Comparative phylogenetic analysis of Blcap/Nnat reveals eutherian-specific imprinted gene

Imprinted genes are parent-of-origin dependent, monoallefically expressed genes present in marsupials and eutherian mammals. Altered expression of imprinted genes plays a significant role in the etiology of a variety of human disorders and diseases. Nevertheless, the regulatory mechanisms of imprinting remain poorly defined. The imprinted gene Neuronatin (Nnat) is an excellent candidate for studying imprinting because it resides within the 8.5-kb intron of the nonimprinted gene Bladder Cancer-Associated Protein (Blcap) and is the only imprinted gene within the region. A phylogenetic comparison of this micro-imprinted domain in human, mouse, and rat revealed several candidates for imprint control, including tandem repeats and putative binding sites for trans-acting factors known to be involved in chromatin remodeling. Genome-wide phylogenetic comparisons of species from the three majorextant mammalian clades failed, however, to show any evidence of Nnat outside the eutherian lineage. Thus, Nnat is the first identified eutherian-specific imprinted gene, demonstrating that imprinted genes did not arise at a single point during evolution. This finding also suggests that the complexity of imprinting regulation observed at other loci may, in part, be directly related to the amount of time they have been imprinted.