Data Availability StatementThe source code of the Virtual Cell software that was used to run simulations is available from https://bitbucket. internal Favipiravir cost metabolite concentrations in a fluctuating environment. The resulting wild-type Virtual Cell strains (WT-VCS) were then exposed to periodic, drastic environmental Favipiravir cost changes, while maintaining selection on homeostasis regulation. In different sets of simulations the nature and frequencies of environmental change were varied. Pre-evolved WT-VCS were highly evolvable, showing rapid evolutionary adaptation after novel environmental change. Moreover, continued low frequency changes resulted in evolutionary restructuring of the genome that enables even faster adaptation with very few mutations. In contrast, when change frequency is usually high, lineages evolve phenotypic plasticity that allows them to be fit in different environments without mutations. Yet, evolving phenotypic plasticity is usually a comparatively slow process. Under intermediate change frequencies, both strategies occur. Conclusions We conclude that evolving a homeostasis mechanisms predisposes lineage to be evolvable to novel environmental conditions. Moreover, after continued evolution, evolvability can be a viable alternative with comparable fitness to regulated phenotypic plasticity in all but the most rapidly changing environments. Electronic supplementary material The online version of this article (doi:10.1186/s12862-017-0918-y) contains supplementary material, which is available to authorized users. and close to a fixed target during fluctuations in external resource (and arise from the internal cellular dynamics that are given by a system of ODEs, representing the activities of the proteins in the cell. The activities of catabolic and anabolic enzymes and pumps directly affect concentrations of and or as a ligand, and have a differential regulatory effect on their downstream genes, depending on their ligand binding state. This ability to regulate gene expression depending on ligand binding state is crucial for the cells capacity to evolve homeostasis. Open in a separate window Fig. 1 Virtual Cell model overview. a Virtual Cells have a circular genome that encodes metabolic and regulatory proteins. An externally available resource molecule (is usually converted to (serves as the energy source for the import reaction (2). In addition, and are converted to an unspecified (4) by anabolic enzymes. Protein expression from Favipiravir cost genes (5) can Favipiravir cost be regulated by TFs if their binding motif matches the genes operator sequence. Binding of a ligand (or and and the homeostasis target value (is usually continually varying, while the homeostasis target remains constant. Cells have a chance proportional to their fitness to contribute offspring to the next generation All proteins are transcribed from a spatially explicit, circular genome. Point mutations affect parameters of individual genes, such as the kinetic constants of enzymes, operator binding sites, and binding motifs and regulatory effect parameters of TFs. Large scale mutation events are the duplication, deletion or translocation of stretches of neighbouring genes Rabbit polyclonal to PEX14 as well as whole genome duplications (WGD). After duplicating, the two identical copies of a gene will diverge due to subsequent, independently accumulating point mutations. We are interested in the genome structure and mutational events on the line of descent (LOD) of a lineage (see Constructing the line of descent in Methods). In most of the analysis we focus on the mutational events fixed shortly before and after environmental change. Evolved wild-types rapidly adapt to novel environments In a previous study we evolved 100 VC populations under fluctuating resource conditions [23]. From these we selected four WT-VCS that successfully evolved homeostasis regulation in their environment for continued evolution in the current study. Here, we subjected populations to different periodic environmental changes at various change frequencies. The environments Favipiravir cost were constructed by changing rate of the molecule, rate of proteins and the stoichiometry of from to of the catabolic reaction (Table ?(Table22 environments 1.