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Hox Gene Clusters of Early Vertebrates: Do They Serve as ReliableMarkers for Genome Evolution?
Shigehiro Kuraku
 Laboratory for Zoology and Evolutionary Biology, Department of Biology, University of Konstanz, 78464 Konstanz, Germany.
Genomics Proteomics Bioinformatics 2011 Jun; 9(3): Uncorrected Proof DOI:Received: Jan 31, 2011; Accepted: Mar 21, 2011
Hox genes, responsible for regional specification along the anteroposterior axis in embryogenesis, are found asclusters in most eumetazoan genomes sequenced to date. Invertebrates possess a single Hox gene cluster withsome exceptions of secondary cluster breakages, while osteichthyans (bony vertebrates) have multiple Hox clus-ters. In tetrapods, four Hox clusters, derived from the so-called two-round whole genome duplications(2R-WGDs), are observed. Overall, the number of Hox gene clusters has been regarded as a reliable marker of  ploidy levels in animal genomes. In fact, this scheme also fits the situations in teleost fishes that experienced anadditional WGD. In this review, I focus on cyclostomes and cartilaginous fishes as lineages that would fill the gap between invertebrates and osteichthyans. A recent study highlighted a possible loss of the HoxC cluster in thegaleomorph shark lineage, while other aspects of cartilaginous fish Hox clusters usually mark their conserved na-ture. In contrast, existing resources suggest that the cyclostomes exhibit a different mode of Hox cluster organiza-tion. For this group of species, whose genomes could have differently responded to the 2R-WGDs from jawedvertebrates, therefore the number of Hox clusters may not serve as a good indicator of their ploidy level.
Key words
: Hox cluster, Chondrichthyes, Cyclostomata, whole genome duplication, hidden paralogy
Hox genes in eumetazoan genomes are generally or-ganized into clusters (
). During development, theorders of genes comprising the Hox clusters are con-verted into information governing specification of different body compartments along the anteroposte-rior axis. In vertebrates, this scheme was originally presented for the patterning of the hindbrain and pha-ryngeal arches (“Hox code”) (
). Later, similar pat-terns were observed in the development of limb buds
*Corresponding author.E-mail: shigehiro.kuraku@uni-konstanz.de© 2011 Beijing Institute of Genomics. All rights reserved.
) and gut endoderm (
). With some exceptions, Hoxgenes closer to the 3'-end of Hox clusters are ex- pressed earlier in development (temporal collinearity)and also more anteriorly in embryos (spatial collin-earity) (
). In all vertebrate genomes sequenced todate, Hox genes are found in multiple clusters, and thenumber of Hox clusters exactly (in tetrapods) or roughly (in teleost fishes) corresponds to their ploidylevels, indicating how many times those species ex- perienced whole genome duplications (WGDs) (
).Hox gene regulation is often introduced as one of the most striking examples of conserved molecular  programs underlying conserved morphological archi-tecture of animal body plans. However, even amongvertebrate model systems serving as traditional labo-
 Kuraku / Hox Clusters of Early VertebratesGenomics Proteomics Bioinformatics 2011 Jun; 9(3): Uncorrected Proof 
ratory animals, Hox cluster composition varies tosome extent as a result of secondary gene losses andcluster doublings (
). Most importantly, our knowl-edge about vertebrate Hox cluster organization andgene regulation has concentrated mostly on traditionallaboratory model systems, all of which belong to asubgroup of vertebrates, Osteichthyes (bony verte- brates). With all technical factors regarding access toanimal resources, recent development in genomic andembryonic studies on cyclostomes and cartilaginousfishes is providing a new frontier of vertebrate Hoxstudies. In this review, focusing on theseearly-branching evolutionary lineages, I summarizethe progress broadening our scope, which previouslydepended exclusively on osteichthyans. In addition,insights into evolutionary processes of Hox genecluster organization are also presented.
Hox Genes in Cartilaginous Fishesand Cyclostomes
Hox gene repertoire in cartilaginous fishes
Among cartilaginous fishes, the first report of Hoxcluster organization came from the horn shark 
 Het-erodontus francisci
). This species is categorized inthe order Heterodontiformes, and this order is re-garded as the most basal among extant members of Galeomorphi. In this species, only two Hox clusters,designated HoxM and HoxN, were sequenced. Pres-ence and absence of particular Hox paralog groups, aswell as lengths of intergenic regions and molecular  phylogeny, consistently supported the homology of HoxM and HoxN clusters to HoxA and HoxD, re-spectively (
7, 8
).Later, in the elephant shark (also called ghost shark or elephant fish),
Callorhinchus milii
, genomic se-quencing of Hox clusters was completed based on the1.4× whole-genome shotgun reads and targeted bacte-rial artificial chromosomes (BAC) clone screening (
). Importantly, this species retains four Hox clusters,containing 45 Hox genes in total (compared to 39 Hoxgenes in human). Also, 1-to-1 homology of these four clusters to osteichthyan HoxA-D was firmly sup- ported. In
C. milii
, seven paralog groups (PGs) weredetected with four members on clusters A-D, namelyPG-1, -3, -4, -5, -9, -10 and -13, while there are onlythree in human, namely PG-4, -9 and -13. This al-lowed a more reliable analysis to investigate the process of cluster duplications. The molecular phy-logenetic analysis supported the scenario with the1-2-4 pattern (
6, 11
), namely the tree topology[(HoxA, HoxB), (HoxC, HoxD)] (
).More recently, the organization of Hox genes andclusters of the lesser spotted dogfish
was revealed by transcriptome sequencingand BAC clone screening (
). This species has beenone of the most promising systems for developmental biology because of its relatively small adult body sizeand oviparity (
). The most striking result in thisstudy was the absence of HoxC members in both ge-nomic and transcriptomic sequencing (
Figure 1
),while the other three clusters were revealed to haveretained a comparable number of Hox genes to that in
C. milii
).Overall, except for the possible absence of theHoxC cluster in
S. canicula
, cartilaginous fishes haveretained more ancestral members of Hox genes thanosteichthyans. More precisely,
have been identified only in cartilaginousfishes, and are thought to have been lost from theHoxD cluster in the basal osteichthyan lineage. Re-tention of ancestral features by cartilaginous fisheshas also been shown in conservation of intergenicsequences in Hox clusters (
). The HoxA cluster wasalso recently sequenced for the little skate
, and compared with that of 
 H. francisci
).This ray–shark comparison equates to a timespan of more than 250 million years (
16, 17 
) and highlighteda higher level of conservation of non-coding se-quences inside the Hox cluster than that in theosteichthyan lineage of a comparable evolutionarydistance (
Hox gene expression in cartilaginous fishes
In cartilaginous fishes, investigations on roles of Hoxgenes have been driven by interests in the evolution of developmental programs responsible for limb/digitformation (
). Analyses on cartilaginous fish Hoxgenes have so far concentrated on species in twooviparous groups, namely those in the genus
S. canicula
S. torazame
) and
L. erinacea
 Kuraku / Hox Clusters of Early Vertebrates
Genomics Proteomics Bioinformatics 2011 Jun; 9(3): Uncorrected Proof 
Figure 1
Timings of whole genome duplications and multiplicity of Hox clusters. Numbers of Hox clusters identified so far areshown in the box in the middle adjacent to taxon names. Exact numbers of Hox clusters are given for taxa represented by specieswith genomic data, while the symbol “?” is included for other taxa. Note that two urochordates were shown to possess single, butatomized Hox clusters (
1, 46, 47 
). The possible loss of the HoxC cluster in the chondrichthyan lineage might have occurred even before the split between sharks and rays/skates. Based on the current understanding that cyclostomes may have a smaller number of Hox clusters than four, two possible evolutionary scenarios were presented on both sides. The “post-2R cyclostome” hypothesis (left),compatible with a large-scale phylogenetic analysis employing non-Hox genes (
), postulates a secondary reduction of Hox clusters.Based on the “mid-2R cyclostomes” hypothesis (right) (
48, 49
), the possibly smaller number of Hox clusters in cyclostomes is ex- plained by their divergence before the second round of the whole genome duplication. Intensity of green color indicates the number of Hox clusters in individual evolutionary steps and taxa.
S. canicula
, 5' Hox genes (
) were reported to be expressed in anested pattern, consistent with both spatial and tem- poral collinearity (
), as seen in osteichthyans(
22, 23
). Expression of 
S. torazame
wasshown in a subpopulation of cells surrounding thehindgut, but not in tissues that would normally ex- press Hox genes, such as the neural tube, somitesand fin folds, suggesting the decoupling of thisgene from the Hox code (
). Hindgut-associatedexpression is also documented for 
 L. erinacea
, and these genes are thoughtto be involved in early hindgut patterning as in am-niotes (
). No expression patterns of Hox genes in PG1-8 had been reported for cartilaginous fishes until very re-cently. As elasmobranchs have been studied as amodel for craniofacial development since the 19thcentury (
), this avenue of research needed to beurgently pursued. Very recently, Oulion
et al 
reportedembryonic expression patterns of 34 Hox genes in
and concluded that their nested expression of Hox genes (Hox code) in branchial arches, hindbrainand somites was maintained in this species and is aground plan of embryonic architecture, which under-went only small amount of changes during jawed ver-tebrate evolution (
Hox gene repertoire in cyclostomes
Cyclostomes are divided into hagfishes (Myxinifor-mes) and lampreys (Petromyzontiformes). These twolineages separated more than 400 million years ago(
). Each of Myxiniformes and Petromyzontiformesconsists of only up to 50 species that diversifiedwithin 200 million years
a long time after the sepa-ration between Myxiniformes and Petromyzontifor-mes (
). Molecular sequence data are reportedmostly for species in the northern hemisphere. InPetromyzontiformes, northern hemisphere speciesform a distinct family Petromyzontidae that diversi-fied only within 50 million years (
).Hox cluster organization in cyclostomes is stillcontroversial because of some difficulties unique tothis group of species (
). Firstly, the so-calledtwo-round whole genome duplications (2R-WGDs)

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