Li G and Holland PW (2010), The origin and evolution of ARGFX homeobox loci...

XB-ART-41941

BMC Evol Biol 2010 Jun 17;10:182. doi: 10.1186/1471-2148-10-182.

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The origin and evolution of ARGFX homeobox loci in mammalian radiation.

Li G , Holland PW .

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BACKGROUND: Many homeobox genes show remarkable conservation between divergent animal phyla. In contrast, the ARGFX (Arginine-fifty homeobox) homeobox locus was identified in the human genome but is not present in mouse or invertebrates. Here we ask when and how this locus originated and examine its pattern of molecular evolution. RESULTS: Phylogenetic and phylogenomic analyses suggest that ARGFX originated by gene duplication from Otx1, Otx2 or Crx during early mammalian evolution, most likely on the stem lineage of the eutherians. ARGFX diverged extensively from its progenitor homeobox gene and its exons have been functional and subject to purifying selection through much of placental mammal radiation. Surprisingly, the coding region is disrupted in most mammalian genomes analysed, with human being the only mammal identified in which the full open reading frame is retained. Indeed, we describe a transcript from human testis that has the potential to encode the full deduced protein. CONCLUSIONS: The unusual pattern of evolution suggests that the ARGFX gene may encode a functional RNA or alternatively it may have 'flickered' between functional and non-functional states in the evolutionary history of mammals, particularly in the period when many mammalian lineages diverged within a relatively short time span.

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Species referenced: Xenopus
Genes referenced: crx fap gsc hesx1 otx1 otx2 tprx1 vsx1

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	Figure 1. Gene structure of human ARGFX. PCR primer positions and amplicons are shown relative to predicted human ARGFX gene structure [6]. Boxes indicate exons, drawn to scale; lines indicate introns, not drawn to scale. Numbers above boxes and beneath lines indicate the lengths of each exon and intron. The 5' and 3' untranslated regions are shown in white and the protein coding regions are shown in black, except for the homeodomain which is red.
	Figure 2. ARGFX gene in vertebrates. The phylogenetic tree of mammals is based on [29-32]. Column 1: ARGFX is inferred to be a probable gene (√), possible pseudogene with disrupted coding region (ψ), secondarily completely lost (×) or not included in current genome data (?). Column 2: Minimal number of retrotransposed ARGFX pseudogenes based on current genome data. Column 3: Synteny with the human ARGFX genomic region is conserved (√) or not (×), or not sequenced (?).
	Figure 3. Comparison of ARGFX, OTX1, OTX2 and CRX gene structures. Human TPRX1, DPRX, HESX1 and GSC gene structures were used as references. Exons are represented by boxes and introns by lines, with the length in nucleotides written above. The 5' and 3' untranslated regions are shown in white and the protein coding regions in black except for homeodomains which are shown in red. Human gene structures follow the NCBI gene annotation; tree shrew and megabat ARGFX intron positions were deduced by reference to retroposed pseudogenes.
	Figure 4. Greater conservation of DNA sequences between human ARGFX, OTX1 and OTX2 genomic regions than with DPRX and TPRX1. Human GSC and HESX1 were also used as references, but no similarity was found. Genomic sequences from the last base pair of upstream gene to the first base pair of downstream gene for each locus (based on UCSC at http://genome.ucsc.edu/ were used, and compared using Shuffle-LAGAN [28] in mVISTA, which can detect sequence rearrangements. Coloured peaks (purple, coding; pink, intergenic; blue, transcribed non-coding) indicate regions of at least 30 bp and 30% similarity.
	Figure 5. Phylogenetic relationship between ARGFX and other PRD class homeobox genes. Maximum likelihood phylogenetic tree constructed using complete deduced human ARGFX protein sequence and the most similar human homeodomain proteins. Bootstrap support values over 50% are shown. Essentially the same topology was recovered by Bayesian analysis except at weakly supported nodes, notably the position of VSX1.
	Figure 6. Synteny and paralogy around the Otx gene family. Map positions of amphioxus Otx and its neighbouring genes are compared to their human orthologues, which map primarily to chromosomes 1, 2, 14, 11 and 19, not chromosome 3. Amphioxus genes are shown in their physical order, and are numbered as in amphioxus (B. floridae) genome assembly v. 1.0. GeneID 20 is amphioxus Otx. GeneID 22 and 23 are most likely two parts of a gene and are treated as one locus. Human orthologues are not necessarily in order. Amphioxus genes 2 and 19 (black boxes) do not have clear human homologues; phylogenetic relationships are not well resolved for amphioxus genes 8, 17 and 24 (grey boxes). Human orthologues of amphioxus gene 13 do not map to on the five main chromosomal regions.
	Figure 7. Conservation of DNA sequence conservation between mammalian ARGFX genomic sequences. Only species with a high genome assembly in this region were used. Sequences were aligned by the LAGAN program [17] in mVISTA. Length of the genomic region for each species is on the right. Macaque is missing a region between exon 2 and exon 4 accounting for higher similarity between human and marmoset than human and macaque in this region. The higher sequence similarity in and around exons is clearly visible, indicative of selective constraints since divergence of the species shown. Coloured peaks (purple, coding; pink, intergenic; light blue, UTR) indicate regions of at least 50 bp and 50% similarity.a. mVISTA plot using repeat-masked genomic sequences; b. mVISTA plot using sequence with no masking of repeats.

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