Evolution enhances mutational robustness and suppresses the emergence of a new phenotype: A new computational approach for studying evolution

The aim of this paper is two-fold. First, we propose a new computational method to investigate the particularities of evolution. Second, we apply this method to a model of gene regulatory networks (GRNs) and explore the evolution of mutational robustness and bistability. Living systems have developed their functions through evolutionary processes. To understand the particularities of this process theoretically, evolutionary simulation (ES) alone is insufficient because the outcomes of ES depend on evolutionary pathways. We need a reference system for comparison. An appropriate reference system for this purpose is an ensemble of the randomly sampled genotypes. However, generating high-fitness genotypes by simple random sampling is difficult because such genotypes are rare. In this study, we used the multicanonical Monte Carlo method developed in statistical physics to construct a reference ensemble of GRNs and compared it with the outcomes of ES. We obtained the following results. First, mutational robustness was significantly higher in ES than in the reference ensemble at the same fitness level. Second, the emergence of a new phenotype, bistability, was delayed in evolution. Third, the bistable group of GRNs contains many mutationally fragile GRNs compared with those in the non-bistable group. This suggests that the delayed emergence of bistability is a consequence of the mutation-selection mechanism.Author summary: Living systems are products of evolution, and their present forms reflect their evolutionary history. Thus, to investigate the particularity of the evolutionary process by computer simulations, an appropriate reference system is needed for comparison with the outcomes of evolutionary simulations. In this study, we considered a model of gene regulatory networks (GRNs). Our idea was to construct a reference ensemble comprising randomly generated GRNs. To produce GRNs with high fitness values, which are rare, we employed a “rare event sampling” method developed in statistical physics. In particular, we focused on the evolution of mutational robustness. Living systems do not lose viability readily, even when some genes are mutated. This trait, called mutational robustness, has developed throughout evolution, along with functionality. Using the abovementioned method, we found that mutational robustness resulting from evolution exceeded that of the reference set. Therefore, mutational robustness is enhanced by evolution. We also found that the emergence of a new phenotype was significantly delayed in evolution. Our results suggest that this delay is a consequence of the fact that mutationally robust GRNs are favored by evolution.