Comparative Biochemistry and Physiology Part B 133 (2002) 571–580 1096-4959/02/$ - see front matter  2002 Elsevier Science Inc. All rights reserved. PII:S1096-4959 Ž 02 . 00121-5 Review Genomics of the HOX gene cluster  Pedro Martinez *, Chris T. Amemiya a, b Department of Anatomy and Cell Biology, University of Bergen, Aarstadveien, 19, 5009 Bergen, Norway a Virginia Mason Research Center. Benaroya Research Institute, Molecular Genetics Department, Seattle, WA 98101, USA b Received 2 May 2002; received in revised form 2 July 2002; accepted 9 July 2002 Abstract The Hox family of homeobox genes encode transcription factors that control different aspects of metazoan development. They appear clustered in the genomes of those animals in which their relative positions have been mapped. Although clustering is assumed to be a general property of Hox genes in all bilaterians, just a few species have been studied in sufficient detail to support this claim. Linear duplication of genes inside the cluster, as well as full-cluster duplications account for the actual complexity of HOX clusters in the different animal groups that have been studied (mainly vertebrates). Understanding how the Hox genes are regulated during development will depend, ultimately, on the generation of more powerful tools for cloning intact HOX clusters and for elucidating their cis-regulatory components. To clarify the roles of the Hox genes themselves, we will need to characterize in detail their downstream targets, and some progress in this direction is coming mainly from the recent use of arrayed libraries. Moreover, a comprehensive study of Hox target genes in tissues and organisms promises, in the long term, to give us a clear idea of the role that Hox genes play during development and how they have evolved over time.  2002 Elsevier Science Inc. All rights reserved. Keywords: Bilaterian; Cluster; Evolution; Genomics; Homeobox; HOX; Informatic tools; Mapping; Realisator; Regulation 1. Introduction Homeobox-containing genes encode a major class of transcription factors regulating many aspects of development (Weatherbee et al., 1998). Genes with homeoboxes have been found in all metazoans thus far examined. On the basis of several criteria, including sequence identity, organ- ization into gene clusters, association with other sequence motifs and position of introns, homeo- domain sequences can be subdivided into at least 20 different classes (Gehring et al., 1994).  Contribution to a special issue of CBP on Comparative Functional Genomics. *Corresponding author. Tel.: q47-5558-6197; fax: q47- 5558-6360. E-mail address: pedro.martinez@pki.uib.no (P. Martinez). Across different phyla, members belonging to particular classes show a high degree of sequence similarity, and in some cases, a striking degree of conservation in expression domains and functions. These features bestow homeobox genes with unique advantages for studying the evolution of development and the origin and diversification of body plans (Averof and Akam, 1995; Sordino et al., 1995; Holland et al., 1999). It is speculated that the changes in homeodomain protein sequenc- es (Galant and Carroll, 2002) and the number of homeobox genes per genome (Holland and Garcia- Fernandez, 1996), as well as the changes in their controlling cis-regulatory sequences (Manzanares et al., 2000; Grandien and Sommer, 2001) and downstream effectors (Lewis et al., 2000), all have