Fig. 6. The evolution of Hox target gene regulation by the stepwise accumulation of monomer binding sites. Represented are two serially homologous structures, one of which is under Hox control (shaded red). The schematic of a cis-regulatory element is shown to the right of each pair of serial homologs. Its expression is indicated by the blue pattern in each structure and is mediated through a binding site (blue circle) for a transcriptional activator. Our model posits that the repression of a target gene by a Hox protein begins with the evolution of a single Hox monomer binding site (red circle) that can mediate partial repression of the activity of a cis-regulatory element. If the binding site becomes fixed, then directional selection for a further decrease in gene activity can fix additional Hox monomer sites that increase the repression of the cis-regulatory element and eventually lead to its qualitative repression. Thus, the qualitative regulation of Hox target genes evolves in a gradual, stepwise fashion and not all at once (the pathway indicated by the crossed out, dotted arrow).