{"doi":"10.1016/j.tig.2020.09.017","title":"All Creatures Great and Small: New Approaches for Understanding Down Syndrome Genetics","abstract":"Down syndrome (DS) is caused by an extra copy of ~500 genes.Understanding how human chromosome 21 (Hsa21) genes contribute to DS phenotypes is essential for developing effective treatment strategies.Many Hsa21 genes functionally interact, and overexpression of these genes perturbs expression of genes throughout the genome.DS research has focused on only a few Hsa21 genes.Diverse model organisms from yeast to mice are being used to study the effects of aneuploidy, to annotate functions of Hsa21 orthologs, and to model aspects of DS pathology. 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. 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. Down syndrome (DS) comprises a collection of phenotypic features that are common in individuals who inherit an extra copy of all or, rarely, part of the long arm of human chromosome 21. All individuals with DS display some level of intellectual disability and will develop the neuropathology of Alzheimer’s disease (AD) at an early age. They also present with hypotonia, cerebellar hypoplasia, and midface skeletal retrusion. Additional common, but not universal, features include congenital heart defects, abnormalities in immune system function, thyroid deficiency, childhood leukemia, and early-onset dementia [1.Capone G.T. Down syndrome: advances in molecular biology and the neurosciences.J. Dev. Behav. Pediatr. 2001; 22: 40-59Crossref PubMed Scopus (89) Google Scholar,2.Antonarakis S.E. et al.Down syndrome.Nat. Rev. Dis. Primers. 2020; 6: 9Crossref PubMed Scopus (92) Google Scholar]. Sex differences have been noted in some features. For example, males are more impaired in the acquisition of cognitive and language skills than are females [3.Kittler P. et al.Sex differences in performance over 7 years on the Wechsler Intelligence Scale for Children - revised among adults with intellectual disability.J. Intellect. Disabil. Res. 2004; 48: 114-122Crossref PubMed Scopus (33) Google Scholar, 4.Aoki S. et al.Developmental trend of children with Down's syndrome - how do sex and neonatal conditions influence their developmental patterns?.Brain and Development. 2018; 40: 181-187Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 5.Startin C.M. et al.Health comorbidities and cognitive abilities across the lifespan in Down syndrome.J. Neurodev. Disord. 2020; 12: 4Crossref PubMed Scopus (30) Google Scholar, 6.Maatta T. et al.Mental health, behaviour and intellectual abilities of people with Down syndrome.Downs Syndr. Res. Pract. 2006; 11: 37-43Crossref PubMed Scopus (74) Google Scholar]. Conversely, congenital heart defects are seen more frequently in females [7.Morris J.K. et al.M","journal":"Trends in Genetics","year":2020,"id":67188,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9375,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":357434,"name":"Katheleen Gardiner","orcid":null,"position":1,"is_corresponding":false},{"id":218382,"name":"Roger H. Reeves","orcid":"0000-0002-3581-0850","position":2,"is_corresponding":false},{"id":355961,"name":"Anna J. Moyer","orcid":"0000-0003-1912-1745","position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":null,"created_at":"2026-07-18T21:15:12.020735Z","pmid":"33097276","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}