by Leander Goldbach, Nora S. Martin, Andreas WagnerThe topography of fitness landscapes strongly influences the outcome of Darwinian evolution. This topography in turn is determined by the effects of genotypic changes on phenotypes, such as the structure and function of biomolecules like proteins and RNA. Thus, understanding the evolution of biomolecules requires an understanding of the relationship between genotype and phenotype. Here, we study how this relationship is influenced by the fundamental biochemical rules that determine which RNA bases can form base-pairs in RNA secondary structure. To this end, we computationally study the secondary structure genotype-phenotype maps of RNA molecules using all ten possible different such RNA base-pairing rules. We simulate adaptive evolution on fitness landscapes in which an RNA’s fitness is defined by its secondary structure. We find that the base-pairing rules strongly affect how likely an evolving population is to find the global peak of a fitness landscape. The base-pairing rule of most biological RNA molecules (A-U, G-C, G-U) is among the top three most favorable rules for adaptive evolution, in which over 80% of evolving populations find a landscape’s highest fitness peak. Simple characteristics of the genotype-phenotype map, such as the fraction of genotypes that constitute local peaks can help to predict how likely evolving populations are to find a landscape’s global fitness peak. These characteristics can in turn be explained by two elementary properties of base-pairing rules that we call promiscuity and degeneracy.