Evolvability is the ability of a biological system to produce phenotypic variation that is both heritable and adaptive. It has long been the subject of anecdotal observations and theoretical work. In recent years, however, the molecular causes of evolvability have been an increasing focus of experimental work. Here, we review recent experimental progress in areas as different as the evolution of drug resistance in cancer cells and the rewiring of transcriptional regulation circuits in vertebrates. This research reveals the importance of three major themes: multiple genetic and non-genetic mechanisms to generate phenotypic diversity, robustness in genetic systems, and adaptive landscape topography. We also discuss the mounting evidence that evolvability can evolve and the question of whether it evolves adaptively.

Robustness, the maintenance of a character in the presence of genetic change, can help preserve adaptive traits but also may hinder evolvability, the ability to bring forth novel adaptations. We used genotype networks to analyze the binding site repertoires of 193 transcription factors from mice and yeast, providing empirical evidence that robustness and evolvability need not be conflicting properties. Network vertices represent binding sites where two sites are connected if they differ in a single nucleotide. We show that the binding sites of larger genotype networks are not only more robust, but the sequences adjacent to such networks can also bind more transcription factors, thus demonstrating that robustness can facilitate evolvability.

The adaptive landscape is an iconic metaphor that pervades evolutionary biology. It was mostly applied in theoretical models until recent years, when empirical data began to allow partial landscape reconstructions. Here, we exhaustively analyse 1,137 complete landscapes from 129 eukaryotic species, each describing the binding affinity of a transcription factor to all possible short DNA sequences. We find that the navigability of these landscapes through single mutations is intermediate to that of additive and shuffled null models, suggesting that binding affinity-and thereby gene expression-is readily fine-tuned via mutations in transcription factor binding sites. The landscapes have few peaks that vary in their accessibility and in the number of sequences they contain. Binding sites in the mouse genome are enriched in sequences found in the peaks of especially navigable landscapes and the genetic diversity of binding sites in yeast increases with the number of sequences in a peak. Our findings suggest that landscape navigability may have contributed to the enormous success of transcriptional regulation as a source of evolutionary adaptations and innovations.