Analysis of central Hox protein types across bilaterian clades: On the origin of central Hox proteins from an Antennapedia/Hox7-like ancestor

Background: Hox proteins are one of the best studied sets of transcription factors in developmental biology. They are the major determinants for establishing morphological differences along the anterior-posterior axis of animals and are generally regarded as highly conserved in function. This view is mostly based on experiments comparing a few (anterior) Hox proteins, however, the extent to which central or abdominal Hox proteins share conserved sequence features or functions remains largely unexplored. Results: To shed light on the origin and functional divergence of the central Hox proteins, we combine a powerful bioinformatics tool (CLANS) with a large-scale phylogeny of species. CLANS is used to differentiate between the various types of central Hox protein sequences present in different species, while the phylogeny provides an evolutionary context to the analysis. The combination of both enables us to infer the relative timepoint at which a given type of central Hox proteins arose. We identify seven distinct central Hox protein sequence types, only one of which is common to all protostome and deuterostome clades (Antp/Hox7). Conclusion: Together, these results lead us to suggest a reevaluation of the usefulness of the increasingly depicted synteny-based classification scheme that assumes a one-to-one orthology between protostome and deuterostome central Hox proteins. Instead, we propose that the use of sequence-based classification schemes capable of resolving the central and posterior Hox proteins provides a more promising and biologically meaningful alternative to resolving these groups. This analysis, which provides a unique overview of the Hox protein sequence types present across protostomes and deuterostomes as well as a relative dating for the emergence of the various central Hox protein types, provides a crucial first step to help shed light on how and when the distinct developmental blueprints for organisms evolved within the evolutionarily immensely successful bilaterian lineage.