutant. The exact fixation probability can only be calculated if the fitnesses of all potential members of the invading quasispecies are known. Quasispecies fixation has two important characteristics: First, a sequence with negative selection coefficient has a posit…
This paper develops a quasispecies model that incorporates the SOS response. We consider a unicellular, asexually replicating population of organisms, whose genomes consist of a single, double-stranded DNA molecule, i.e. one chromosome. We assume that repair of post-replication mismatched base-pairs occurs with probability $ λ$, and that the SOS response is triggered when the total number of mismatched base-pairs exceeds $ l_S $. We further assume that the per-mismatch SOS elimination rate is characterized by a first-order rate constant $ κ_{SOS} $. For a single fitness peak landscape where th…
This paper develops a formulation of the quasispecies equations appropriate for polysomic, semiconservatively replicating genomes. This paper is an extension of previous work on the subject, which considered the case of haploid genomes. Here, we develop a more general formulation of the quasispecies equations that is applicable to diploid and even polyploid genomes. Interestingly, with an appropriate classification of population fractions, we obtain a system of equations that is formally identical to the haploid case. As with the work for haploid genomes, we consider both random and immortal D…
We present stochastic, finite-population formulations of the Crow-Kimura and Eigen models of quasispecies theory, for fitness functions that depend in an arbitrary way on the number of mutations from the wild type. We include back mutations in our description. We show that the fluctuation of the population numbers about the average values are exceedingly large in these physical models of evolution. We further show that horizontal gene transfer reduces by orders of magnitude the fluctuations in the population numbers and reduces the accumulation of deleterious mutations in the finite population…
Recombination is introduced into Eigen's theory of quasispecies evolution. Comparing numerical simulations of the rate equations in the non-recombining and recombining cases show that recombination has a strong effect on the error threshold and, for a wide range of mutation rates, gives rise to two stable fixed points in the dynamics. This bi-stability results in the existence of two error thresholds. We prove that, under some assumptions on the fitness landscape but for general crossover probability, a fixed point localized about the sequence with superior fitness is globally stable for low m…
We discuss a population of sequences subject to mutations and frequency-dependent selection, where the fitness of a sequence depends on the composition of the entire population. This type of dynamics is crucial to understand the evolution of genomic regulation. Mathematically, it takes the form of a reaction-diffusion problem that is nonlinear in the population state. In our model system, the fitness is determined by a simple mathematical game, the hawk-dove game. The stationary population distribution is found to be a quasispecies with properties different from those which hold in fixed fitne…
Consider a mathematical model of evolutionary adaptation of fitness landscape and mutation matrix as a reaction to population changes. As a basis, we use an open quasispecies model, which is modified to include explicit death flow. We assume that evolutionary parameters of mutation and selection processes vary in a way to maximize the mean fitness of the system. From this standpoint, Fisher's theorem of natural selection is being rethought and discussed. Another assumption is that system dynamics has two significant timescales. According to our central hypothesis, major evolutionary transition…
A quasispecies is a set of interrelated genotypes that have reached a situation of equilibrium while evolving according to the usual Darwinian principles of selection and mutation. Quasispecies studies invariably assume that it is possible for any genotype to mutate into any other, but recent finds indicate that this assumption is not necessarily true. Here we revisit the traditional quasispecies theory by adopting a network structure to constrain the occurrence of mutations. Such structure is governed by a random-graph model, whose single parameter (a probability p) controls both the graph's …
Eigen's quasispecies system with explicit space and global regulation is considered. Limit behavior and stability of the system in a functional space under perturbations of a diffusion matrix with nonnegative spectrum are investigated. It is proven that if the diffusion matrix has only positive eigenvalues then the solutions of the distributed system converge to the equilibrium solution of the corresponding local dynamical system. These results imply that the error threshold does not change if the spatial interactions under the principle of global regulation are taken into account.
We investigate the error threshold for the emergence of quasispecies in the Eigen model. By mapping to to an effective Hamiltonian ruled by the "imaginary-time" Schrödinger equation, a variational ansatz is proposed and applied to calculate various quantities associated with the quasispecies. The variational ansatz gives correct predictions for the survival population of the wild-type sequence and also reveals an unexpected universal scaling behaviors near the error threshold. We check the validity of the variational ansatz by numerical methods and find excellent agreement. Though the emergenc…
We investigate the competition between two quasispecies residing on two disparate neutral networks. Under the assumption that the two neutral networks have different topologies and fitness levels, it is the mutation rate that determines which quasispecies will eventually be driven to extinction. For small mutation rates, we find that the quasispecies residing on the neutral network with the lower replication rate will disappear. For higher mutation rates, however, the faster replicating sequences may be outcompeted by the slower replicating ones in case the connection density on the second neu…
Quasilocalization under coupled mutation-selection dynamics
Core Facility for Bioinformatics, Philippine Genome Center, University of the Philippines System（菲律宾大学系统菲律宾基因组中心核心生物设施）；National Institute of Physics, University of the Philippines Diliman（菲律宾大学迪利曼分校国家物理研究所）
We consider an asexual population evolving on rugged fitness landscapes which are defined on the multi-dimensional genotypic space and have many local optima. We track the most populated genotype as it changes when the population jumps from a fitness peak to a better one during the process of adaptation. This is done using the dynamics of the shell model which is a simplified version of the quasispecies model for infinite populations and standard Wright-Fisher dynamics for large finite populations. We show that the population fraction of a genotype obtained within the quasispecies model and th…
The quasispecies model introduced by Eigen in 1971 has close connections with the isometry group of the space of binary sequences relative to the Hamming distance metric. Generalizing this observation we introduce an abstract quasispecies model on a finite metric space $X$ together with a group of isometries $Γ$ acting transitively on $X$. We show that if the domain of the fitness function has a natural decomposition into the union of $t$ $G$-orbits, $G$ being a subgroup of $Γ$, then the dominant eigenvalue of the evolutionary matrix satisfies an algebraic equation of degree at most $t\cdot {\…
I consider a class of fitness landscapes, in which the fitness is a function of a finite number of phenotypic "traits", which are themselves linear functions of the genotype. I show that the stationary trait distribution in such a landscape can be explicitly evaluated in a suitably defined "thermodynamic limit", which is a combination of infinite-genome and strong selection limits. These considerations can be applied in particular to identify relevant features of the evolution of promoter binding sites, in spite of the shortness of the corresponding sequences.
We study Eigen's quasispecies model in the asymptotic regime where the length of the genotypes goes to infinity and the mutation probability goes to 0. A limiting infinite system of differential equations is obtained. We prove the convergence of the trajectories, as well as the convergence of the equilibrium solutions. We give the analogous results for a discrete-time version of Eigen's model, which coincides with a model proposed by Moran.
Using methods of statistical physics, we present rigorous theoretical calculations of Eigen's quasispecies theory with the truncated fitness landscape which dramatically limits the available sequence space of a reproducing quasispecies. Depending on the mutation rates, we observe three phases, a selective one, an intermediate one with some residual order and a completely randomized phase. Our results are applicable for the general case of fitness landscape.
In this article we present a new p-adic generalization of the Eigen-Schuster model where the genomes (sequences) are represented by words written in the alphabet 0,1,,p-1, where p is a prime number, with a time variable length. The time evolution of the concentration of a sequence is controlled by a p-adic evolution equation. The long term behavior of the concentration of a sequence depends on a fitness function f, a mutation measure Q, and an initial concentration distribution. The new model provides essentially two types of asymptotic scenarios for evolution. If the complexity of sequences g…
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 $ μ$, the product of sequence length and per base pair mismatch probability, exceeds $ 2 \ln \frac{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 t…
We express the Crow-Kimura and Eigen models of quasispecies theory in a functional integral representation. We formulate the spin coherent state functional integrals using the Schwinger Boson method. In this formulation, we are able to deduce the long-time behavior of these models for arbitrary replication and degradation functions. We discuss the phase transitions that occur in these models as a function of mutation rate. We derive for these models the leading order corrections to the infinite genome length limit.
The concept of fitness is introduced, and a simple derivation of the Fundamental Theorem of Natural Selection (which states that the average fitness of a population increases if its variance is nonzero) is given. After a short discussion of the adaptative walk model, a short review is given of the quasispecies approach to molecular evolution and to the error threshold. The relevance of flat fitness landscapes to molecular evolution is stressed. Finally a few examples which involve wider concepts of fitness, and in particular two-level selection, are shortly reviewed.
We study the adaptation dynamics of an initially maladapted asexual population with genotypes represented by binary sequences of length $L$. The population evolves in a maximally rugged fitness landscape with a large number of local optima. We find that whether the evolutionary trajectory is deterministic or stochastic depends on the effective mutational distance $d_{\mathrm{eff}}$ upto which the population can spread in genotype space. For $d_{\mathrm{eff}}=L$, the deterministic quasispecies theory operates while for $d_{\mathrm{eff}} < 1$, the evolution is completely stochastic. Between thes…
A simplified form of the time dependent evolutionary dynamics of a quasispecies model with a rugged fitness landscape is solved via a mapping onto a random flux model whose asymptotic behavior can be described in terms of a random walk. The statistics of the number of changes of the dominant genotype from a finite set of genotypes are exactly obtained confirming existing conjectures based on numerics.
We study a classical multitype Galton--Watson process with mutation and selection. The individuals are sequences of fixed length over a finite alphabet. On the sharp peak fitness landscape together with independent mutations per locus, we show that, as the length of the sequences goes to $\infty$ and the mutation probability goes to 0, the asymptotic relative frequency of the sequences differing on $k$ digits from the master sequence approaches $$(σe^{-a}-1)\frac{a^k}{k!}\sum_{i\geq1}\frac{i^k}{σ^i}\,,$$ where $σ$ is the selective advantage of the master sequence and $a$ is the product of the …
This Letter studies the quasispecies dynamics of a population capable of genetic repair evolving on a time-dependent fitness landscape. We develop a model that considers an asexual population of single-stranded, conservatively replicating genomes, whose only source of genetic variation is due to copying errors during replication. We consider a time-dependent, single-fitness-peak landscape where the master sequence changes by a single point mutation every time $ τ$. We are able to analytically solve for the evolutionary dynamics of the population in the point-mutation limit. In particular, our …
The quasispecies model was introduced in 1971 by Manfred Eigen to discuss the first stages of life on Earth. It provides an appealing mathematical framework to study the evolution of populations in biology, for instance viruses. We present briefly the model and we focus on its stationary solutions. These formulae have a surprisingly rich combinatorial structure, involving for instance the Eulerian and Stirling numbers, as well as the up--down coefficients of permutations.
This is an introductory review of deterministic mutation-selection models for asexual populations (i.e., quasispecies theory) and related topics. First, the basic concepts of fitness, mutations, and sequence space are introduced. Different types of mutation-selection dynamics are defined and their relation to problems of statistical physics are outlined. Then the stationary population distribution in simple, single peak fitness landscapes is discussed at length, with particular emphasis on the error threshold phenomenon. Extensions of the theory covering e.g. epistatic interactions, diploid or…
This study focuses on open quasispecies systems with competition and death flow, described by modified Eigen and Crow-Kimura models. We examine the evolutionary adaptation process as a reaction to changes in rates. One of the fundamental assumptions, which forms the basis of our mathematical model, is the existence of two different timescales: internal dynamics time and evolutionary time. The latter is much slower and exhibits significant adaptation events. These conditions allow us to represent the whole evolutionary process through a series of steady-state equations, where all the elements c…
This paper is concerned with the evolution of haploid organisms that reproduce asexually. In a seminal piece of work, Eigen and coauthors proposed the quasispecies model in an attempt to understand such an evolutionary process. Their work has impacted antiviral treatment and vaccine design strategies. Yet, predictions of the quasispecies model are at best viewed as a guideline, primarily because it assumes an infinite population size, whereas realistic population sizes can be quite small. In this paper we consider a population genetics-based model aimed at understanding the evolution of such o…
Growing efforts to measure fitness landscapes in molecular and microbial systems are premised on a tight relationship between landscape topography and evolutionary trajectories. This relationship, however, is far from being straightforward: depending on their mutation rate, Darwinian populations can climb the closest fitness peak (survival of the fittest), settle in lower regions with higher mutational robustness (survival of the flattest), or fail to adapt altogether (error catastrophes). These bifurcations highlight that evolution does not necessarily drive populations "from lower peak to hi…
We explore some aspects of the relationship between biological evolution processes and the mathematical theory of records. For Eigen's quasispecies model with an uncorrelated fitness landscape, we show that the evolutionary trajectories traced out by a population initially localized at a randomly chosen point in sequence space can be described in close analogy to record dynamics, with two complications. First, the increasing number of genotypes that become available with increasing distance from the starting point implies that fitness records are more frequent than for the standard case of ind…
We show that the Eigen model and the asexual Wright-Fisher model can be obtained as different limit cases of a unique stochastic model. This derivation makes clear which are the exact differences between these two models. The two key concepts introduced with the Eigen model, the error threshold and the quasispecies, are not affected by these differences, so that they are naturally present also in population genetics models. According to this fact, in the last part of the paper, we use the classical diploid mutation-selection equation and the single peak fitness approximation to obtain the erro…
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…
We investigate the fitness advantage associated with the robustness of a phenotype against deleterious mutations using deterministic mutation-selection models of quasispecies type equipped with a mesa shaped fitness landscape. We obtain analytic results for the robustness effect which become exact in the limit of infinite sequence length. Thereby, we are able to clarify a seeming contradiction between recent rigorous work and an earlier heuristic treatment based on a mapping to a Schrödinger equation. We exploit the quantum mechanical analogy to calculate a correction term for finite sequence …
The goal of this dissertation is to study the sequence polymorphism in retrotransposable elements of Entamoeba histolytica. The Quasispecies theory, a concept of equilibrium (stationary), has been used to understand the behaviour of these elements. Two datasets of retrotransposons of Entamoeba histolytica have been used. We present results from both datasets of retrotransposons (SINE1s) of E. histolytica. We have calculated the mutation rate of EhSINE1s for both datasets and drawn a phylogenetic tree for newly determined EhSINE1s (dataset II). We have also discussed the variation in lengths of…
We consider the quasispecies description of a population evolving in both the "master sequence" landscape (where a single sequence is evolutionarily preferred over all others) and the REM landscape (where the fitness of different sequences is an independent, identically distributed, random variable). We show that, in both cases, the error threshold is analogous to a first order thermodynamical transition, where the overlap between the average genotype and the optimal one drops discontinuously to zero.
We study self-replicating molecules under externally varying conditions. Changing conditions such as temperature variations and/or alterations in the environment's resource composition lead to both non-constant replication and decay rates of the molecules. In general, therefore, molecular evolution takes place in a dynamic rather than a static fitness landscape. We incorporate dynamic replication and decay rates into the standard quasispecies theory of molecular evolution, and show that for periodic time-dependencies, a system of evolving molecules enters a limit cycle for $t\to\infty$. For fa…
We introduce a new way to study molecular evolution within well-established Hamilton-Jacobi formalism, showing that for a broad class of fitness landscapes it is possible to derive dynamics analytically within the $1/N$-accuracy, where $N$ is genome length. For smooth and monotonic fitness function this approach gives two dynamical phases: smooth dynamics, and discontinuous dynamics. The latter phase arises naturally with no explicit singular fitness function, counter-intuitively. The Hamilton-Jacobi method yields straightforward analytical results for the models that utilize fitness as a func…
We study a continuous time model for the frequency distribution of an infinitely large asexual population in which both beneficial and deleterious mutations occur and the fitness is additive. When beneficial mutations are ignored, the exact solution for the frequency distribution is known to be a Poisson distribution. Here we include beneficial mutations and obtain exact expressions for the frequency distribution at all times using an eigenfunction expansion method. We find that the stationary distribution is non-Poissonian and related to the Bessel function of the first kind. We also provide …
The goal of this work is to propose a finite population counterpart to Eigen's model, which incorporates stochastic effects. We consider a Moran model describing the evolution of a population of size $m$ of chromosomes of length $\ell$ over an alphabet of cardinality $κ$. The mutation probability per locus is $q$. We deal only with the sharp peak landscape: the replication rate is $σ>1$ for the master sequence and 1 for the other sequences. We study the equilibrium distribution of the process in the regime where $\ell, m\to +\infty$, $q\to 0$, $\ell q \to a$, $m/\ell\toα$. We obtain an equatio…
We pursue the task of developing a finite population counterpart to Eigen's model. We consider the classical Wright-Fisher model describing the evolution of a population of size $m$ of chromosomes of length $\ell$ over an alphabet of cardinality $κ$. The mutation probability per locus is $q$. The replication rate is $σ>1$ for the master sequence and $1$ for the other sequences. We study the equilibrium distribution of the process in the regime where $\ell\to+\infty$, $m\to+\infty$, $q\to0$, $\ell q\to a\in\,]0,+\infty[$, $\frac{m}{\ell}\toα\in [0,+\infty]$. We obtain an equation $αψ(a)=\lnκ$ i…
We study general properties of the leading eigenvalue $\overline{w}(q)$ of Eigen's evolutionary matrices depending on the probability $q$ of faithful reproduction. This is a linear algebra problem that has various applications in theoretical biology, including such diverse fields as the origin of life, evolution of cancer progression, and virus evolution. We present the exact expressions for $\overline{w}(q),\overline{w}'(q),\overline{w}''(q)$ for $q=0,0.5,1$ and prove that the absolute minimum of $\overline{w}(q)$, which always exists, belongs to the interval $[0,0.5]$. For the specific case …
We investigate the evolutionary dynamics of a finite population of sequences adapting to NK fitness landscapes. We find that, unlike in the case of an infinite population, the average fitness in a finite population is maximized at a small but finite, rather than vanishing, mutation rate. The highest local maxima in the landscape are visited for even larger mutation rates, close to a transition point at which the population delocalizes (i.e., leaves the fitness peak at which it was localized) and starts traversing the sequence space. If the mutation rate is increased even further, the populatio…
A framework for the mathematical modeling of evolution in group structured populations is introduced. The population is divided into a fixed large number of groups of fixed size. From generation to generation, new groups are formed that descend from previous groups, through a two-level Fisher-Wright process, with selection between groups and within groups and with migration between groups at rate $m$. When $m=1$, the framework reduces to the often used trait-group framework, so that our setting can be seen as an extension of that approach. Our framework allows the analysis of previously introd…
