#### Jorg, T.,Martin, O. C.,Wagner, A.

Background: Neutral networks or sets consist of all genotypes with a given phenotype. The size and structure of these sets has a strong influence on a biological system's robustness to mutations, and on its evolvability, the ability to produce phenotypic variation; in the few studied cases of molecular phenotypes, the larger this set, the greater both robustness and evolvability of phenotypes. Unfortunately, any one neutral set contains generally only a tiny fraction of genotype space. Thus, current methods cannot measure neutral set sizes accurately, except in the smallest genotype spaces. Results: Here we introduce a generalized Monte Carlo approach that can measure neutral set sizes in larger spaces. We apply our method to the genotype-to-phenotype mapping of RNA molecules, and show that it can reliably measure neutral set sizes for molecules up to 100 bases. We also study neutral set sizes of RNA structures in a publicly available database of functional, noncoding RNAs up to a length of 50 bases. We find that these neutral sets are larger than the neutral sets in 99.99% of random phenotypes. Software to estimate neutral network sizes is available at http://www.bioc.uzh.ch/wagner/publications-software.html. Conclusion: The biological RNA structures we examined are more abundant than random structures. This indicates that their robustness and their ability to produce new phenotypic variants may also be high.