Interaction Analysis of Longevity Interventions Using Survival Curves.

A long-standing problem in ageing research is to understand how different factors contributing to longevity should be expected to act in combination under the assumption that they are independent. Standard interaction analysis compares the extension of mean lifespan achieved by a combination of interventions to the prediction under an additive or multiplicative null model, but neither model is fundamentally justified. Moreover, the target of longevity interventions is not mean life span but the entire survival curve. Here we formulate a mathematical approach for predicting the survival curve resulting from a combination of two independent interventions based on the survival curves of the individual treatments, and quantify interaction between interventions as the deviation from this prediction. We test the method on a published data set comprising survival curves for all combinations of four different longevity interventions in Caenorhabditis elegans. We find that interactions are generally weak even when the standard analysis indicates otherwise.

Greedy adaptive walks on a correlated fitness landscape.

We study adaptation of a haploid asexual population on a fitness landscape defined over binary genotype sequences of length L. We consider greedy adaptive walks in which the population moves to the fittest among all single mutant neighbors of the current genotype until a local fitness maximum is reached. The landscape is of the rough mount Fuji type, which means that the fitness value assigned to a sequence is the sum of a random and a deterministic component. The random components are independent and identically distributed random variables, and the deterministic component varies linearly with the distance to a reference sequence. The deterministic fitness gradient c is a parameter that interpolates between the limits of an uncorrelated random landscape (c=0) and an effectively additive landscape (c→∞). When the random fitness component is chosen from the Gumbel distribution, explicit expressions for the distribution of the number of steps taken by the greedy walk are obtained, and it is shown that the walk length varies non-monotonically with the strength of the fitness gradient when the starting point is sufficiently close to the reference sequence. Asymptotic results for general distributions of the random fitness component are obtained using extreme value theory, and it is found that the walk length attains a non-trivial limit for L→∞, different from its values for c=0 and c=∞, if c is scaled with L in an appropriate combination.

Phase transition in random adaptive walks on correlated fitness landscapes.

We study biological evolution on a random fitness landscape where correlations are introduced through a linear fitness gradient of strength c. When selection is strong and mutations rare the dynamics is a directed uphill walk that terminates at a local fitness maximum. We analytically calculate the dependence of the walk length on the genome size L. When the distribution of the random fitness component has an exponential tail, we find a phase transition of the walk length D between a phase at small c, where walks are short (D∼lnL), and a phase at large c, where walks are long (D∼L). For all other distributions only a single phase exists for any c>0. The considered process is equivalent to a zero temperature Metropolis dynamics for the random energy model in an external magnetic field, thus also providing insight into the aging dynamics of spin glasses.

Multidimensional epistasis and the transitory advantage of sex.

Identifying and quantifying the benefits of sex and recombination is a long-standing problem in evolutionary theory. In particular, contradictory claims have been made about the existence of a benefit of recombination on high dimensional fitness landscapes in the presence of sign epistasis. Here we present a comparative numerical study of sexual and asexual evolutionary dynamics of haploids on tunably rugged model landscapes under strong selection, paying special attention to the temporal development of the evolutionary advantage of recombination and the link between population diversity and the rate of adaptation. We show that the adaptive advantage of recombination on static rugged landscapes is strictly transitory. At early times, an advantage of recombination arises through the possibility to combine individually occurring beneficial mutations, but this effect is reversed at longer times by the much more efficient trapping of recombining populations at local fitness peaks. These findings are explained by means of well-established results for a setup with only two loci. In accordance with the Red Queen hypothesis the transitory advantage can be prolonged indefinitely in fluctuating environments, and it is maximal when the environment fluctuates on the same time scale on which trapping at local optima typically occurs.

Adaptation in tunably rugged fitness landscapes: the rough Mount Fuji model.

Much of the current theory of adaptation is based on Gillespie's mutational landscape model (MLM), which assumes that the fitness values of genotypes linked by single mutational steps are independent random variables. On the other hand, a growing body of empirical evidence shows that real fitness landscapes, while possessing a considerable amount of ruggedness, are smoother than predicted by the MLM. In the present article we propose and analyze a simple fitness landscape model with tunable ruggedness based on the rough Mount Fuji (RMF) model originally introduced by Aita et al. in the context of protein evolution. We provide a comprehensive collection of results pertaining to the topographical structure of RMF landscapes, including explicit formulas for the expected number of local fitness maxima, the location of the global peak, and the fitness correlation function. The statistics of single and multiple adaptive steps on the RMF landscape are explored mainly through simulations, and the results are compared to the known behavior in the MLM model. Finally, we show that the RMF model can explain the large number of second-step mutations observed on a highly fit first-step background in a recent evolution experiment with a microvirid bacteriophage.

Exact results for amplitude spectra of fitness landscapes.

Starting from fitness correlation functions, we calculate exact expressions for the amplitude spectra of fitness landscapes as defined by Stadler [1996. Landscapes and their correlation functions. J. Math. Chem. 20, 1] for common landscape models, including Kauffman's NK-model, rough Mount Fuji landscapes and general linear superpositions of such landscapes. We further show that correlations decaying exponentially with the Hamming distance yield exponentially decaying spectra similar to those reported recently for a model of molecular signal transduction. Finally, we compare our results for the model systems to the spectra of various experimentally measured fitness landscapes. We claim that our analytical results should be helpful when trying to interpret empirical data and guide the search for improved fitness landscape models.

Adaptive walks and extreme value theory.

We study biological evolution in a high-dimensional genotype space in the regime of rare mutations and strong selection. The population performs an uphill walk which terminates at local fitness maxima. Assigning fitness randomly to genotypes, we show that the mean walk length is logarithmic in the number of initially available beneficial mutations, with a prefactor determined by the tail of the fitness distribution. This result is derived analytically in a simplified setting where the mutational neighborhood is fixed during the adaptive process, and confirmed by numerical simulations.