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


RESULTS
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.


CONCLUSIONS
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.
Centre for Genetics and Genomics, School of Biology, The University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK.
Andreas
A
Leidenroth
Jane E
JE
Hewitt
D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D018398:Homeodomain Proteins / Q000235:genetics*; D008322:Mammals / Q000235:genetics*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011544:Pseudogenes; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D026801:Synteny
D018398:Homeodomain Proteins