The human double-homeodomain retrogene DUX4 is expressed in the testis and 
epigenetically repressed in somatic tissues. Facioscapulohumeral muscular 
dystrophy (FSHD) is caused by mutations that decrease the epigenetic repression 
of DUX4 in somatic tissues and result in mis-expression of this transcription 
factor in skeletal muscle. DUX4 binds sites in the human genome that contain a 
double-homeobox sequence motif, including sites in unique regions of the genome 
as well as many sites in repetitive elements. Using ChIP-seq and RNA-seq on 
myoblasts transduced with DUX4 we show that DUX4 binds and activates 
transcription of mammalian apparent LTR-retrotransposons (MaLRs), endogenous 
retrovirus (ERVL and ERVK) elements, and pericentromeric satellite HSATII 
sequences. Some DUX4-activated MaLR and ERV elements create novel promoters for 
genes, long non-coding RNAs, and antisense transcripts. Many of these novel 
transcripts are expressed in FSHD muscle cells but not control cells, and thus 
might contribute to FSHD pathology. For example, HEY1, a repressor of 
myogenesis, is activated by DUX4 through a MaLR promoter. DUX4-bound motifs, 
including those in repetitive elements, show evolutionary conservation and some 
repeat-initiated transcripts are expressed in healthy testis, the normal 
expression site of DUX4, but more rarely in other somatic tissues. Testis 
expression patterns are known to have evolved rapidly in mammals, but the 
mechanisms behind this rapid change have not yet been identified: our results 
suggest that mobilization of MaLR and ERV elements during mammalian evolution 
altered germline gene expression patterns through transcriptional activation by 
DUX4. Our findings demonstrate a role for DUX4 and repetitive elements in 
mammalian germline evolution and in FSHD muscular dystrophy.