Wylie A A, Murphy S K, Orton T C, Jirtle R L
Department of Radiation Oncology and Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Genome Res. 2000 Nov;10(11):1711-8. doi: 10.1101/gr.161600.
The evolution of genomic imprinting in mammals occurred more than 100 million years ago, and resulted in the formation of genes that are functionally haploid because of parent-of-origin-dependent expression. Despite ample evidence from studies in a number of species suggesting the presence of imprinted 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 1) is a paternally expressed gene that encodes for a transmembrane protein containing six epidermal growth factor (EGF) repeat motifs closely related to those present in the delta/notch/serrate family of signaling molecules. The paternal expression, chromosomal localization, and biological function of DLK1 also make it a likely candidate gene for the callipyge phenotype in sheep. Many of the predicted structural and regulatory features of the DLK1/GTL2 domain are highly analogous to those implicated in IGF2/H19 imprint regulation, including two hemimethylated consensus binding sites for the vertebrate enhancer blocking protein, CTCF. These results provide evidence that a common mechanism and domain organization may be used for juxtapositioned, reciprocally imprinted genes.
哺乳动物基因组印记的进化发生在一亿多年前，导致了一些基因的形成，这些基因由于亲本来源依赖性表达而在功能上呈单倍体状态。尽管对多个物种的研究有大量证据表明人类14号染色体上存在印记基因，但其身份一直难以确定。在此，我们报告鉴定出两个相互印记的基因，GTL2和DLK1，它们共同在人类14号染色体q32区域定义了一个新的印记簇。母本表达的GTL2（基因陷阱位点2）基因编码一种非翻译RNA。DLK1（果蝇δ同源样蛋白1）是一个父本表达的基因，编码一种跨膜蛋白，该蛋白含有六个与δ/Notch/锯齿状信号分子家族中存在的表皮生长因子（EGF）重复基序密切相关的基序。DLK1的父本表达、染色体定位和生物学功能也使其成为绵羊臀部丰满表型的一个可能候选基因。DLK1/GTL2区域的许多预测结构和调控特征与IGF2/H19印记调控中涉及的特征高度相似，包括脊椎动物增强子阻断蛋白CTCF的两个半甲基化共有结合位点。这些结果提供了证据，表明一种共同的机制和结构域组织可能用于相邻的、相互印记的基因。
