In mice and rats, the intronless gene
Dux, encoded by a 4.9 kb retrogene array of more than 28 copies, is located at chromosome 10, whereas the 23
Dux paralog copies in human double homeobox 4 (
DUX4); only 1–12 bases different from mouse
Dux have been identified, in which 14 encoding mRNAs are transcribed in 2-cell-stage embryos as
Dux [
20]. The further study of these 14 mRNAs’ expression regulation will help us to understand the difference between
Dux and its paralog. The intronless orthologs to human
DUX4 are also found in other primates, elephants, hyraxes, and tenrecs. Similar to
Dux, the
DUX4 family also contains a 3.3 kb copies array (D4Z4) located at the distal end of chromosome 4 [
21]. An intron-containing variant, double homeobox B-like (
Duxbl), is only found in rodents, and its pseudogene is found in primates [
21]. The intronless
Dux/
DUX4 was hypothesized to arise from the common intron-containing ancestor in placental mammals through the reverse-transcription and retrotransposition models [
22]. During convergent evolution, environment pressure may further dictate the location of gene insertion. Genomic microsatellite organizations of
Dux and
DUX4 are usually located at the heterochromatinized regions, and their expression is often silenced in most types of cells, including embryonic stem cells [
9,
23]. Epigenetic regulations, such as DNA methylation, are a key determinant for their expression [
23]. Despite the considerable sequence divergence in their DNA-binding domains, DUX and DUX4 shared a more conserved homeodomain 2 (HD2) domain to recognize the 5′-TGA-3′ motif [
24] and activate a subset of genes associated with cleavage-stage embryos [
9]. Interestingly, the swapping of the homeodomain 1 (HD1) and HD2 regions of DUX4 with the corresponding regions from DUX substantially attenuates the activation of Zscan4c and MERVL induced by DUX expression in mouse muscle cells [
25]. Additionally, mouse Dux is myotoxic and shares a partial functional homology with its human paralog DUX4, the aberrant expression of which is linked to facioscapulohumeral muscular dystrophy [
26], which further confirms the conserved roles of Dux/DUX4 in gene regulation.