Mechanisms of regulatory evolution. The diagram depicts the two possible modes of regulatory changes that generate novel developmental control mechanisms. New domains of gene activation are achieved by the gain of a novel regulatory element or the gain of an upstream transcription factor (right). If such novel regulatory wiring follows a gene duplication, it may liberate protein evolution and open a developmental trajectory towards co-option (m/M = mesodermal enhancer/transcription factor. e/E = ectodermal enhancer /transcription factor).