All Creatures Great and Small: New Approaches for Understanding Down Syndrome Genetics
Open accessAbstract
Human chromosome 21 (Hsa21) contains more than 500 genes, making trisomy 21 one of the most complex genetic perturbations compatible with life. The ultimate goal of Down syndrome (DS) research is to design therapies that improve quality of life for individuals with DS by understanding which subsets of Hsa21 genes contribute to DS-associated phenotypes throughout the lifetime. However, the complexity of DS pathogenesis has made developing appropriate animal models an ongoing challenge. Here, we examine lessons learned from a variety of model systems, including yeast, nematode, fruit fly, and zebrafish, and discuss emerging methods for creating murine models that better reflect the genetic basis of trisomy 21.
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Mouse models have allowed advances in deciphering mechanisms governing brain development and function and the consequences of Down syndrome-related manipulations.
“These models have allowed the scientific community to make incredible advances in deciphering the mechanisms governing brain development and function, as well as the consequences of DS-related manipulations for those mechanisms18–22.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [20]
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Self-citationGuipponi, M., Brunschwig, K., Chamoun, Z., Scott, H. S., Shibuya, K., Kudoh, J., Delezoide, A., El‐Samadi, S., Chettouh, Z., Rossier, C., et al. (2000) · Genomics · doi:10.1006/geno.2000.6250 · Cited by 23 · see citing works
Systematic Functional Characterization of Human 21st Chromosome Orthologs in Caenorhabditis elegans
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Regulator of Calcineurin (RCAN-1) Regulates Thermotaxis Behavior in Caenorhabditis elegans
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Chromosomal aneuploidy in Saccharomyces cerevisiae.
Spencer, F. A., Connelly, C. J., Gerring, S. L., Shero, J. H., Sikorski, R. S., & Hieter, P. (1989) · PubMed · Cited by 3 · see citing works
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3 of the 98 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [62]Liu H, (2020) Dscam gene triplication causes neocortical overinhibition in Down syndrome. bioRxiv
Cited by
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A 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
Self-citationImpact of the Olig Family on Neurodevelopmental Disorders
Szu, J., Wojcinski, A., Jiang, P., & Kesari, S. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.659601 · Cited by 36 · see citing works
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Consequences of trisomy 21 for brain development in Down syndrome
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Compensation of gene dosage on the mammalian X
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Moyer, A. J., Fernandez, F., Li, Y., Klinedinst, D. K., Florea, L., Kazuki, Y., Oshimura, M., & Reeves, R. H. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.049712 · Cited by 17 · see citing works
Self-citationMyocardial reprogramming by HMGN1 underlies heart defects in trisomy 21
Ranade, S. S., Li, F., Whalen, S., Pelonero, A., Ye, L., Huang, Y., Brand, A., Nishino, T., Mital, R., Boileau, R. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09593-9 · Cited by 16 · see citing works
Down syndrome and leukemia: An insight into the disease biology and current treatment options
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Wu, D., Zhang, Y., Cheng, B., Mori, S., Reeves, R. H., & Gao, F. (2021) · Brain Communications · doi:10.1093/braincomms/fcab062 · Cited by 11 · see citing works
Self-citationResearch advances in huntingtin-associated protein 1 and its application prospects in diseases
Wu, Y., Wang, Y., Lu, Y., Yan, J., Zhao, H., Yang, R., & Pan, J. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1402996 · Cited by 11 · see citing works
Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice
Roh, J. D., Bae, M. H., Kim, H., Yang, Y., Lee, Y., Cho, Y., Lee, S., Li, Y., Yang, E., Jang, H., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02865-2 · Cited by 11 · see citing works
Hawley, L. E., Stringer, M., Deal, A. J., Folz, A., Goodlett, C. R., & Roper, R. J. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106359 · Cited by 10 · see citing works
“…of others are modulated (dosage compensation); or that trisomy may directly or indirectly affect homeostasis in cells, tissues, organs and systems (Ait Yahya-Graison et al., 2007; Antonarakis et al., 2020; Duchon et al., 2021; Hwang et al., 2021; Kojima and Cimini, 2019; Moyer et al., 2021).”
Genetics and etiology of congenital heart disease
Narayan, P., Richter, F., & Morton, S. U. (2024) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2024.01.009 · Cited by 10 · see citing works
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Huang, Y., Huang, J., Wang, C., & Su, P. (2023) · Children · doi:10.3390/children10081351 · Cited by 9 · see citing works
Ahmed, M. M., Block, A., Busquet, N., & Gardiner, K. (2021) · Genes · doi:10.3390/genes12101528 · Cited by 7 · see citing works
Self-citationIncreased seizure susceptibility and neocortical excitability in TcMAC21 Down syndrome mice
Chinnasamy, V., Stafstrom, C. E., & Shao, L. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.09.016 · Cited by 5 · see citing works
Raza, M. A., Folz, A., Victorino, D. B., Xing, Z., Chen, X., Zuo, X., Borden, L. K., Potier, M., Mobley, W. C., Dierssen, M., et al. (2026) · STAR Protocols · doi:10.1016/j.xpro.2026.104717 · Cited by 5 · see citing works
Self-citationInfantile Spasms in Pediatric Down Syndrome: Potential Mechanisms Driving Therapeutic Considerations
Stafstrom, C. E., & Shao, L. (2024) · Children · doi:10.3390/children11121513 · Cited by 5 · see citing works
Vertebrate and Invertebrate Animal Models for the Study of Down Syndrome
Granholm, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26168092 · Cited by 3 · see citing works
Stander, R. M. H., Ayyappan, N., Sikorski, D., van der Heijden, M. E., & Hsiao, K. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03744-2 · Cited by 4 · see citing works
King, A. C., & Zenker, A. K. (2023) · Frontiers in Toxicology · doi:10.3389/ftox.2023.1187302 · Cited by 3 · see citing works
A new Down syndrome rat model races forward
Roper, R. J., & Goodlett, C. R. (2022) · Trends in Genetics · doi:10.1016/j.tig.2022.05.001 · Cited by 3 · see citing works
Ganguly, B. B., & Kadam, N. N. (2024) · Gene Reports · doi:10.1016/j.genrep.2024.102106 · Cited by 3 · see citing works
Comparative analysis of craniofacial shape in two mouse models of Down syndrome: Ts65Dn and TcMAC21
Singh, N., Richtsmeier, J. T., & Reeves, R. H. (2024) · Journal of Anatomy · doi:10.1111/joa.14012 · Cited by 2 · see citing works
Self-citationAstroglial Activation Is Exacerbated in a Down Syndrome Mouse Model
Zhou, Z., Bi, Y., Zhi, C., Chen, S., Chen, D., Wei, Z. C., & Jiang, X. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.04.003 · Cited by 2 · see citing works
Down syndrome: a model for chromosome abnormalities
Overk, C., & Mobley, W. C. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85654-6.00007-1 · Cited by 2 · see citing works
Singh, N., Reeves, R. H., & Richtsmeier, J. T. (2025) · Journal of Anatomy · doi:10.1111/joa.70066 · Cited by 1 · see citing works
Self-citationThe Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review
Robles, C. V., Robles, C. V., Revilla, A. P. A., Suárez‐Valencia, V. D. J., & Salinas-Santander, M. A. (2026) · European Journal of Neuroscience · doi:10.1111/ejn.70623 · Cited by 1 · see citing works
Chromosomal etiology of Down syndrome
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Colvin, K. L., Elliott, R. J., Goodman, D. M., Harral, J. W., Barrett, E. G., & Yeager, M. E. (2023) · FASEB BioAdvances · doi:10.1096/fba.2023-00091
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In vivo and in vitro models for research on Down syndrome
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Biomarcadores amiloidogênicos na síndrome de Down
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Approach to diagnosis and management of genetic neurodevelopmental disorders
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Simple Worm, Complex Disorder: Studying Down Syndrome Mechanisms in the Unassuming Model C. elegans
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From birth to disease: 3D telomere archtecture and aurora kinase changes in Down syndromePreprint
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Metabolomic Profiles in Down Syndrome: A Scoping Review of Convergent and Context‐Dependent Patterns
Guerrero, C. G., Guadrón‐Llanos, A. M., Calderón-Zamora, L., la Herrán-Arita, A. K. D., Cruz‐Narváez, Y., Duarte-de-la-Peña, G., & Magaña‐Gómez, J. A. (2026) · Journal of Intellectual Disability Research · doi:10.1111/jir.70125
Dysregulated calcium signaling underlies hyposalivation and microbial dysbiosis in Down syndrome
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Rossmassler, K., Timkovich, A. E., Niemeyer, B., Schade, K. A., Dunn, L. N., Harris, M. C., Harris, R. A., Chillamcherla, S., Rachubinski, A. L., Espinosa, J. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.20.751055
Stafstrom, C. E., & Shao, L. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15197471
- Authors
- Moyer, A. J., Gardiner, K., & Reeves, R. H.
- Affiliations
- Johns Hopkins University (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Reeves, Roger H.
- Venue
- Trends in Genetics
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 37
- Issue
- 5
- Pages
- 444-459
- ISSN
- 0168-9525 (ISSN-L)
- PMC
- PMC8208824
- OpenAlex
- W3094039995
- Cited by
- 49
- References
- 98
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 6 · 2021: 6
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in Genetics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (1F31HD098826-01, HD098540, HD038384, T32GM07814, U54HD079123-01A1)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- Down syndrome, chromosome 21 genes, mouse model, yeast model, nematode model, Drosophila model, zebrafish model, therapeutic target
- MeSH terms
- Aneuploidy, Animals, Pan troglodytes, Chromosomes, Human, Pair 21, Disease Models, Animal, Down Syndrome, Drosophila, Humans, Yeasts, Zebrafish, Genomics, Mice, Rats
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