Although all bilaterian animals have a related set of Hox genes, the genomic organization of this gene complement comes in different flavors. In some unrelated species, Hox genes are clustered; in others, they are not. This indicates that the bilaterian ancestor had a clustered Hox gene family and that, subsequently, this genomic organization was either maintained or lost. Remarkably, the tightest organization is found in vertebrates, raising the embarrassingly finalistic possibility that vertebrates have maintained best this ancestral configuration. Alternatively, could they have co-evolved with an increased ;organization' of the Hox clusters, possibly linked to their genomic amplification, which would be at odds with our current perception of evolutionary mechanisms? When discussing the why's and how's of Hox gene clustering, we need to account for three points: the mechanisms of cluster evolution; the underlying biological constraints; and the developmental modes of the animals under consideration. By integrating these parameters, general conclusions emerge that can help solve the aforementioned dilemma.
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