Chai J-H, Locke D P, Greally J M, Knoll J H M, Ohta T, Dunai J, Yavor A, Eichler E E, Nicholls R D
Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Am J Hum Genet. 2003 Oct;73(4):898-925. doi: 10.1086/378816. Epub 2003 Sep 23.
Prader-Willi and Angelman syndromes (PWS and AS) typically result from an approximately 4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3). HERC2 and other duplicons map to these BP regions, with the 2-Mb PWS/AS imprinted domain just distal of BP2. Previously, the presence of genes and their imprinted status have not been examined between BP1 and BP2. Here, we identify two known (CYFIP1 and GCP5) and two novel (NIPA1 and NIPA2) genes in this region in human and their orthologs in mouse chromosome 7C. These genes are expressed from a broad range of tissues and are nonimprinted, as they are expressed in cells derived from normal individuals, patients with PWS or AS, and the corresponding mouse models. However, replication-timing studies in the mouse reveal that they are located in a genomic domain showing asynchronous replication, a feature typically ascribed to monoallelically expressed loci. The novel genes NIPA1 and NIPA2 each encode putative polypeptides with nine transmembrane domains, suggesting function as receptors or as transporters. Phylogenetic analyses show that NIPA1 and NIPA2 are highly conserved in vertebrate species, with ancestral members in invertebrates and plants. Intriguingly, evolutionary studies show conservation of the four-gene cassette between BP1 and BP2 in human, including NIPA1/2, CYFIP1, and GCP5, and proximity to the Herc2 gene in both mouse and Fugu. These observations support a model in which duplications of the HERC2 gene at BP3 in primates first flanked the four-gene cassette, with subsequent transposition of these four unique genes by a HERC2 duplicon-mediated process to form the BP1-BP2 region. Duplicons therefore appear to mediate genomic fluidity in both disease and evolutionary processes.
普拉德-威利综合征和安吉尔曼综合征（PWS和AS）通常源于人类15号染色体q11-q13区域约4兆碱基的缺失，在两个近端位点（BP1和BP2）之一和一个远端位点（BP3）存在聚集的断点（BP）。HERC2和其他重复子定位于这些BP区域，2兆碱基的PWS/AS印记域位于BP2的远端。此前，尚未对BP1和BP2之间的基因存在情况及其印记状态进行研究。在此，我们在该区域的人类中鉴定出两个已知基因（CYFIP1和GCP5）以及两个新基因（NIPA1和NIPA2），并在小鼠7号染色体C区域鉴定出它们的直系同源基因。这些基因在多种组织中表达，且不具有印记，因为它们在来自正常个体、PWS或AS患者以及相应小鼠模型的细胞中均有表达。然而，对小鼠的复制时间研究表明，它们位于一个显示异步复制的基因组区域，这一特征通常归因于单等位基因表达位点。新基因NIPA1和NIPA2各自编码具有九个跨膜结构域的推定多肽，提示其可能作为受体或转运蛋白发挥功能。系统发育分析表明，NIPA1和NIPA2在脊椎动物物种中高度保守，在无脊椎动物和植物中有其祖先成员。有趣的是，进化研究表明，人类中BP1和BP2之间的四基因盒具有保守性，包括NIPA1/2、CYFIP1和GCP5，并且在小鼠和河豚中均与Herc2基因相邻。这些观察结果支持这样一种模型：灵长类动物中BP3处HERC2基因的重复首先围绕四基因盒两侧，随后通过HERC2重复子介导的过程使这四个独特基因转位，从而形成BP1-BP2区域。因此，重复子似乎在疾病和进化过程中均介导了基因组的流动性。
