Unsupervised inference of protein fitness landscape from deep mutational scan

The recent technological advances underlying the screening of large combinatorial libraries in high- throughput mutational scans, deepen our understanding of adaptive protein evolution and boost its applications in protein design. Nevertheless, the large number of possible genotypes requires suitable computational methods for data analysis, the prediction of mutational effects and the generation of optimized sequences. We describe a computational method that, trained on sequencing samples from multiple rounds of a screening experiment, provides a model of the genotype-fitness relationship. We tested the method on five large-scale mutational scans, yielding accurate predictions of the mutational effects on fitness. The inferred fitness landscape is robust to experimental and sampling noise and exhibits high generalization power in terms of broader sequence space exploration and higher fitness variant predictions. We investigate the role of epistasis and show that the inferred model provides structural information about the 3D contacts in the molecular fold

Set-based Multiobjective Fitness Landscapes: A Preliminary Study

Fitness landscape analysis aims to understand the geometry of a given optimization problem in order to design more efficient search algorithms. However, there is a very little knowledge on the landscape of multiobjective problems. In this work, following a recent proposal by Zitzler et al. (2010), we consider multiobjective optimization as a set problem. Then, we give a general definition of set-based multiobjective fitness landscapes. An experimental set-based fitness landscape analysis is conducted on the multiobjective NK-landscapes with objective correlation. The aim is to adapt and to enhance the comprehensive design of set-based multiobjective search approaches, motivated by an a priori analysis of the corresponding set problem properties

Evidence of coevolution in multi-objective evolutionary algorithms

This paper demonstrates that simple yet important characteristics of coevolution can occur in evolutionary algorithms when only a few conditions are met. We find that interaction-based fitness measurements such as fitness (linear) ranking allow for a form of coevolutionary dynamics that is observed when 1) changes are made in what solutions are able to interact during the ranking process and 2) evolution takes place in a multi-objective environment. This research contributes to the study of simulated evolution in a at least two ways. First, it establishes a broader relationship between coevolution and multi-objective optimization than has been previously considered in the literature. Second, it demonstrates that the preconditions for coevolutionary behavior are weaker than previously thought. In particular, our model indicates that direct cooperation or competition between species is not required for coevolution to take place. Moreover, our experiments provide evidence that environmental perturbations can drive coevolutionary processes; a conclusion that mirrors arguments put forth in dual phase evolution theory. In the discussion, we briefly consider how our results may shed light onto this and other recent theories of evolution

Multi-layer local optima networks for the analysis of advanced local search-based algorithms

A Local Optima Network (LON) is a graph model that compresses the fitness landscape of a particular combinatorial optimization problem based on a specific neighborhood operator and a local search algorithm. Determining which and how landscape features affect the effectiveness of search algorithms is relevant for both predicting their performance and improving the design process. This paper proposes the concept of multi-layer LONs as well as a methodology to explore these models aiming at extracting metrics for fitness landscape analysis. Constructing such models, extracting and analyzing their metrics are the preliminary steps into the direction of extending the study on single neighborhood operator heuristics to more sophisticated ones that use multiple operators. Therefore, in the present paper we investigate a twolayer LON obtained from instances of a combinatorial problem using bitflip and swap operators. First, we enumerate instances of NK-landscape model and use the hill climbing heuristic to build the corresponding LONs. Then, using LON metrics, we analyze how efficiently the search might be when combining both strategies. The experiments show promising results and demonstrate the ability of multi-layer LONs to provide useful information that could be used for in metaheuristics based on multiple operators such as Variable Neighborhood Search.Comment: Accepted in GECCO202

Visualising Basins of Attraction for the Cross-Entropy and the Squared Error Neural Network Loss Functions

Quantification of the stationary points and the associated basins of attraction of neural network loss surfaces is an important step towards a better understanding of neural network loss surfaces at large. This work proposes a novel method to visualise basins of attraction together with the associated stationary points via gradient-based random sampling. The proposed technique is used to perform an empirical study of the loss surfaces generated by two different error metrics: quadratic loss and entropic loss. The empirical observations confirm the theoretical hypothesis regarding the nature of neural network attraction basins. Entropic loss is shown to exhibit stronger gradients and fewer stationary points than quadratic loss, indicating that entropic loss has a more searchable landscape. Quadratic loss is shown to be more resilient to overfitting than entropic loss. Both losses are shown to exhibit local minima, but the number of local minima is shown to decrease with an increase in dimensionality. Thus, the proposed visualisation technique successfully captures the local minima properties exhibited by the neural network loss surfaces, and can be used for the purpose of fitness landscape analysis of neural networks.Comment: Preprint submitted to the Neural Networks journa

Microbial metal resistance and metabolism across dynamic landscapes: high-throughput environmental microbiology.

Multidimensional gradients of inorganic compounds influence microbial activity in diverse pristine and anthropogenically perturbed environments. Here, we suggest that high-throughput cultivation and genetics can be systematically applied to generate quantitative models linking gene function, microbial community activity, and geochemical parameters. Metal resistance determinants represent a uniquely universal set of parameters around which to study and evaluate microbial fitness because they represent a record of the environment in which all microbial life evolved. By cultivating microbial isolates and enrichments in laboratory gradients of inorganic ions, we can generate quantitative predictions of limits on microbial range in the environment, obtain more accurate gene annotations, and identify useful strategies for predicting and engineering the trajectory of natural ecosystems