Phenotypes can be robust and evolvable if mutations have non-local effects on sequence constraints.

The mapping between biological genotypes and phenotypes plays an important role in evolution, and understanding the properties of this mapping is crucial to determine the outcome of evolutionary processes. One of the most striking properties observed in several genotype-phenotype (GP) maps is the positive correlation between the robustness and evolvability of phenotypes. This implies that a phenotype can be strongly robust against mutations and at the same time evolvable to a diverse range of alternative phenotypes. Here, we examine the causes for this positive correlation by introducing two analytically tractable GP map models that follow the principles of real biological GP maps. The first model is based on gene-like GP maps, reflecting the way in which genetic sequences are organized into protein-coding genes, and the second one is based on the GP map of RNA secondary structure. For both models, we find that a positive correlation between phenotype robustness and evolvability only emerges if mutations at one sequence position can have non-local effects on the sequence constraints at another position. This highlights that non-local effects of mutations are closely related to the coexistence of robustness and evolvability in phenotypes, and are likely to be an important feature of many biological GP maps.