Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme

Some mutations, known as cryptic mutations, have no observable effect on an organism's phenotype unless combined with other mutations or environmental changes. As the originally cryptic variation can turn out to be beneficial in such new conditions, it has been proposed that it may facilitate evolutionary adaptation — or 'evolvability', but this has not been rigorously demonstrated experimentally because of the complexity of both natural genomes and environments. In a study of a simplified system in vitro — the catalytic activity of a single RNA enzyme — Andreas Wagner and colleagues demonstrate that a population that has accumulated more cryptic variation adapts more rapidly to a new chemical environment than a competing population with fewer variations. The existence of such a pre-adaptation mechanism would have fundamental implications for animal and plant breeding, as well as for complex trait diseases in humans. Cryptic variation is caused by the robustness of phenotypes to mutations1. Cryptic variation has no effect on phenotypes in a given genetic or environmental background, but it can have effects after mutations or environmental change2,3,4,5. Because evolutionary adaptation by natural selection requires phenotypic variation, phenotypically revealed cryptic genetic variation may facilitate evolutionary adaptation6,7,8. This is possible if the cryptic variation happens to be pre-adapted, or “exapted”9, to a new environment, and is thus advantageous once revealed. However, this facilitating role for cryptic variation has not been proven, partly because most pertinent work focuses on complex phenotypes of whole organisms whose genetic basis is incompletely understood. Here we show that populations of RNA enzymes with accumulated cryptic variation adapt more rapidly to a new substrate than a population without cryptic variation. A detailed analysis of our evolving RNA populations in genotype space shows that cryptic variation allows a population to explore new genotypes that become adaptive only in a new environment. Our observations show that cryptic variation contains new genotypes pre-adapted to a changed environment. Our results highlight the positive role that robustness and epistasis can have in adaptive evolution10,11.