Hox, ParaHox, ProtoHox: facts and guesses.

The Hox gene cluster has captivated the imagination of evolutionary and developmental biologists worldwide. In this review, the origin of the Hox and ParaHox gene clusters by duplication of a ProtoHox gene cluster, and the changes in their gene numbers in major Metazoan Transitions are reviewed critically. Re-evaluation of existing data and recent findings in Cnidarians, Acoels, and critical stages of vertebrate evolution suggest alternative scenarios for the origin, structure, and changes in Hox gene numbers in relevant events of Metazoan evolution. I discuss opposing views and propose that (i) the ProtoHox cluster had only two genes, and not four as commonly believed: a corollary is that the origin of Bilaterians was coincident with the invention of new Hox and ParaHox gene classes, which may have facilitated such a transition; (ii) the ProtoHox cluster duplication was a cis duplication event, rather than a trans duplication event, as previously suggested, and (iii) the ancestral vertebrate cluster possessed 14 Hox genes, and not the 13 generally assumed. These hypotheses could be verified or refuted in the near future, but they may help critical discussion of the evolution of the Hox/ParaHox family in the metazoan kingdom.