Novel imprinted DLK11 GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF21 H19 regulation

The evolution of genomic imprinting in mammals occurred more than 100 milli on years ago, and resulted in the formation of genes that are functionally haploid because of parent-of-origin-dependent expression. Despite ample evi dence from studies in a number of species suggesting the presence of imprin ted genes on human chromosome 14, their identity has remained elusive. Here we report the identification of two reciprocally imprinted genes, GTL2 and DLK1, which together define a novel imprinting cluster on human chromosome 14q32. The maternally expressed GTL2 (gene trap locus 2) gene encodes for a nontranslated RNA. DLK1 (delta, Drosophila, homolog-like I) is a paternal ly expressed gene that encodes for a transmembrane protein containing six e pidermal growth factor (EGF) repeat motifs closely related to those present in the delta/notch/serrate Family of signaling molecules. The paternal exp ression, chromosomal localization, and biological function of DLK1 also mak e it a likely candidate gene For the callipyge phenotype in sheep. Many of the predicted structural and regulatory features of the DIK1/GTL2 domain ar e highly analogous to those implicated in IGF2/H19 imprint regulation, incl uding two hemimethylated consensus binding sites for the vertebrate enhance r blocking protein, CTCF. These results provide evidence that a common mech anism and domain organization may be used For juxtapositioned, reciprocally imprinted genes.