Evolutionary Developmental Biology: Hox Gene Evolution


Hox genes are the homologues of the homeobox‐containing genes in the homeotic complex (HOM‐C) of the fruit fly Drosophila and encode transcription factors that play crucial roles in determining positional identity along the anterior–posterior body axis during animal development. Their expansion and duplication during metazoan evolution suggests that they have played a major role in generating animal diversity. In the protostomes, Hox genes are organised into a single cluster of genes that in some phyla has undergone gene loss and in others has become dispersed. On the contrary, cluster integrity is generally maintained in the deuterostomes, and during chordate evolution the single deuterostome cluster has undergone internal expansion as well as whole cluster duplications, generating animals with four or more clusters. Whereas these expansions and duplications are correlated with an increase in animal diversity, the main mechanisms driving metazoan evolution from a Hox perspective probably involve alterations in cis‐regulatory sequences of Hox genes and, to a lesser extent, changes in their coding sequences.

Key Concepts:

  • The prototype Hox gene potentially evolved from an ancestral NK homeobox gene very early in metazoan evolution.

  • Tandem and genome‐wide duplications generated the prototypical vertebrate Hox clusters.

  • Hox genes encode transcription factors that may have originally patterned bilaterian's evolving nervous system; however, as body organisation became more complicated and cells became more interdependent, Hox genes’ function may have co‐evolved with the function of other HB‐containing genes to jointly specify positional information in the derivatives of all three germ layers.

  • The clustering of Hox genes appears to be necessary for animals that use signalling pathways during development. This supports the presence of global control mechanisms that regulate all or a subset of genes within the cluster.

  • Organisms in which cells are primarily determined in early embryogenesis and develop autonomously begin to lose Hox cluster integrity.

  • The major morphological diversity in vertebrate lineages does not appear to be causally related to changes in the number or complement of the Hox genes. Therefore, Hox input into morphological diversity is likely to occur through altered cis‐regulation and/or downstream targets of Hox genes.

  • As the genome sequence of more species becomes available, the molecular phylogenetics of Hox cluster evolution will become clearer with an emphasis in understanding the evolution of the regulatory modules that partition Hox expression domains.

Keywords: homeobox (HB); gene cluster; metazoan; transcriptional regulation; colinearity; pattern formation; whole‐genome duplication (WGD); paralogous groups (PGs)

Figure 1.

Early branches of the metazoan cladogram showing the five main phyla leading up to bilaterian animals. Representatives of each phylum are indicated in parenthesis. Major features during the course of Hox gene evolution are indicated. ‘A’, anterior specifying gene; ‘C’, central specifying gene and ‘P’, posterior specifying gene.

Figure 2.

A cladogram of representative phyla from the Protostomes. The Arthropoda phyla has been further subdivided into two (Hexapoda and Crustacea) of its possible four subphyla. Hox genes are represented by coloured boxes with the first paralogue (Hox1) displayed on the left‐hand side of the figure. Where linkages are known, Hox genes are linked together by a black bar. In representatives where the overall cluster organisation is not known (such as in the shrimp and nautilus), linkages are not indicated. In some organisms, more than one paralogue has been identified such as in the nautilus which has two Hox5 and two Hox6 genes. In this figure, ‘A’ and ‘P’ correspond to anterior and posterior expression domains of the genes (i.e. spatial colinearity of the cluster).

Figure 3.

Representatives of the Deuterostomes that are made up of four phyla: Echinodermata, Hemichordata, Xenoturbellida (not shown) and Chordata. The phylum Chordata includes three subphyla: Cephalochordata, Urochordata and Vertebrata. The Vertebrata subphylum is expanded to show representative classes and orders used to highlight different evolutionary features of the Hox genes and their clusters as discussed in the text. The number of clusters in lampreys has not been resolved raising the possibility that they diverged after the first round of whole‐genome duplication (1R‐WGD), before the second round (2R‐WGD). Hox genes which are pseudogenes are indicated as white boxes. The first paralogue (Hox1) is displayed on the left‐hand side of the figure. ‘A’ and ‘P’ flanking the representative Hox clusters for tetrapods indicates anterior‐ and posterior‐expressed genes with respect to cluster organisation (i.e. spatial colinearity). Another round of WGD occurred during the radiation of the bony fishes and is indicated by an arrow labelled TSGD ().



Aboobaker AA and Blaxter ML (2003) Hox gene loss during dynamic evolution of the nematode cluster. Current Biology 13: 37–40.

Akam M (1989) Hox and HOM: homologous gene clusters in insects and vertebrates. Cell 57: 347–349.

Andreeva TF, Kuk C, Korchagina NM, C'Ikc'm M and Dondya AK (2001) Cloning and analysis of structural organization of Hox genes in the Polychaete Nereis virens. Ontogenez 32: 225–233.

Arenas‐Mena C, Cameron AR and Davidson EH (2000) Spatial expression of Hox cluster genes in the ontogeny of a sea urchin. Development 127: 4631–4643.

Averof M and Akam M (1995) Hox genes and the diversification of insect and crustacean body plans. Nature 376: 420–423.

Averof M and Patel NH (1997) Crustacean appendage evolution associated with changes in Hox gene expression. Nature 388: 682–686.

Burke AC, Nelson CE, Morgan BA and Tabin C (1995) Hox genes and the evolution of vertebrate axial morphology. Development 121: 333–346.

Butts T, Holland PW and Ferrier DE (2008) The urbilaterian Super‐Hox cluster. Trends in Genetics 24: 259–262.

Chiori R, Jager M, Denker E et al. (2009) Are Hox genes ancestrally involved in axial patterning? Evidence from the hydrozoan Clytia hemisphaerica (Cnidaria). PLoS One 4: e4231.

Chiu CH, Amemiya C, Dewar K et al. (2002) Molecular evolution of the HoxA cluster in the three major gnathostome lineages. Proceedings of the National Academy of Sciences of the USA 99: 5492–5497.

Chourrout D, Delsuc F, Chourrout P et al. (2006) Minimal ProtoHox cluster inferred from bilaterian and cnidarian Hox complements. Nature 442: 684–687.

Cook CE, Jimenez E, Akam M and Salo E (2004) The Hox gene complement of acoel flatworms, a basal bilaterian clade. Evolution and Development 6: 154–163.

Cook CE, Smith ML, Telford MJ, Bastianello A and Akam M (2001) Hox genes and the phylogeny of the arthropods. Current Biology 11: 759–763.

Di‐Poi N, Montoya‐Burgos JI, Miller H et al. (2010) Changes in Hox genes’ structure and function during the evolution of the squamate body plan. Nature 464: 99–103.

Duboule D and Dolle P (1989) The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. EMBO Journal 8: 1497–1505.

Escriva H, Manzon L, Youson J and Laudet V (2002) Analysis of lamprey and hagfish genes reveals a complex history of gene duplications during early vertebrate evolution. Molecular Biology and Evolution 19: 1440–1450.

Finnerty JR, Pang K, Burton P, Paulson D and Martindale MQ (2004) Origins of bilateral symmetry: Hox and dpp expression in a sea anemone. Science 304: 1335–1337.

Force A, Amores A and Postlethwait JH (2002) Hox cluster organization in the jawless vertebrate Petromyzon marinus. Journal of Experimental Zoology 294: 30–46.

Galant R and Carroll SB (2002) Evolution of a transcriptional repression domain in an insect Hox protein. Nature 415: 910–913.

Garcia‐Fernandez J (2005) The genesis and evolution of homeobox gene clusters. Nature Reviews Genetics 6: 881–892.

Graham A, Papalopulu N and Krumlauf R (1989) The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 57: 367–378.

Hejnol A and Martindale MQ (2009) Coordinated spatial and temporal expression of Hox genes during embryogenesis in the acoel Convolutriloba longifissura. BMC Biology 7: 65.

Hoegg S, Brinkmann H, Taylor JS and Meyer A (2004) Phylogenetic timing of the fish‐specific genome duplication correlates with the diversification of teleost fish. Journal of Molecular Evology 59: 190–203.

Hoegg S and Meyer A (2005) Hox clusters as models for vertebrate genome evolution. Trends in Genetics 21: 421–424.

Holland PW (2001) Beyond the Hox: how widespread is homeobox gene clustering? Journal of Anatomy 199: 13–23.

Hui JH, McDougall C, Monteiro AS et al. (2011) Extensive Chordate and Annelid Macrosynteny reveals ancestral homeobox gene organization. Molecular Biological Evolution 29: 157–165.

Iijima M, Akiba N, Sarashina I, Kuratani S and Endo K (2006) Evolution of Hox genes in molluscs: a comparison among seven morphologogically diverse classes. Journal of Molluscan Study 72: 259–266.

Ikuta T, Yoshida N, Satoh N and Saiga H (2004) Ciona intestinalis Hox gene cluster: its dispersed structure and residual colinear expression in development. Proceedings of the National Academy of Sciences of the USA 101: 15118–15123.

Irvine SQ, Carr JL, Bailey WJ et al. (2002) Genomic analysis of Hox clusters in the sea lamprey Petromyzon marinus. Journal of Experimental Zoology 294: 47–62.

King BL, Gillis JA, Carlisle HR and Dahn RD (2011) A natural deletion of the HoxC cluster in elasmobranch fishes. Science 334: 1517.

Kuraku S, Takio Y, Tamura K et al. (2008) Noncanonical role of Hox14 revealed by its expression patterns in lamprey and shark. Proceedings of the National Academy of Sciences of the USA 105: 6679–6683.

Larroux C, Fahey B, Degnan SM et al. (2007) The NK homeobox gene cluster predates the origin of Hox genes. Current Biology 17: 706–710.

Lewis EB (1978) A gene complex controlling segmentation in Drosophila. Nature 276: 565–570.

Liubicich DM, Serano JM, Pavlopoulos A et al. (2009) Knockdown of Parhyale ultrabithorax recapitulates evolutionary changes in crustacean appendage morphology. Proceedings of the National Academy of Sciences of the USA 106: 13892–13896.

Lowe CJ, Wu M, Salic A et al. (2003) Anteroposterior patterning in hemichordates and the origins of the chordate nervous system. Cell 113: 853–865.

McGinnis W (1994) A century of homeosis, a decade of homeoboxes. Genetics 137: 607–611.

Merabet S, Hudry B, Saadaoui M and Graba Y (2009) Classification of sequence signatures: a guide to Hox protein function. BioEssays 31: 500–511.

Minguillon C and Garcia‐Fernandez J (2003) Genesis and evolution of the Evx and Mox genes and the extended Hox and ParaHox gene clusters. Genome Biology 4: R12.

Monteiro AS, Schierwater B, Dellaporta SL and Holland PW (2006) A low diversity of ANTP class homeobox genes in Placozoa. Evolution and Development 8: 174–182.

Moreno E, Nadal M, Baguna J and Martinez P (2009) Tracking the origins of the bilaterian Hox patterning system: insights from the acoel flatworm Symsagittifera roscoffensis. Evolution and Development 11: 574–581.

Moses AM, Pollard DA, Nix DA et al. (2006) Large‐scale turnover of functional transcription factor binding sites in Drosophila. PLoS Computational Biology 2: e130.

Negre B and Ruiz A (2007) HOM‐C evolution in Drosophila: is there a need for Hox gene clustering? Trends in Genetics 23: 55–59.

Pavlopoulos A, Kontarakis Z, Liubicich DM et al. (2009) Probing the evolution of appendage specialization by Hox gene misexpression in an emerging model crustacean. Proceedings of the National Academy of Sciences of the USA 106: 13897–13902.

Pierce RJ, Wu W, Hirai H et al. (2005) Evidence for a dispersed Hox gene cluster in the platyhelminth parasite Schistosoma mansoni. Molecular Biology and Evolution 22: 2491–2503.

Ravi V, Lam K, Tay BH et al. (2009) Elephant shark (Callorhinchus milii) provides insights into the evolution of Hox gene clusters in gnathostomes. Proceedings of the National Academy of Sciences of the USA 106: 16327–16332.

Ronshaugen M, McGinnis N and McGinnis W (2002) Hox protein mutation and macroevolution of the insect body plan. Nature 415: 914–917.

de Rosa R, Grenier JK, Andreeva T et al. (1999) Hox genes in brachiopods and priapulids and protostome evolution. Nature 399: 772–776.

Ryan JF, Pang K, Mullikin JC, Martindale MQ and Baxevanis AD (2010) The homeodomain complement of the ctenophore Mnemiopsis leidyi suggests that Ctenophora and Porifera diverged prior to the ParaHoxozoa. EvoDevo 1: 9.

Seo HC, Edvardsen RB, Maeland AD et al. (2004) Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica. Nature 431: 67–71.

Shapiro MD, Marks ME, Peichel CL et al. (2004) Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428: 717–723.

Slack JM, Holland PW and Graham CF (1993) The zootype and the phylotypic stage. Nature 361: 490–492.

Smith JJ, Antonacci F, Eichler EE and Amemiya CT (2009) Programmed loss of millions of base pairs from a vertebrate genome. Proceedings of the National Academy of Sciences of the USA 106: 11212–11217.

Stern DL (1998) A role of ultrabithorax in morphological differences between Drosophila species. Nature 396: 463–466.

Urata M, Tsuchimoto J, Yasui K and Yamaguchi M (2009) The Hox8 of the hemichordate Balanoglossus misakiensis. Developmental Genes and Evolution 219: 377–382.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Nolte, Christof, Ahn, Youngwook, and Krumlauf, Robb(Jul 2012) Evolutionary Developmental Biology: Hox Gene Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001063.pub3]