TY - JOUR
T1 - Identification of Four Highly Conserved Genes between Breakpoint Hotspots BP1 and BP2 of the Prader-Willi/Angelman Syndromes Deletion Region That Have Undergone Evolutionary Transposition Mediated by Flanking Duplicons
AU - Chai, J. H.
AU - Locke, D. P.
AU - Greally, J. M.
AU - Knoll, J. H.M.
AU - Ohta, T.
AU - Dunai, J.
AU - Yavor, A.
AU - Eichler, E. E.
AU - Nicholls, R. D.
N1 - Funding Information:
We thank Dr. Diane M. Dunn, for mouse 10-kb plasmid clones used in early stages of this project, Dr. Frazer Murray, for the chicken cDNA clone, Dr. Mitch Klebig, for c 32DSD mice, and Dr. Merlin G. Butler, for providing unpublished data. We also thank Jessica Lapasia, Jennifer Scheidt, and Ileine Sanchez for technical assistance. D.P.L. was supported in part by National Institutes of Health (NIH) predoctoral Medical Genetics training grant HD07518. This work was supported by NIH grants HD31491 and HD36079 (to R.D.N.), ES10631 (to R.D.N. and E.E.E.), HG02385 (to E.E.E.), and DK02467 and DK56786 (to J.M.G.); March of Dimes Birth Defects Foundation grant 6-FY99-902 (to R.D.N.), and a Muscular Dystrophy Association grant (to R.D.N.).
PY - 2003/10/1
Y1 - 2003/10/1
N2 - Prader-Willi and Angelman syndromes (PWS and AS) typically result from an ∼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.
AB - Prader-Willi and Angelman syndromes (PWS and AS) typically result from an ∼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.
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U2 - 10.1086/378816
DO - 10.1086/378816
M3 - Article
C2 - 14508708
AN - SCOPUS:0142027581
SN - 0002-9297
VL - 73
SP - 898
EP - 925
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -
