Duplication of the entire 22.9 Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities
Abstract
Down syndrome is caused by a genomic imbalance of human chromosome 21 which is mainly observed as trisomy 21. The regions on human chromosome 21 are syntenically conserved in three regions on mouse chromosomes 10, 16 and 17. Ts65Dn mice, the most widely used model for Down syndrome, are trisomic for approximately 56.5% of the human chromosome 21 syntenic region on mouse chromosome 16. To generate a more complete trisomic mouse model of Down syndrome, we have established a 22.9 Mb duplication spanning the entire human chromosome 21 syntenic region on mouse chromosome 16 in mice using Cre/loxP-mediated long-range chromosome engineering. The presence of the intact duplication in mice was confirmed by fluorescent in situ hybridization and BAC-based array comparative genomic hybridization. The expression levels of the genes within the duplication interval reflect gene-dosage effects in the mutant mice. The cardiovascular and gastrointestinal phenotypes of the mouse model were similar to those of patients with Down syndrome. This new mouse model represents a powerful tool to further understand the molecular and cellular mechanisms of Down syndrome.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Dp16 mice exhibit hyperactive IFN signaling and recapitulate many phenotypes of DS including developmental delays, cranial malformations, and cognitive deficits.
“Notably, Dp16 mice exhibit hyperactive IFN signaling and recapitulate many phenotypes of DS including developmental delays, cranial malformations, and cognitive deficits.38,40,42,43,44,45”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [42]
The Dp16 mouse model of DS carries a segmental duplication of the largest region of genes orthologous to HSA21, encoded on mouse chromosome 16 (MMU16).
“The Dp16 mouse model of DS carries a segmental duplication of the largest region of genes orthologous to HSA21, which is encoded on mouse chromosome 16 (MMU16).42”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [42]
Dp16 mice only triplicate about half of the protein-coding genes on HSA21 and as a segmental duplication rather than a freely segregating chromosome.
“Dp16 mice only triplicate about half of the protein-coding genes on HSA21 and even those existing as a segmental duplication rather than a freely segregating chromosome.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [42]
Cites
Initial sequencing and comparative analysis of the mouse genome
Mouse Genome Sequencing Consortium (2002) · Nature · doi:10.1038/nature01262 · Cited by 7,187 · see citing works
The Comprehensive Knockout Mouse Project Consortium (2004) · Nature Genetics · doi:10.1038/ng0904-921 · Cited by 608 · see citing works
Kahlem, P., Sultan, M., Herwig, R., Steinfath, M., Balzereit, D., Eppens, B., Saran, N. G., Pletcher, M. T., South, S. T., Stetten, G., et al. (2004) · Genome Research · doi:10.1101/gr.1951304 · Cited by 249 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Korbel, J. O., Tirosh-Wagner, T., Urban, A. E., Chen, X.-N., Kasowski, M., Dai, L., Grubert, F., Erdman, C., Gao, M. C., Lange, K., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813248106 · Cited by 399 · see citing works
Trisomy 21 consistently activates the interferon response
Sullivan, K. D., Lewis, H. C., Hill, A. A., Pandey, A., Jackson, L. P., Cabral, J. M., Smith, K. P., Liggett, L. A., Gomez, E. B., Galbraith, M. D., et al. (2016) · eLife · doi:10.7554/elife.16220 · Cited by 362 · see citing works
Pinto, B., Morelli, G., Rastogi, M., Savardi, A., Fumagalli, A., Petretto, A., Bartolucci, M., Varea, E., Catelani, T., Contestabile, A., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.010 · Cited by 135 · see citing works
Communication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome
Contestabile, A., Benfenati, F., & Gasparini, L. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.003 · Cited by 134 · see citing works
Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions
Sturgeon, X., & Gardiner, K. J. (2011) · Mammalian Genome · doi:10.1007/s00335-011-9321-y · Cited by 117 · see citing works
Aziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031013 · Cited by 118 · see citing works
Waugh, K. A., Minter, R., Baxter, J., Chi, C., Galbraith, M. D., Tuttle, K. D., Eduthan, N. P., Kinning, K. T., Andrysik, Z., Araya, P., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01399-7 · Cited by 117 · see citing works
Altered cell and RNA isoform diversity in aging Down syndrome brains
Palmer, C. R., Liu, C. S., Romanow, W. J., Lee, M.-H., & Chun, J. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114326118 · Cited by 89 · see citing works
Galbraith, M. D., Rachubinski, A. L., Smith, K. P., Araya, P., Waugh, K. A., Enriquez-Estrada, B., Worek, K., Granrath, R. E., Kinning, K. T., Paul Eduthan, N., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg6218 · Cited by 88 · see citing works
Zheng, Q., Li, G., Wang, S., Zhou, Y., Liu, K., Gao, Y., Zhou, Y., Zheng, L., Zhu, L., Deng, Q., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe1340 · Cited by 85 · see citing works
Atas-Ozcan, H., Brault, V., Duchon, A., & Herault, Y. (2021) · Genes · doi:10.3390/genes12111833 · Cited by 78 · see citing works
Zheng, Q., Song, B., Li, G., Cai, F., Wu, M., Zhao, Y., Jiang, L., Guo, T., Shen, M., Hou, H., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci152170 · Cited by 73 · see citing works
Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of down Syndrome.
Goodliffe, J. W., Olmos-Serrano, J. L., Aziz, N. M., Pennings, J. L. A., Guedj, F., Bianchi, D. W., & Haydar, T. F. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2513-15.2016 · Cited by 65 · see citing works
Neurodevelopment in Down syndrome: Concordance in humans and models
Klein, J. A., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.941855 · Cited by 47 · see citing works
“They do recapitulate other phenotypes seen in DS such as cardiovascular abnormalities, skeletal development, and motor function (Li et al., 2007; LanaElola et al., 2016, 2021) and thus could be used as appropriate models to study these changes in DS.”
BackgroundMethodAnalysis of motor dysfunction in down Syndrome reveals motor neuron degeneration.
Watson-Scales, S., Kalmar, B., Lana-Elola, E., Gibbins, D., La Russa, F., Wiseman, F., Williamson, M., Saccon, R., Slender, A., Olerinyova, A., et al. (2018) · PLOS Genetics · doi:10.1371/journal.pgen.1007383 · Cited by 45 · see citing works
Self-citationA transchromosomic rat model with human chromosome 21 shows robust down syndrome features.
Kazuki, Y., Gao, F. J., Yamakawa, M., Hirabayashi, M., Kazuki, K., Kajitani, N., Miyagawa-Tomita, S., Abe, S., Sanbo, M., Hara, H., et al. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.12.015 · Cited by 41 · see citing works
Wang, X., Yang, Q., Zhou, X., Keene, C. D., Ryazanov, A. G., & Ma, T. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13916 · Cited by 17 · see citing works
Ishihara, K. (2021) · Genes · doi:10.3390/genes12101598 · Cited by 8 · see citing works
Araya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7 · see citing works
“42 To define the impact of tripli-cation of HSA21 genes on the development and progression of AD-related phenotypes, we evaluated developmental mile-stones in neonates from postnatal day 3 (P3) to P21 and performed extensive cognitive and behavioral profiling in adult mice longitudinally at 3, 5,…”
Influential
- Authors
- Li, Z., Yu, T., Morishima, M., Pao, A., LaDuca, J., Conroy, J., Nowak, N., Matsui, S.-I., Shiraishi, I., & Yu, Y. E.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Kyoto Prefectural University of Medicine (JP)
- Corresponding author
- Yu, Y. Eugene
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-05
- Volume
- 16
- Issue
- 11
- Pages
- 1359-1366
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2138298735
- Cited by
- 218
- References
- 3
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 16 · 2023: 13 · 2022: 18 · 2021: 21 · 2020: 11 · 2019: 5 · 2018: 7 · 2017: 10 · 2016: 8 · 2015: 7 · 2014: 7 · 2013: 7 · 2012: 13
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 16056., P30CA016056)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- Down syndrome, mouse chromosome 16, Ts65Dn mouse model, gene dosage effect, cardiovascular anomalies, gastrointestinal anomalies
- MeSH terms
- Animals, Chromosomes, Human, Pair 21, Digestive System Abnormalities, Humans, Translocation, Genetic, Cardiovascular Abnormalities, Gene Duplication, Synteny, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
