Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site

Prader-Willi syndrome (PWS) results from loss of function of a 1.0- to 1.5- Mb domain of imprinted, paternally expressed genes in human Chromosome (Chr ) 15q11-q13. The loss of imprinted gene expression in the homologous region in mouse Chr 7C leads to a similar neonatal PWS phenotype. Several protein -coding genes in the human PWS region are intronless, possibly arising by r etrotransposition. Here we present evidence for continued acquisition of ge nes by the mouse PWS region during evolution. Bioinformatic analyses identi fied a BAC containing four genes, Mkrn3, Magel2, Ndn, Frat3, and the Atp5l- ps1 pseudogene, the latter two genes derived from recent L1-mediated retrot ransposition. Analyses of eight overlapping BACs indicate that these genes are clustered within 120 kb in two inbred strains, in the order tel-Atp5l-p s1-Frat3-Mkrn3-Magel2-Ndn-cen. Imprinting analyses show that Frat3 is diffe rentially methylated and expressed solely from the paternal allele in a tra nsgenic mouse model of Angelman syndrome, with no expression from the mater nal allele in a mouse model of PWS. Loss of Frat3 expression may, therefore , contribute to the phenotype of mouse models of PWS. The identification of five intronless genes in a small genomic interval suggests that this regio n is prone to retroposition in germ cells or their zygotic and embryonic ce ll precursors, and that it allows the subsequent functional expression of t hese foreign sequences. The recent evolutionary acquisition of genes that a dopt the same imprint as older, flanking genes indicates that the newly acq uired genes become 'innocent bystanders' of a primary epigenetic signal cau sing imprinting in the PWS domain.