Dissection of a down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome
Open accessAbstract
As an aneuploidy, trisomy is associated with mammalian embryonic and postnatal abnormalities. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 [Down syndrome (DS)]. Although increased gene dosage effects because of a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e. a 'free trisomy' independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects in mammals. To fill this gap, here we describe a strategy that employed two new mouse models of DS, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparison of these models revealed the gene dosage-independent impacts of an extra chromosome at the phenotypic and molecular levels for the first time. They are reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome plays a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.
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With the development of the Ts66Yah and other DS mouse models, the contributions of these non-Hsa21 genes are becoming understood.
“With the development of the Ts66Yah and other DS mouse models, the contributions of these non-Hsa21 genes are becoming understood (Duchon et al., 2022; Xing et al., 2023).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Xing et al., 2023
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Cites
Down Syndrome, Partial Trisomy 21, and Absence of Alzheimer’s Disease: The Role of APP
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Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of down Syndrome.
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Ts66Yah, a mouse model of down syndrome with improved construct and face validity
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Research works printed but not linked: 2
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“…group (dark bars and symbols) was significantly greater than the respective euploid group (open symbols) of the same age, sex, and brain region. expression of triplicated Dyrk1a is controlled in a temporally specific manner — being overexpressed at some developmental ages and not at others.”
Background
- Authors
- Xing, Z., Li, Y., Cortes-Gomez, E., Jiang, X., Gao, S., Pao, A., Shan, J., Song, Y., Perez, A., Yu, T., Highsmith, M. R., Boadu, F., Conroy, J. M., Singh, P. K., Bakin, A. V., Cheng, J., Duan, Z., Wang, J., Liu, S., Tycko, B., & Yu, Y. E.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Children's Hospital of Zhejiang University (CN)
- Albert Einstein College of Medicine (US)
- University of Missouri (US)
- University of Washington (US)
- Hackensack University Medical Center (US)
- Corresponding author
- Yu, Y Eugene
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-04-04
- Volume
- 32
- Issue
- 13
- Pages
- 2205-2218
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC10281752
- OpenAlex
- W4362523064
- Cited by
- 23
- References
- 7
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 4 · 2023: 4
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P30CA016056, R21GM114645, R03TR003344, R01DC019735, R01HD109750, R01HD090180)
- 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, gene dosage effect, spatial learning impairment, aneuploidy, mouse models of Down syndrome
- MeSH terms
- Aneuploidy, Animals, Chromosomes, Disease Models, Animal, Down Syndrome, Humans, Male, Mammals, Trisomy, Gene Dosage, Mice
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