Evolution of the Hox Gene Cluster


The Hox genes are a family of developmental control genes containing a homeobox motif, and tend to be organised in distinctive clustered arrays in animals. Organisation within the cluster can relate to how the genes function. Whilst much has been discovered about the Hox gene cluster in traditional model systems of developmental biology, increasing amounts of data from a wider variety of species are illuminating more about the nature of the Hox cluster deep in animal ancestry, as well as revealing the evolutionary flexibility and derivations along present‐day lineages. The consensus view of the Hox cluster is that it patterns the anterior–posterior axis of bilaterally symmetrical (bilaterian) animals and exhibits the phenomenon of colinearity. There is, however, much evolutionary change within this system. This diversity in the Hox system is linked to the evolution of animal diversity and informs our understanding of the pre‐bilaterian origins of the Hox genes themselves.

Key Concepts:

  • Spatial colinearity is the phenomenon whereby the order of the expression domains of the Hox genes along the anterior–posterior axis of the embryo corresponds with the order of the genes along the chromosome.

  • Temporal colinearity is a further form of colinearity in which the Hox genes in some taxa are activated progressively, with the earliest time at which a gene is activated matching its position within the Hox cluster.

  • Anterior–posterior patterning by the Hox genes is distinct from the initial determination of the anterior–posterior axis and instead involves the specification of different developmental fates within the anterior–posterior axis of an embryo. This is one of the major roles of the Hox genes within the bilaterians, but the Hox genes do have further roles in development subsequent to this anterior–posterior patterning function.

  • A range of Hox gene organisation has evolved across different lineages, forming organised, disorganised, split and atomised Hox clusters, such that the Hox genes of some species are not actually organised into a Hox gene cluster.

Keywords: homeobox; bilaterian; cnidarian; Hox gene; Hox cluster

Figure 1.

The diversity of Hox gene organisation in the animal kingdom and potential ancestral states. The phylogenetic relationships amongst the named species is shown, along with some indication of the major animal clades named along the branches of the tree. Note, the phylogenetic position of the Acoela is still the matter of some debate (see main text). Hox gene symbols are coloured to represent the four main types of Hox gene that are commonly recognised: Anterior (orange), Group 3 (green), Central (blue) and Posterior (red). The grey genes that have expanded within the Bombyx mori cluster are of an unclassified type. Horizontal lines connecting Hox genes represent known linkage and clustering, with parallel diagonal bars indicating large intergenic distances between genes on the same chromosome (i.e. linkage but not clustering). Genes that are known not to be linked are shown as off‐set, however, the distribution of the Oikopleura dioica and Nematostella vectensis genes is not known to the chromosomal level as this information is taken from the whole genome sequence assemblies in which the scaffolds tend to be assembled to a sub‐chromosomal level (Seo et al., ; Ryan et al., ). The Schistosoma mansoni data is taken from (Pierce et al., ), which does not include every S. mansoni Hox gene (Gu et al., ) but still indicates a dispersed cluster. Potential ancestral states of the Hox cluster are shown in magenta boxes (1, 2 and 3) along the basal parts of the tree. (1) The cnidarian–bilaterian ancestor may have had at least two or three genes. Cnidarians are generally recognised as having Anterior and Posterior genes, but may also have Central or Group 3 genes according to some authors (see main text), denoted by the bracketed gene. (2) The urbilaterian likely had four or five Hox genes, with an Anterior, two Central and a Posterior gene as well as a possible Group 3 (bracketed) according to (Jiménez‐Guri et al., ). (3) The Protostome–Deuterostome ancestor had at least seven Hox genes (de Rosa et al., ). The numbers of genes in these hypothesised ancestral clusters are necessarily minimum numbers.



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

Amemiya CT, Prohaska SJ, Hill‐Force A et al. (2008) The amphioxus Hox cluster: characterization, comparative genomics, and evolution. Journal of Experimental Zoology Molecular and Developmental Evolution 310B: 465–477.

Balavoine G, de Rosa R and Adoutte A (2002) Hox clusters and bilaterian phylogeny. Molecular Phylogenetics and Evolution 24: 366–373.

Cameron RA, Rowen L, Nesbitt R et al. (2006) Unusual gene order and organization of the sea urchin Hox cluster. Journal of Experimental Zoology Molecular and Developmental Evolution 306B: 45–58.

Cartwright P, Dick M and Buss LW (1993) HOM/Hox type homeoboxes in the chelicarate Limulus polyphemus. Molecular Phylogenetics and Evolution 2: 185–192.

Chai C‐L, Zhang Z, Huang F‐F et al. (2008) A genomewide survey of homeobox genes and identification of novel structure of the Hox cluster in the silkworm, Bombyx mori. Insect Biochemistry and Molecular Biology 38: 1111–1120.

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.

Cho S‐J, Vallès Y, Kim KM et al. (2012) Additional duplicated Hox genes in the earthworm: Perionyx excavatus Hox genes consist of eleven groups. Gene 493: 260–266.

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

Di‐Poï N, Montoya‐Burgos JI and Duboule D (2009) Atypical relaxation of structural constraints in Hox gene clusters of the green anole lizard. Genome Research 19: 602–610.

Duboule D (1994) Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony. Development (Supplement): 135–142.

Duboule D (1998) Hox is in the hair: a break in colinearity? Genes & Development 12: 1–4.

Duboule D (2007) The rise and fall of Hox gene clusters. Development 134: 2549–2560.

Durston AJ, Jansen HJ, In der Rieden P and Hooiveld HW (2011) Hox collinearity – a new perspective. International Journal of Developmental Biology 55: 899–908.

Egger B, Steinke D, Tarui H et al. (2009) To be or not to be a flatworm: the acoel controversy. PLoS ONE 4: e5502.

Falciani F, Hausdorf B, Schröder R et al. (1996) Class 3 Hox genes in insects and the origin of zen. Proceedings of the National Academy of Sciences of the USA 93: 8479–8484.

Ferrier DEK (2010) Evolution of Hox complexes. Chp 6. Pg 91‐100. In: Deutsch JS (ed.) Hox genes: studies from the 20th to the 21st century. Austin, TX: Landes Bioscience and New York, NY: Springer Science.

Ferrier DEK and Holland PWH (2001) Ancient origin of the Hox gene cluster. Nature Reviews Genetics 2: 33–38.

Ferrier DEK and Minguillón C (2003) Evolution of the Hox/ParaHox gene clusters. International Journal of Developmental Biology 47: 605–611.

Ferrier DEK, Minguillón C, Holland PWH and Garcia‐Fernàndez J (2000) The amphioxus Hox cluster: deuterostome posterior flexibility and Hox14. Evolution & Development 2: 284–293.

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

Force A, Lynch M, Pickett FB et al. (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151: 1531–1545.

Fröbius AC, Matus DQ and Seaver EC (2008) Genomic organization and expression demonstrate spatial and temporal Hox gene colinearity in the lophotrochozoan Capitella sp. PLoS ONE 3: e4004.

Gauchat D, Mazet F, Berney C et al. (2000) Evolution of Antp‐class genes and differential expression of Hydra Hox/ParaHox genes in anterior patterning. Proceedings of the National Academy of Sciences of the USA 97: 4493–4498.

Géant É, Mouchel‐Vielh E, Coutanceau J‐P et al. (2006) Are Cirripedia hopeful monsters? Cytogenetic approach and evidence for a Hox gene cluster in the cirripede crustacean Sacculina carcini. Development Genes and Evolution 216: 443–449.

Gehring W (2012) The animal body plan, the prototypic body segment, and eye evolution. Evolution & Developmentel 14: 34–46.

Godwin AR and Capecchi MR (1998) Hoxc13 mutant mice lack external hair. Genes & Development 12: 11–20.

Graham A, Maden M and Krumlauf R (1991) The murine Hox‐2 genes display dynamic dorsoventral patterns of expression during central nervous system development. Development 112: 255–264.

Gu J‐L, Chen S‐X, Dou T‐H et al. (2012) Hox genes from the parasitic flatworm Schistosoma japonicum. Genomics 99: 59–65.

Hejnol A, Obst M, Stamatakis A et al. (2009) Assessing the root of bilaterian animals with scalable phylogenoimc methods. Proceedings of the Royal Society B (Biological Sciences) 276: 4261–4270.

Hoegg S, Boore JL, Kuehi JV and Meyer A (2007) Comparative phylogenomic analyses of teleost fish Hox gene clusters: lessons from the cichlid fish Astatotilapia burtoni. BMC Genomics 8: 317.

Holland LZ, Albalat R, Azumi K et al. (2008) The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Research 18: 1100–1111.

Holland PWH, Booth HAF and Bruford EA (2007) Classification and nomenclature of all human homeobox genes. BMC Biology 5: 47.

Hui JHL, Holland PWH and Ferrier DEK (2008) Do cnidarians have a ParaHox cluster? Analysis of synteny around a Nematostella homeobox gene cluster. Evolution & Development 10: 725–730.

Hui JHL, McDougall C, Monteiro AS et al. (2012) Extensive chordate and annelid macrosynteny reveals ancestral homeobox gene organization. Molecular Biology and Evolution 29: 157–165.

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.

Jaillon O, Aury JM, Brunet F et al. (2004) Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto‐karyotype. Nature 431: 946–957.

Jiménez‐Guri E, Paps J, Garcia‐Fernàndez J and Saló E (2006) Hox and ParaHox genes in Nemertodermatida, a basal bilaterian clade. International Journal of Developmental Biology 50: 675–679.

Kamm K, Schierwater B, Jakob W et al. (2006) Axial patterning and diversification in the Cnidaria predate the Hox system. Current Biology 16: 920–926.

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

Kmita M and Duboule D (2003) Organizing axes in time and space; 25 years of collinear tinkering. Science 301: 331–333.

Kourakis MJ and Martindale MQ (2001) Hox gene duplication and deployment in the annelid leech Helobdella. Evolution & Development 3: 145–153.

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.

Lemons D and McGinnis W (2006) Genomic evolution of Hox gene clusters. Science 313: 1918–1922.

Montavon T, Le Garrec J‐F, Kerszberg M and Duboule D (2008) Modelling Hox gene regulation in digits: reverse collinearity and the molecular origin of thumbness. Genes & Development 22: 346–359.

Monteiro AS and Ferrier DEK (2006) Hox genes are not always colinear. International Journal of Biological Sciences 2: 95–103.

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

Mungpakdee S, Seo H‐C, Angotzi AR et al. (2008) Differential evolution of the 13 Atlantic Salmon Hox clusters. Molecular Biology and Evolution 25: 1333–1343.

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.

Osborne PW and Ferrier DEK (2010) Chordate Hox and ParaHox gene clusters differ dramatically in their repetitive element content. Molecular Biology and Evolution 27: 217–220.

Philippe H, Brinkman H, Copley R et al. (2011) Acoelomorph flatworms are deuterostomes related to Xenoturbella. Nature 470: 255–258.

Philippe H, Brinkmann H, Martinez P et al. (2007) Acoel flatworms are not Platyhelminthes: evidence from phylogenomics. PLoS ONE 2: e717.

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.

Powers TP and Amemiya CT (2004) Evidence for a Hox14 paralog group in vertebrates. Current Biology 14: R183–R184.

Putnam NH, Butts T, Ferrier DEK et al. (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature 453: 1064–1071.

Putnam NH, Srivastava M, Hellsten U et al. (2007) Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317: 86–94.

Ravi V, Lam K, Tay B‐H 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.

Ryan J, Mazza ME, Pang K et al. (2007) Pre‐bilaterian origins of the Hox cluster and the Hox code: evidence from the sea anemone, Nematostella vectensis. PLoS ONE 2: e153.

Schwager EE, Schoppmeier M, Pechmann M and Damen WGM (2007) Duplicated Hox genes in the spider Cupiennius salei. Frontiers in Zoology 4: 10.

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

Shigenobu S, Bickel RD, Brisson JA et al. (2010) Comprehensive survey of developmental genes in the pea aphid, Acyrthosiphon pisum: frequent lineage‐specific duplications and losses of developmental genes. Insect Molecular Biology 19(suppl. 2): 47–62.

Stauber M, Jäckle H and Schmidt‐Ott U (1999) The anterior determinant bicoid of Drosophila is a derived Hox class 3 gene. Proceedings of the National Academy of Sciences of the USA 96: 3786–3789.

Van Auken K, Weaver DC, Edgar LG and Wood WB (2000) Caenorhabditis elegans embryonic axial patterning requires two recently discovered posterior‐group Hox genes. Proceedings of the National Academy of Sciences of the USA 97: 4499–4503.

Yasukochi Y, Ashakumary LA, Wu C et al. (2004) Organization of the Hox gene cluster of the silkworm, Bombyx mori: a split of the Hox cluster in a non‐Drosophila insect. Development Genes and Evolution 214: 606–614.

Yuan J, He Z, Yuan X et al. (2010) Speciation of polyploidy cyprinidae fish of common carp, crucian carp, and silver crucian carp derived from duplicated Hox genes. Journal of Experimental Zoology Molecular and Developmental Evolution 314B: 445–456.

Zou S‐M, Jiang X‐Y, He Z‐Z et al. (2007) Hox gene clusters in blunt snout bream, Megalobrama amblycephala and comparison with those of zebrafish, fugu and medaka genomes. Gene 400: 60–70.

Further Reading

Deutsch JS (ed.) (2010) Hox genes: studies from the 20th to the 21st century. In: Advances in Experimental Medicine and Biology, vol. 689. New York, NY: Springer Science and Austin, TX: Landes Bioscience.

Papageorgiou S (ed.) (2007) Hox gene expression. New York, NY: Springer Science and Austin, TX: Landes Bioscience.

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Ferrier, David EK(Aug 2012) Evolution of the Hox Gene Cluster. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023989]