Quasispecies Made Simple

Quasispecies are clouds of genotypes that appear in a population at mutation–selection balance. This concept has recently attracted the attention of virologists, because many RNA viruses appear to generate high levels of genetic variation that may enhance the evolution of drug resistance and immune escape. The literature on these important evolutionary processes is, however, quite challenging. Here we use simple models to link mutation–selection balance theory to the most novel property of quasispecies: the error threshold—a mutation rate below which populations equilibrate in a traditional mutation–selection balance and above which the population experiences an error catastrophe, that is, the loss of the favored genotype through frequent deleterious mutations. These models show that a single fitness landscape may contain multiple, hierarchically organized error thresholds and that an error threshold is affected by the extent of back mutation and redundancy in the genotype-to-phenotype map. Importantly, an error threshold is distinct from an extinction threshold, which is the complete loss of the population through lethal mutations. Based on this framework, we argue that the lethal mutagenesis of a viral infection by mutation-inducing drugs is not a true error catastophe, but is an extinction catastrophe

Deterministic and stochastic regimes of asexual evolution on rugged fitness landscapes

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 these two limiting cases, the dynamics are described by a local quasispecies theory below a crossover time $T_{\times}$ while above $T_{\times}$, the population gets trapped at a local fitness peak and manages to find a better peak either via stochastic tunneling or double mutations. In the stochastic regime $d_\mathrm{eff} < 1$, we identify two subregimes associated with clonal interference and uphill adaptive walks, respectively. We argue that our findings are relevant to the interepretation of evolution experiments with microbial populations.Comment: Revised version, to appear in Genetics. Note on the role of selection in defining d_eff added; new figure 4 include

The Importance of DNA Repair in Tumor Suppression

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. We postulate that inactivation of post-methylation repair mechanisms are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.Comment: 7 pages, 5 figures; Approximation replaced with exact calculation; Minor error corrected; Minor changes to model syste

Quasispecies evolution in general mean-field landscapes

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.Comment: 6 pages, 2 figures, Europhysics Letters style (included) Finite-size scaling analysis sketched. To appear in Europhysics Letter