A family history of DUX4: Phylogenetic analysis of DUXA, B, C and Duxbl reveals the ancestral DUX gene

Centre for Genetics and Genomics, School of Biology, The University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK.
BMC Evolutionary Biology (Impact Factor: 3.37). 11/2010; 10(1):364. DOI: 10.1186/1471-2148-10-364
Source: PubMed


DUX4 is causally involved in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD). It has previously been proposed to have arisen by retrotransposition of DUXC, one of four known intron-containing DUX genes. Here, we investigate the evolutionary history of this multi-member double-homeobox gene family in eutherian mammals.
Our analysis of the DUX family shows the distribution of different homologues across the mammalian class, including events of secondary loss. Phylogenetic comparison, analysis of gene structures and information from syntenic regions confirm the paralogous relationship of Duxbl and DUXB and characterize their relationship with DUXA and DUXC. We further identify Duxbl pseudogene orthologues in primates. A survey of non-mammalian genomes identified a single-homeobox gene (sDUX) as a likely representative homologue of the mammalian DUX ancestor before the homeobox duplication. Based on the gene structure maps, we suggest a possible mechanism for the generation of the DUX gene structure.
Our study underlines how secondary loss of orthologues can obscure the true ancestry of individual gene family members. Their relationships should be considered when interpreting the relevance of functional data from DUX4 homologues such as Dux and Duxbl to FSHD.

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Available from: Jane E Hewitt
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    • "The DUX4 gene itself originates from a repetitive element, as it is a processed pseudogene of the ancestral DUXC gene. Interestingly, DUX4 and not DUXC has been selectively retained in the primate lineage (Clapp et al., 2007; Leidenroth and Hewitt, 2010). In healthy subjects DUX4 is expressed only in the germ line, while it is epigenetically silenced in somatic tissues (Snider et al., 2010). "
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    ABSTRACT: Repetitive elements comprise over two-thirds of the human genome. For a long time, these elements have received little attention since they were considered non-functional. On the contrary, recent evidence indicates that they play central roles in genome integrity, gene expression, and disease. Indeed, repeats display meiotic instability associated with disease and are located within common fragile sites, which are hotspots of chromosome re-arrangements in tumors. Moreover, a variety of diseases have been associated with aberrant transcription of repetitive elements. Overall this indicates that appropriate regulation of repetitive elements' activity is fundamental. Polycomb group (PcG) proteins are epigenetic regulators that are essential for the normal development of multicellular organisms. Mammalian PcG proteins are involved in fundamental processes, such as cellular memory, cell proliferation, genomic imprinting, X-inactivation, and cancer development. PcG proteins can convey their activity through long-distance interactions also on different chromosomes. This indicates that the 3D organization of PcG proteins contributes significantly to their function. However, it is still unclear how these complex mechanisms are orchestrated and which role PcG proteins play in the multi-level organization of gene regulation. Intriguingly, the greatest proportion of Polycomb-mediated chromatin modifications is located in genomic repeats and it has been suggested that they could provide a binding platform for Polycomb proteins. Here, these lines of evidence are woven together to discuss how repetitive elements could contribute to chromatin organization in the 3D nuclear space.
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    • "It was previously shown (Bae et al., 2011) that in frog, Siamois and Twin form homodimers and heterodimers on the GSC promoter. This suggests that an extra homeodomain , most probably acquired in a duplication event (Leidenroth and Hewitt, 2010), was not redundant. Rather, this additional homeobox may affect the way DUX proteins function as single units, without dimer formation. "
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    ABSTRACT: Human embryonic stem cells differentiate into gastrula organizer cells that express typical markers and induce secondary axes when injected into frog embryos. Here, we report that these human organizer cells express DUXO (DUX of the Organizer), a novel member of the double-homeobox (DUX) family of transcription factors, a group of genes unique to placental mammals. Both of DUXO's homeodomains share high similarity with those of Siamois and Twin, the initial inducers of the amphibian gastrula organizer. DUXO overexpression in human embryoid bodies induces organizer related genes, whereas its knock down hampers formation of the organizer and its derivatives. Finally, we show that DUXO regulates GOOSECOID, the canonical organizer marker, in a direct manner, suggesting that DUXO is a major regulator of human organizer formation.
    Preview · Article · Aug 2012 · Stem Cell Research
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    • "All the analyzed species showed the maintenance of the DUX ORF and an array organization containing at least 10 repeated units. Furthermore a survey of non-mammalian genomes identified a likely ancestor of the mammalian DUX gene [33]. Conversely, the appearance of clustered Beta satellite sequences can be traced back to the gorilla, where the bulk of the repeats were mapped interstitially to 4p and to the p arm of chromosome Y [28] [29]. "
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    ABSTRACT: We performed a detailed genomic investigation of the chimpanzee locus syntenic to human chromosome 4q35.2, associated to the facioscapulohumeral dystrophy. Two contigs of approximately 150kb and 200kb were derived from PTR chromosomes 4q35 and 3p12, respectively: both regions showed a very similar sequence organization, including D4Z4 and Beta satellite linked clusters. Starting from these findings, we derived a hypothetical evolutionary history of human 4q35, 10q26 and 3p12 chromosome regions focusing on the D4Z4-Beta satellite linked organization. The D4Z4 unit showed an open reading frame (DUX4) at both PTR 4q35 and 3p12 regions; furthermore some subregions of the Beta satellite unit showed a high degree of conservation between chimpanzee and humans. In conclusion, this paper provides evidence that at the 4q subtelomere the linkage between D4Z4 and Beta satellite arrays is a feature that appeared late during evolution and is conserved between chimpanzee and humans.
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