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 retrotransposition. Here we present evidence for continued acquisition of genes by the mouse PWS region during evolution. Bioinformatic analyses identified a BAC containing four genes, Mkrn3, Magel2, Ndn, Frat3, and the Atp5l-ps1 pseudogene, the latter two genes derived from recent L1-mediated retrotransposition. Analyses of eight overlapping BACs indicate that these genes are clustered within 120 kb in two inbred strains, in the order tel-Atp5l-ps1-Frat3-Mkrn3-Magel2-Ndn-cen. Imprinting analyses show that Frat3 is differentially methylated and expressed solely from the paternal allele in a transgenic mouse model of Angelman syndrome, with no expression from the maternal 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 region is prone to retroposition in germ cells or their zygotic and embryonic cell precursors, and that it allows the subsequent functional expression of these foreign sequences. The recent evolutionary acquisition of genes that adopt the same imprint as older, flanking genes indicates that the newly acquired genes become 'innocent bystanders' of a primary epigenetic signal causing imprinting in the PWS domain.
Chai
J H
JH
Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, CRB 528, 415 Curie Blvd., Philadelphia, Pennsylvania 19104-6140, USA.
Locke
D P
DP
Ohta
T
T
Greally
J M
JM
Nicholls
R D
RD
D000818:Animals; D002352:Carrier Proteins; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D019175:DNA Methylation; D018392:Genomic Imprinting; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins; D011218:Prader-Willi Syndrome / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011544:Pseudogenes / Q000235:genetics; D018626:Retroelements / Q000235:genetics*; D026801:Synteny
D002352:Carrier Proteins; D009363:Neoplasm Proteins; C491814:Peg12 protein, mouse; D011518:Proto-Oncogene Proteins; D018626:Retroelements