Molecular evolution of the homeodomain family of transcription factors

The homeodomain family of transcription factors plays a fundamental role in a diverse set of functions that include body plan specification, pattern f ormation and cell fate determination during metazoan development. Members o f this family are characterized by a helix-turn-helix DNA-binding motif kno wn as the homeodomain. Homeodomain proteins regulate various cellular proce sses by specifically binding to the transcriptional control region of a tar get gene. These proteins have been conserved across a diverse range of spec ies, from yeast to human. A number of inherited human disorders are caused by mutations in homeodomain-containing proteins. In this study, we present an evolutionary classification of 129 human homeodomain proteins. Phylogene tic analysis of these proteins, whose sequences were aligned based on the t hree-dimensional structure of the homeodomain, was performed using a distan ce matrix approach. The homeodomain proteins segregate into six distinct cl asses, and this classification is consistent with the known functional and structural characteristics of these proteins. An ancestral sequence signatu re that accurately describes the unique sequence characteristics of each of these classes has been derived. The phylogenetic analysis, coupled with th e chromosomal localization of these genes, provides powerful clues as to ho w each of these classes arose from the ancestral homeodomain.