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

被引:166
作者
Chai, JH
Locke, DP
Greally, JM
Knoll, JHM
Ohta, T
Dunai, J
Yavor, A
Eichler, EE
Nicholls, RD
机构
[1] Univ Penn, Dept Psychiat, Ctr Neurobiol & Behav, CRB 528, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA
[3] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA
[4] Albert Einstein Coll Med, Dept Med, Div Hematol, Bronx, NY 10467 USA
[5] Univ Missouri, Sch Med, Childrens Mercy Hosp & Clin, Div Med Res,Lab Human Mol Genet, Kansas City, MO 64108 USA
关键词
D O I
10.1086/378816
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Prader-Willi and Angelman syndromes (PWS and AS) typically result from an similar to4-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.
引用
收藏
页码:898 / 925
页数:28
相关论文
共 86 条
[1]   Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints [J].
Amos-Landgraf, JM ;
Ji, YG ;
Gottlieb, W ;
Depinet, T ;
Wandstrat, AE ;
Cassidy, SB ;
Driscoll, DJ ;
Rogan, PK ;
Schwartz, S ;
Nicholls, RD .
AMERICAN JOURNAL OF HUMAN GENETICS, 1999, 65 (02) :370-386
[2]   The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region [J].
Boccaccio, I ;
Glatt-Deeley, H ;
Watrin, F ;
Roëckel, N ;
Lalande, M ;
Muscatelli, F .
HUMAN MOLECULAR GENETICS, 1999, 8 (13) :2497-2505
[3]   The human gene for the poly(A)-specific ribonuclease (PARN) maps to 16p13 and has a truncated copy in the Prader-Willi/Angelman syndrome region on 15q11→q13 [J].
Buiting, K ;
Körner, C ;
Ulrich, B ;
Wahle, E ;
Horsthemke, B .
CYTOGENETICS AND CELL GENETICS, 1999, 87 (1-2) :125-131
[4]   INHERITED MICRODELETIONS IN THE ANGELMAN AND PRADER-WILLI SYNDROMES DEFINE AN IMPRINTING CENTER ON HUMAN-CHROMOSOME-15 [J].
BUITING, K ;
SAITOH, S ;
GROSS, S ;
DITTRICH, B ;
SCHWARTZ, S ;
NICHOLLS, RD ;
HORSTHEMKE, B .
NATURE GENETICS, 1995, 9 (04) :395-400
[5]   Prader-Willi syndrome and a deletion/duplication within the 15q11-q13 region [J].
Butler, MG ;
Bittel, D ;
Talebizadeh, Z .
JOURNAL OF MEDICAL GENETICS, 2002, 39 (03) :202-204
[6]  
BUTLER MG, IN PRESS PEDIATRICS
[7]   Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization [J].
Cavaillé, J ;
Buiting, K ;
Kiefmann, M ;
Lalande, M ;
Brannan, CI ;
Horsthemke, B ;
Bachellerie, JP ;
Brosius, J ;
Hüttenhofer, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (26) :14311-14316
[8]   Retrotransposed genes such as Frat3 in the mouse Chromosome 7C Prader-Willi syndrome region acquire the imprinted status of their insertion site [J].
Chai, JH ;
Locke, DP ;
Ohta, T ;
Greally, JM ;
Nicholls, RD .
MAMMALIAN GENOME, 2001, 12 (11) :813-821
[9]  
CHENG SD, 1994, AM J HUM GENET, V55, P753
[10]   ALLELIC INACTIVATION REGULATES OLFACTORY RECEPTOR GENE-EXPRESSION [J].
CHESS, A ;
SIMON, I ;
CEDAR, H ;
AXEL, R .
CELL, 1994, 78 (05) :823-834