The genesis and evolution of homeobox gene clusters

Key Points Hox, ParaHox and NK genes are related ANTP-class homeobox genes that are organized into chromosomal clusters in several metazoan lineages. Both Hox and ParaHox clusters are thought to have arisen by duplication and divergence from an ancient ProtoHox cluster that was present in an ancestral animal. Phylogenetic and chromosomal reconstructions indicate that the Hox and ParaHox clusters, as well as other ANTP homeobox classes (Evx, Meox, Gbx, Mnx and En) originated after successive gene duplications and chromosomal breakages from a founder ProtoHox -like gene. A large array of ANTP-class homeobox genes — the homeobox megacluster that includes the Hox, ParaHox and NK clusters — existed early in metazoan evolution. It contained up to 25 homeobox genes, and probably originated before the divergence of cnidarians and bilaterians. An NK cluster of seven homeobox genes existed before the divergence of protostomes and deuterosomes. The organization of the cluster has been maintained largely intact in fruitflies and mosquitoes, but has been split into three in chordates. Hox, ParaHox and NK cluster genes are preferentially expressed in ectodermal, endodermal and mesodermal derivatives, respectively. I speculate that the origin of the three gene clusters was related to the origin, patterning and diversification of the three bilaterian germ layers. The above thesis implies that cnidarians are primitively bilaterian triploblasts; that these gene clusters have been evolving independently in the distinct clades; and that their present-day functions are a composite of ancestral and derived functions. The selective constraint that has favoured the maintenance of homeobox gene clustering is probably the need for close gene linkage; this would enable sequential chromatin decondensation and thereby allow the temporal deployment of gene expression. The linkage constraint is maintained for the Hox and ParaHox clusters in animals that have a slow mode of development, and for the NK cluster in insects. In the lineages for which the constraint has disappeared, the clusters tend to disintegrate by phylogenetic inertia. Once called the 'Rosetta stone' of developmental biology, the homeobox continues to fascinate both evolutionary and developmental biologists. The birth of the homeotic, or Hox, gene cluster, and its subsequent evolution, has been crucial in mediating the major transitions in metazoan body plan. Comparative genomics studies indicate that the more recently d