The imprinted NPAP1 gene in the Prader-Willi syndrome region belongs to a POM121-related family of retrogenes.

We have recently shown that the human Nuclear pore-associated protein (NPAP1)/C15orf2 gene encodes a nuclear pore-associated protein. This gene is one of several paternally expressed imprinted genes in the genomic region 15q11q13. Because the Prader-Willi syndrome is known to be caused by the loss of function of paternally expressed genes in 15q11q13, a phenotypic contribution of NPAP1 cannot be excluded. NPAP1 appears to be under strong positive Darwinian selection in primates, suggesting an important function in primate biology. Interestingly, however, in contrast to all other protein-coding genes in 15q11q13, NPAP1 has no ortholog in the mouse. Our investigation of the evolutionary origin of NPAP1 showed that the gene is specific to primate species and absent from the 15q11q13-orthologous regions in all nonprimate mammals. However, we identified a group of paralogous genes, which we call NPAP1L, in all placental mammals except rodents. Phylogenetic analysis revealed that NPAP1, NPAP1L, and another group of genes (UPF0607), which is also restricted to primates, are closely related to the vertebrate transmembrane nucleoporin gene POM121, although they lack the transmembrane domain. These three newly identified groups of genes all lack conserved introns, and hence, are likely retrogenes. We hypothesize that, in the common ancestor of placentals, the POM121 gene retrotransposed and gave rise to an NPAP1-ancestral retrogene NPAP1L/NPAP1/UPF0607. Our results suggest that the nuclear pore-associated gene NPAP1 originates from the vertebrate nucleoporin gene POM121 and--after several steps of retrotransposition and duplication-has been subjected to genomic imprinting and positive selection after integration into the imprinted SNRPN-UBE3A chromosomal domain.