Abstract
BackgroundDUX4 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.ResultsOur 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.ConclusionsOur 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.
Highlights
DUX4 is causally involved in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD)
Our particular interest in the DUX family stems from the involvement of one member (DUX4) in the molecular pathogenesis of facioscapulohumeral muscular dystrophy (FSHD) [3]
Our study illustrates how the true underlying relationships of homologues in gene families can be obscured by secondary loss of orthologues and misunderstood, especially as genomic tBLASTn searches are likely to identify active genes maintained by selection, but miss decaying pseudogenes that may represent the true orthologues
Summary
DUX4 is causally involved in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD). We investigate the evolutionary history of this multimember double-homeobox gene family in eutherian mammals. Our particular interest in the DUX family stems from the involvement of one member (DUX4) in the molecular pathogenesis of facioscapulohumeral muscular dystrophy (FSHD) [3]. In most cases of this genetic disorder, patients have a contraction of the 3.3 kb D4Z4 tandem repeat array on 4q35. The DUX4-containing D4Z4 elements are present at high and variable copy number on 4q35 with 11 to >100 repeats in controls [6]. A near identical tandem array is present on 10q26, but contractions are not associated with FSHD
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