Phylogenetic Studies of the Homeodomain Protein Family

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This research program focuses on the computational analysis of the homeodomain group of proteins, which play a fundamental role in the specification of body plan, pattern formation, and cell fate determination during metazoan development. A variety of bioinformatic approaches are used to understand the evolution and function of these proteins and their role in human disease. Homeobox (or Hox) genes are organized in conserved genomic clusters across a range of phylogenetic taxa and are considered partially responsible for patterning the primary body axis. Over evolutionary time, the functional diversification of these Hox genes has contributed to the diversification of animal body plans. To investigate the origin and early evolution of Hox genes and the "Hox code," we have focused on the sea anemone Nematostella. Cnidarians, including corals, sea anemones, and jellyfish, constitute an outgroup to bilaterians animals having bilateral symmetry and have the potential to provide unique insights into early Hox evolution. We have found phylogenetic evidence suggesting that a rudimentary Hox code in the cnidarian-bilaterian ancestor played a role in patterning the animal's primary (and possibly secondary) body axis. Moreover, thanks to strong stabilizing selection on this Hox code, certain core characteristics have been maintained despite being deployed in a bewildering array of animal forms for over a half billion years. In addition, we have examined the possible role of Wnt genes in ancestral metazoan axial patterning, gene functions thought to pre-date the Hox system. Strong evidence suggests that Hox genes were "co-opted" into this pathway sometime between their origin and the last common ancestor of cnidarians and bilaterians. Current work is focused on using next-generation sequencing technologies to further understand the evolution of a number of protein families that are important to development. As an outgrowth of our studies on the homeodomain class of proteins, we have developed and continue to maintain the Homeodomain Resource. The Homeodomain Resource is a curated collection of sequence, structure, interaction, genomic and functional information on the homeodomain family. The current version builds upon previous versions by the addition of new, complete sets of homeodomain sequences from fully sequenced genomes, the expansion of existing curated homeodomain information and the improvement of data accessibility through better search tools and more complete data integration. This release contains 1534 full-length homeodomain-containing sequences, 93 experimentally derived homeodomain structures, 101 homeodomain proteinprotein interactions, 107 homeodomain DNA-binding sites and 206 homeodomain proteins implicated in human genetic disorders. The Homeodomain Resource is freely available at http:/research.nhgri.nih.gov/homeodomain/.