Using mouse forward genetics to define novel target space

Rapid advances in genomics technologies have identified a wealth of new therapeutic targets, but typically these targets are weakly validated with only circumstantial evidence to link them to human disease. The next challenge is testing gene-to-disease connections in a relevant animal model, a time-consuming and uncertain process using conventional reverse-genetic approaches such as knockout and transgenic mice. By contrast, forward genetics proceeds by measuring a physiological process that is relevant to disease, then identifying the gene products that impinge on this process. This ‘phenotype-first’ approach solves the bottleneck of target validation by using clinically relevant assays in a mammalian whole-animal system as a discovery platform. As an unbiased approach to gene discovery and validation, forward genetics will identify novel drug targets and increase the success rate of drug development.