Fig. 6. Meta-cis regulation as a mechanism that triggers vertebrate Hox cluster consolidation. (A) Schematic of a type D cluster present in the ancestral bilaterian animal. Hox genes (black boxes) are present in various transcriptional orientations (arrows), dispersed over a large fragment, which also includes foreign (non-Hox) genes (white boxes). Genes are kept together owing to the presence of cis-acting regulatory sequences (blue circles), which are shared between several neighboring genes. (B) A type D/O cluster present in an ancestral chordate. Owing to the emergence of a meta-cis regulatory sequence in a control region (CR, brown), the genomic organization of target genes is improved as a consequence of positive selection. Progressively, foreign genes are lost together with some large intergenic fragments, which optimizes the meta-cis control. (C) After genome duplication, consolidation is favored owing to the increasing possibility to recruit novel meta-cis regulation (red, yellow, green boxes and arrows), in particular through the intrinsic capacity of a potent control region (CR in B) to generate regulatory novelties by `regulatory priming' (red and dark green in C; see text). This leads to a concentration of large-scale enhancers to form a `global control region' (GCR), which might continue to recruit and/or evolve novel regulatory elements owing to its intrinsic properties. As a consequence, duplicated clusters are further consolidated.