Genomic imprinting, representing parent-specific expression of alleles at a locus, raises many questions about how—and especially why—epigenetic silencing of mammalian genes evolved. We present the first in-depth study of how a human imprinted domain evolved, analyzing a domain containing several imprinted genes that are involved in human disease. Using comparisons of orthologous genes in humans, marsupials, and the platypus, we discovered that the Prader-Willi/Angelman syndrome region on human Chromosome 15q was assembled only recently (105–180 million years ago). This imprinted domain arose after a region bearing UBE3A (Angelman syndrome) fused with an unlinked region bearing SNRPN (Prader-Willi syndrome), which had duplicated from the non-imprinted SNRPB/B′. This region independently acquired several retroposed gene copies and arrays of small nucleolar RNAs from different parts of the genome. In their original configurations, SNRPN and UBE3A are expressed from both alleles, implying that acquisition of imprinting occurred after their rearrangement and required the evolution of a control locus. Thus, the evolution of imprinting in viviparous mammals is ongoing.
Humans and other mammals have two copies of the genome. For most genes, both copies are active. However, some genes are active only when they are inherited from the father, others only when inherited from the mother. These “imprinted” genes are clustered in domains that are controlled coordinately. Only mammals show genomic imprinting. It is not understood how or why genes became imprinted during mammalian evolution. The authors used comparisons between humans and the most distantly related mammals, marsupials and monotremes, to discover how one of these imprinted domains evolved. The authors studied an imprinted domain on human Chromosome 15, mutations which cause Prader-Willi and Angelman syndromes (PWS-AS). They discovered that the PWS and AS genes lie on different chromosomes in kangaroos and platypus and are not imprinted. Other imprinted genes in the domain, including the putative control region, are absent from the genome and derived from copies of genes from yet other chromosomes. The arrangement in kangaroos and platypus is present also in the chicken genome, so it must be ancestral. This study concludes that the PWS-AS imprinted region was assembled relatively recently from non-imprinted components that were moved together or copied from all over the genome.