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
Open accessAbstract
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.
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The 15q11.2(BP1-BP2) deletion contains four genes: NIPA1, NIPA2, CYFIP1 and TUBGCP5.
“The deletion contains four genes: non-imprinted in Prader–Willi/Angelman syndrome 1 (NIPA1) and 2 (NIPA2) genes, CYFIP1 and tubulin gamma complex associated protein 5 gene (TUBGCP5) [6].”
The 15q11.2 BP1-BP2 microdeletion involves four genes: TUBGCP5, CYFIP1, NIPA1, and NIPA2.
“The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [19]
The four genes in the BP1-BP2 region are highly conserved and biallelically expressed.
“Chai et al. [19] showed that these four genes are highly conserved and biallelically expressed.”
From The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review (2015) · cites this paper as [19]
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References 93 · Cited by 218
Research works printed but not linked: 10
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- Authors
- 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.
- Affiliations
- University of Pennsylvania (US)
- Case Western Reserve University (US)
- Albert Einstein College of Medicine (US)
- Children's Mercy Hospital (US)
- Corresponding author
- Nicholls, R.D.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 73
- Issue
- 4
- Pages
- 898-925
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1180611
- OpenAlex
- W2075314429
- Cited by
- 218
- References
- 93
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 10 · 2020: 9 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 10 · 2013: 7 · 2012: 12
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7k08dk002467-06, 7r03dk056786-02, 5r01hd036079-06)
- National Human Genome Research Institute (HG02385, R01HG002385)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56786, DK02467)
- National Institute of Environmental Health Sciences (ES10631, R01ES010631)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007518, HD31491, R01HD031491, HD36079, HD07518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- Prader-Willi syndrome, Angelman syndrome, chromosome 15q11-q13, HERC2, duplicons, NIPA1, CYFIP1, genomic imprinting, DNA replication timing, transposition, gene duplication, fugu, transmembrane proteins, phylogenetic conservation
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Chromosome Mapping, Chromosomes, Human, Pair 15, Exons, Humans, Introns, Membrane Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Phylogeny, Prader-Willi Syndrome, Repetitive Sequences, Nucleic Acid, Angelman Syndrome, DNA Primers, Genes, Duplicate, Expressed Sequence Tags, Gene Duplication, Cation Transport Proteins, Adaptor Proteins, Signal Transducing, Mice
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