Hypothesis for the ancestral association of the Hox cluster with the reproductive side of the animal. (a) In early metazoans, Hox gene precursors had multiple developmental roles, which probably included gonad formation, and, in our illustration, sensory epithelium development. (b) Hox gene dosage after duplication would result in developmental changes in the structures formed; in this case, enhanced gonad and sensory organ development. Autoregulatory interactions become intergenic interactions. Temporal colinearity may concomitantly result as a byproduct of distance-dependent chromatin regulatory functions previously in place or after the asymmetric loss of intergenic regulatory interactions. (c) The duplicates undergo subfunctionalization of the original coding and regulatory multi-functionality; that is, the new genes independently adopt specializations within their original functions. (d,e) Additional tandem duplication and subsequent coding and regulatory subfunctionalization. (e,f) Once in place, recruitment of vectorial Hox cluster gene expression to anteroposterior diversification is possible. Legs, wings and sensory bristles can be differentially deployed along the anteroposterior axis. In (c–e), protein evolution is driven by functional specializations outside the colinear domain of expression.