Introduction:

‘Orphans’ was the name given to the these Hox related genes earlier, till Brooke et al in 1998 made it clear that these orphan genes were in fact clustered in Amphioxus, Branchiostoma floridae. This cluster was named ParaHox, which is the paralogue of the Hox cluster. Para Hox genes encode very similar homeodoamain and its very easy to get confused with those of HOX genes in absence of linkage analysis and expression data. In Amphioxus ,these Hox-like genes (Gsx [genomic screened homeobox], Xlox/Ipf1 [Xenopus laevis homeobox 8/insulin promoter factor 1], and Cdx [caudal-type homeobox]) are found to be closely linked to each other.

Molecular phylogenetics suggests that Gsx is most closely related to Hox 1–2, Xlox to Hox 3, and Cdx to Hox 9 and other posterior Hox genes.The precise mechanism for the generation of Hox and ParaHox genes remains uncertain but most studies believe that that the cluster of Gsx-Xlox-Cdx (para Hox genes) and hox genes are paralogues resulting from a duplication of ancient hypothetical “Protohox” cluster, hence the name “ParaHox” genes.

Importance :
Various studies of ParaHox genes in vertebrates and invertebrates show that they all have roles in developmental processes. Gsx genes are known for the role in brain patterning , whereas Xlox is expressed in the invertebrate gut and is involved in development of the vertebrate pancreas .Cdx genes are involved in patterning of the posterior gut and neural tube.

Distribution:
These parahox genes are present in clades of both Protostomes and Deuterostomes, it can be inferred that this gene complement and cluster organization are ancestral, dating at least to the basal bilaterian. In humans a ParaHox cluster is found on chromosome 13q12.2 ,consisting genes GSH1, IPF1 (also known as PDX1 or Xlox in other organisms),and CDX2.The human genome also contains paralogues of the Gsx and Cdx families (GSH2, CDX1, and CDX4) dispersed on 3 other chromosomes.It has been proposed that all three ParaHox genes were present in the last common ancestor to the lophotrochozoan protostomes and the deuterostomes and that gene loss event has occurred in the ecdysozoan lineage.Unlike Hox genes, ParaHox genes seem much more evolutionary labile.For instance, both Drosophila melanogaster and Caenorhabditis elegans (Ecdysozoans) lack Xlox, and C. elegans also lacks Gsx, and in the fly Gsx (called Ind) is not linked with Caudal. In the ascidian Ciona intestinalis, all three genes are found, but again there is no evidence of clustering.

ParaHox clusters in Cnidarian Nematostella :

Studies conducted in 2006 by Kamm et al. came out with a hypothesis that Cnidaria do not have true Hox genes and the clusters of Hox-like genes in these diploblasts arose from independent duplications to those that produced the Hox and ParaHox loci of Bilateria.But some remarkable work ,a year later by Putnam et al.(ALSO READ HOX GENES IN NEMATOSTELLA) in science journal showed evidence that the gene clusters on Nematostella scaffolds 3 and 61 are indeed homologous to the Hox gene cluster of bilaterians,meaning that the two sets of genes descend from a common shared ancestral gene cluster.The strength of the evidence not only lies in the analysis of Hox genes but also through the neighboring environment of the genome ,remarkably several genes linked to Hox genes in the human genome had homologs neighboring the Nematostella homeobox clusters.

But the picture concerning the Parahox genes was not crystal clear,even though homologous genes for bilaterian ParaHox genes were known to occur in Nematostella since 10 years (Finnerty and Martindale 1999).But the synteny data (from Human to Nematostella analysis) obtained for Hox genes by Putnam et al didn’t support when it comes to ParaHox genes.

Jerome H. L. Hui, et al used a different approach to search for synteny between the putative Nematostella ParaHox cluster and the ParaHox genes of bilaterians.In addition to searching for the locations of Nematostella homologs of human genes, authors also did a reciprocal analysis from Nematostella to bilaterian genomes, at two different spatial scales. After all the analysis they could see a clear signal of homology between the pair of Nematostella homeobox genes on scaffold 27 and the ParaHox gene cluster of bilaterians.(For the detail strategy employed read the material and methods of the original article )
The region of Nematostella scaffold 27 closest to the putative cnidarian ParaHox cluster is gene dense,containing orthologs of human ParaHox associated genes like human Graf protein (NveGraf), WD 19 repeat protein (NveWdr19), Sar1 protein (NveSar1), hypothetical protein (NveCG1218), and Pomp protein (NvePomp), based on both domain structure and phylogenetic analyses.Interestingly,the orthologs of NveGraf, NveSar1, and NvePomp were located in the same region as ParaHox genes in human (5q31 and 13q12.3), suggesting these three genes were located in the ParaHox region in the Cnidaria-Bilateria ancestor.Not only this Graf and Pomp are located on the same scaffold as the ParaHox genes in the mollusc Lottia gigantea.All these data generated by the authors prove that the Nematostella vectensis homeobox cluster on scaffold 27 is a cnidarian ParaHox cluster,beyond any doubt.

References:

Brooke NM, Garcia-Fernandez J, Holland PWH. The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster. Nature (1998) 392:920–922

Garcia-Fernandez, 2005 J. Garcia-Fernandez, The genesis and evolution of homeobox gene clusters, Nat. Rev., Genet. 6 (2005), pp. 881–892.

Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization.
Putnam NH, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A, Terry A, Shapiro H, Lindquist E, Kapitonov VV, Jurka J, Genikhovich G, Grigoriev IV, Lucas SM, Steele RE, Finnerty JR, Technau U, Martindale MQ, Rokhsar DS.
Science. 2007 Jul 6;317(5834):86-94.

Do cnidarians have a ParaHox cluster? Analysis of synteny around a Nematostella homeobox gene cluster.
Hui JH, Holland PW, Ferrier DE.
Evol Dev. 2008 Nov-Dec;10(6):725-30.

Image Credit : Pelagosphera / FlickR

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