Phenotypic diversity is crucial for many biological processes, from antibody production to the evolution of species. Possibly the best-known source of such variation is the modification through mutation of many different genes; however, Resnick and Inga now show that individual 'master genes' could also have the potential to generate enormous amounts of genetic-based phenotypic diversity.

To test this theory, the authors investigated human and murine p53 , the product of which is a transcription factor that controls the expression of more than 50 downstream genes through direct binding to response elements (REs). These target genes are involved in a wide range of processes, including apoptosis, growth arrest, DNA repair and checkpoint responses.

The authors compared the in vivo transactivation capacity of wild type and mutant p53 using an isogenic yeast-based system that measures the activity of target REs upstream of the colour-marker reporter gene ADE2. Varying the levels of p53 expression allowed Resnick and Inga to identify mutants with altered binding affinities through changes in colony colour, which indicated differences in the patterns of target-gene activation and transcription.

The partial-function mutants were found to differ greatly in their ability to induce transcription from the target REs. This confirms that single amino-acid changes in a sequence-specific transcription factor can act as a potential source of rapid phenotypic diversification.

On the basis of their results, the authors propose a master gene hypothesis and use a piano analogy to explain their model. The master gene (the hand) is a single transcriptional activator or repressor that controls the expression of many target genes (the keys). Null mutations correspond to non-functional hands, whereas partial mutants lead to a range of different effects. For example, new notes are struck if different but related REs are recognized, and the intensity of individual notes can vary according to different levels of transactivation. Such changes could lead to a vast array of potential outcomes, which correspond to different biological responses.

Resnick and Inga have established that mutations in a single master gene can lead to a range of simultaneous changes in both the selection and the extent of transcriptional modulation at individual targets. Moreover, this process creates phenotypic diversity without the constraints of altering protein–protein interactions and thereby provides opportunities for accelerated evolutionary change.