The non-deterministic genotype-phenotype map of RNA secondary structure

Selection and variation are both key aspects in the evolutionary process. Previous research on the mapping between molecular sequence (genotype) and molecular fold (phenotype) has shown the presence of several structural properties in different biological contexts, implying that these might be universal in evolutionary spaces. The deterministic genotype-phenotype (GP) map that links short RNA sequences to minimum free energy secondary structures has been studied extensively because of its computational tractability and biologically realistic nature. However, this mapping ignores the phenotypic plasticity of RNA. We define a GP map that incorporates non-deterministic phenotypes, and take RNA as a case study; we use the Boltzmann probability distribution of folded structures and examine the structural properties of non-deterministic (ND) GP maps for RNA sequences of length 12 and coarse-grained RNA structures of length 30 (RNAshapes30). A framework is presented to study robustness, evolvability and neutral spaces in the non-deterministic map. This framework is validated by demonstrating close correspondence between the non-deterministic quantities and sample averages of their deterministic counterparts. When using the non-deterministic framework we observe the same structural properties as in the deterministic GP map, such as bias, negative correlation between genotypic robustness and evolvability, and positive correlation between phenotypic robustness and evolvability. ### Competing Interest Statement The authors have declared no competing interest.