In this article, a biallelic reversible mutation model with linear and quadratic selection is analyzed. The approach reconnects to one proposed by Kimura ( Possibility of extensive neutral evolution under stabilizing selection with special reference to nonrandom use of codons (PNAS,1981)), who starts from a diffusion model and derives its equilibrium distribution up to a constant. We use a boundary-mutation Moran model, which approximates a general mutation model for small effective mutation rates, and derive its equilibrium distribution for polymorphic and monomorphic variants in small to moderately sized populations. Using this model, we show that biased mutation rates and linear selection alone can cause patterns of polymorphism rates within and substitution rates between populations that are usually ascribed to balancing or overdominant selection. We illustrate this using a data set of short introns and fourfold degenerate sites from Drosophila simulans and Drosophila melanogaster.
In population genetics, extant samples are usually used for inference of past population genetic forces. With the Kingman coalescent and the backward diffusion equation, inference of the marginal likelihood proceeds from an extant sample backward in time. Conditional on an extant sample, the Moran model can also be used backward in time with identical results, up to a scaling of time. In particular, all three approaches -- the coalescent, the backward diffusion, and the Moran model -- lead to the identical marginal likelihood of the sample. If probabilities of ancestral states are also inferre…
The evolution of the allelic proportion $x$ of a biallelic locus subject to the forces of mutation and drift is investigated in a diffusion model, assuming small scaled mutation rates. The overall scaled mutation rate is parametrized with $θ=(μ_1+μ_0)N$ and the ratio of mutation rates with $α=μ_1/(μ_1+μ_0)=1-β$. The equilibrium density of this process is beta with parameters $αθ$ and $βθ$. Away from equilibrium, the transition density can be expanded into a series of modified Jacobi polynomials. If the scaled mutation rates are small, i.e., $θ\ll 1$, it may be assumed that polymorphism derives…
We derive exact formulae for the allele frequency spectrum under the coalescent with mutation, conditioned on allele counts at some fixed time in the past. We consider unlinked biallelic markers mutating according to a finite sites, or infinite sites, model. This work extends the coalescent theory of unlinked biallelic markers, enabling fast computations of allele frequency spectra in multiple populations. Our results have applications to demographic inference, species tree inference, and the analysis of genetic variation in closely related species more generally.
With the multiallelic parent-independent mutation-drift model, the equilibrium proportions of alleles are known to be Dirichlet distributed. A special case is the biallelic model, in which the proportions are beta distributed. A sample taken from these models is then Dirichlet-multinomially or beta-binomially distributed, respectively. Maximum likelihood (ML) estimators for the mutation parameters of the biallelic parent-independent mutation model are available via an expectation maximization algorithm. Assuming small scaled mutation rates, the distribution of a sample of size $M$ can be expan…
Inference of the marginal likelihood of sample allele configurations using backward algorithms yields identical results with the Kingman coalescent, the Moran model, and the diffusion model (up to a scaling of time). For inference of probabilities of ancestral population allele frequencies at any given point in the past - either of discrete ancestral allele configurations as in the coalescent, or of ancestral allele proportions as in the backward diffusion - backward approaches need to be combined with corresponding forward ones. This is done in so-called forward-backward algorithms. In this a…
The appearance of cancer in a tissue is thought to be the result of two or more successive mutations. We propose a stochastic model that allows for an exact computation of the distribution of the waiting time for a second mutation. This models the time of appearance of the first cancerous cell in a tissue. Our model is an alternative to the Moran model with mutations.
We construct an individual-based metapopulation model of population genetics featuring migration, mutation, selection and genetic drift. In the case of a single `island', the model reduces to the Moran model. Using the diffusion approximation and timescale separation arguments, an effective one-variable description of the model is developed. The effective description bears similarities to the well-mixed Moran model with effective parameters which depend on the network structure and island sizes, and is amenable to analysis. Predictions from the reduced theory match the results from stochastic …
We consider the Moran process with two populations competing under an iterated Prisoners' Dilemma in the presence of mutation, and concentrate on the case where there are multiple Evolutionarily Stable Strategies. We perform a complete bifurcation analysis of the deterministic system which arises in the infinite population size. We also study the Master equation and obtain asymptotics for the invariant distribution and metastable switching times for the stochastic process in the case of large but finite population. We also show that the stochastic system has asymmetries in the form of a skew f…
Mutation and drift play opposite roles in genetics. While mutation creates diversity, drift can cause gene variants to disappear, especially when they are rare. In the absence of natural selection and migration, the balance between the drift and mutation in a well-mixed population defines its diversity. The Moran model captures the effects of these two evolutionary forces and has a counterpart in social dynamics, known as the Voter model with external opinion influencers. Two extreme outcomes of the Voter model dynamics are consensus and coexistence of opinions, which correspond to low and hig…
The interrelationships of the fundamental biological processes natural selection, mutation, and stochastic drift are quantified by the entropy rate of Moran processes with mutation, measuring the long-run variation of a Markov process. The entropy rate is shown to behave intuitively with respect to evolutionary parameters such as monotonicity with respect to mutation probability (for the neutral landscape), relative fitness, and strength of selection. Strict upper bounds, depending only on the number of replicating types, for the entropy rate are given and the neutral fitness landscape attains…
Selection, mutation and random drift affect the dynamics of allele frequencies and consequently of quantitative traits. While the macroscopic dynamics of quantitative traits can be measured, the underlying allele frequencies are typically unobserved. Can we understand how the macroscopic observables evolve without following these microscopic processes? The problem has previously been studied by analogy with statistical mechanics: the allele frequency distribution at each time is approximated by the stationary form, which maximizes entropy. We explore the limitations of this method when mutatio…
Coalescent processes, including mutation, are derived from Moran type population models admitting large offspring numbers. Including mutation in the coalescent process allows for quantifying the turnover of alleles by computing the distribution of the number of original alleles still segregating in the population at a given time in the past. The turnover of alleles is considered for specific classes of the Moran model admitting large offspring numbers. Versions of the Kingman coalescent are also derived whose rates are functions of the mean and variance of the offspring distribution. High vari…
Selection Mechanisms, Stationary Distributions, and Reversibility in Multiallelic Moran Models
University of Massachusetts Dartmouth（麻省大学达特茅斯分校）；New England Complex Systems Institute（新英格兰复杂系统研究所）；Gleb Wataghin Institute of Physics, State University of Campinas (UNICAMP)（坎皮纳斯州立大学格莱布·瓦塔金物理学院）
Genetic contribution of advantaged ancestors in the biparental Moran model -- finite selection
Université Paris-Saclay, AgroParisTech, INRAE, UMR MIA Paris-Saclay（巴黎萨克雷大学、农业巴黎技术学院、法国国家农业食品环境研究院）；Université Paris-Saclay, CNRS, Laboratoire de mathématiques d’Orsay（巴黎萨克雷大学、法国国家科学研究中心）
We extend the Moran model with single-crossover recombination to include general recombination and mutation. We show that, in the case without resampling, the expectations of products of marginal processes defined via partitions of sites form a closed hierarchy, which is exhaustively described by a finite system of differential equations. One thus has the exceptional situation of moment closure in a nonlinear system. Surprisingly, this property is lost when resampling (i.e., genetic drift) is included.
We demonstrate a vast expansion of the theory of evolutionary stability to finite populations with mutation, connecting the theory of the stationary distribution of the Moran process with the Lyapunov theory of evolutionary stability. We define the notion of stationary stability for the Moran process with mutation and generalizations, as well as a generalized notion of evolutionary stability that includes mutation called an incentive stable state (ISS) candidate. For sufficiently large populations, extrema of the stationary distribution are ISS candidates and we give a family of Lyapunov quant…
The stationary sampling distribution of a neutral decoupled Moran or Wright-Fisher diffusion with neutral mutations is known to first order for a general rate matrix with small but otherwise unconstrained mutation rates. Using this distribution as a starting point we derive results for maximum likelihood estimates of scaled mutation rates from site frequency data under three model assumptions: a twelve-parameter general rate matrix, a nine-parameter reversible rate matrix, and a six-parameter strand-symmetric rate matrix. The site frequency spectrum is assumed to be sampled from a fixed size p…
The growing probabilities of additional offspring with the beneficial reversal allele for various population sizes, $N$, sequence lengths, $L$, selective advantages, $s$, fitness parameters, $k$, and measuring parameters, $C$, were calculated in an asymmetric sharply-peaked landscape using the decoupled continuous-time mutation-selection model. The growing probability in the stochastic region was inversely proportional to the measuring parameter when $C<1/Ns^*$, bent when $C\approx 1/Ns^*$ and became saturated when $C>1/Ns^*$, where $s^*$ is the effective selective advantage. The saturated gro…
We consider the classical Wright-Fisher model with mutation and selection. Mutations occur independently in each locus, and selection is performed according to the sharp peak landscape. In the asymptotic regime studied in [3], a quasispecies is formed. We find explicitly the distribution of this quasispecies, which turns out to be the same distribution as for the Moran model.
The formula for the probability of fixation of a new mutation is widely used in theoretical population genetics and molecular evolution. Here we derive a series of identities, inequalities and approximations for the exact probability of fixation of a new mutation under the Moran process (equivalent results hold for the approximate probability of fixation for the Wright-Fisher process after an appropriate change of variables). We show that the behavior of the logarithm of the probability of fixation is particularly simple when the selection coefficient is measured as a difference of Malthusian …
We introduce a multi-allele Wright-Fisher model with non-recurrent, reversible mutation and directional selection. In this setting, the allele frequencies at a single locus track the path of a hybrid jump-diffusion process with state space given by the vertex and edge set of a graph. Vertices represent monomorphic population states and edge-positions mark the biallelic proportions of ancestral and derived alleles during polymorphic segments. We derive the stationary distribution in mutation-selection-drift equilibrium and obtain the expected allele frequency spectrum under large population siz…
The entropy rates of the Wright-Fisher process, the Moran process, and generalizations are computed and used to compare these processes and their dependence on standard evolutionary parameters. Entropy rates are measures of the variation dependent on both short-run and long-run behavior, and allow the relationships between mutation, selection, and population size to be examined. Bounds for the entropy rate are given for the Moran process (independent of population size) and for the Wright-Fisher process (bounded for fixed population size). A generational Moran process is also presented for com…
We propose the entropy of random Markov trajectories originating and terminating at a state as a measure of the stability of a state of a Markov process. These entropies can be computed in terms of the entropy rates and stationary distributions of Markov processes. We apply this definition of stability to local maxima and minima of the stationary distribution of the Moran process with mutation and show that variations in population size, mutation rate, and strength of selection all affect the stability of the stationary extrema.
The propagation of a beneficial mutation in a spatially extended population is usually studied using the phenomenological stochastic Fisher-Kolmogorov (SFKPP) equation. We derive here an individual based, stochastic model founded on the spatial Moran process where fluctuations are treated exactly. At high selection pressure, the results of this model are different from the classical FKPP. At small selection pressure, the front behavior can be mapped into a Brownian motion with drift, the properties of which can be derived from microscopic parameters of the Moran model. Finally, we show that th…
We consider the classic Moran process modeling the spread of genetic mutations, as extended to structured populations by Lieberman et al.\ (Nature, 2005). In this process, individuals are the vertices of a connected graph $G$. Initially, there is a single mutant vertex, chosen uniformly at random. In each step, a random vertex is selected for reproduction with a probability proportional to its fitness: mutants have fitness $r>1$, while non-mutants have fitness 1. The vertex chosen to reproduce places a copy of itself to a uniformly random neighbor in $G$, replacing the individual that was ther…
We consider a multi-type Moran model (in continuous time) with selection and type-dependent mutation. This paper is concerned with the evolution of genealogical information forward in time. For this purpose we define and analytically characterize a path-valued Markov process that contains in its state at time $t$ the extended ancestral lines (adding genealogical distances) of the population alive at time $t$. The main result is a representation for the conditional distribution of the extended ancestral lines of a subpopulation alive at a fixed time $T$ (present time) given the type information…
We consider the Moran model in continuous time with two types, mutation, and selection. We concentrate on the ancestral line and its stationary type distribution. Building on work by Fearnhead (J. Appl. Prob. 39 (2002), 38-54) and Taylor (Electron. J. Probab. 12 (2007), 808-847), we characterise this distribution via the fixation probability of the offspring of all individuals of favourable type (regardless of the offspring's types). We concentrate on a finite population and stay with the resulting discrete setting all the way through. This way, we extend previous results and gain new insight …
Evolutionary game dynamics in finite populations provides a new framework to understand the selection of traits with frequency-dependent fitness. Recently, a simple but fundamental law of evolutionary dynamics, which we call σ law, describes how to determine the selection between two competing strategies: in most evolutionary processes with two strategies, A and B, strategy A is favored over B in weak selection if and only if σR + S > T + σP. This relationship holds for a wide variety of structured populations with mutation rate and weak selection under certain assumptions. In this paper, we p…
The mean fixation time of a deleterious mutant allele is studied beyond the diffusion approximation. As in Kimura's classical work [M. Kimura, Proc. Natl. Acad. Sci. U.S.A. Vol.77, 522 (1980)], that was motivated by the problem of fixation in the presence of amorphic or hypermorphic mutations, we consider a diallelic model at a single locus comprising a wild-type A and a mutant allele A' produced irreversibly from A at small uniform rate v. The relative fitnesses of the mutant homozygotes A'A', mutant heterozygotes A'A and wild-type homozygotes AA are 1-s, 1-h and 1, respectively, where it is …
