{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:31:44Z","timestamp":1790713904338,"version":"4.1.0"},"reference-count":88,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA016056"],"award-info":[{"award-number":["P30CA016056"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21GM114645"],"award-info":[{"award-number":["R21GM114645"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03TR003344"],"award-info":[{"award-number":["R03TR003344"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DC019735"],"award-info":[{"award-number":["R01DC019735"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD109750"],"award-info":[{"award-number":["R01HD109750"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD090180"],"award-info":[{"award-number":["R01HD090180"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,19]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 \u2018free trisomy\u2019 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad056","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T18:23:18Z","timestamp":1680632598000},"page":"2205-2218","source":"Crossref","is-referenced-by-count":24,"title":["Dissection of a Down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome"],"prefix":"10.1093","volume":"32","author":[{"given":"Zhuo","family":"Xing","sequence":"first","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center The Children\u2019s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Li","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center The Children\u2019s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Cortes-Gomez","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Biostatistics and Bioinformatics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Jiang","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine, National Clinical Research Center for Child Health The Children\u2019s Hospital, , Hangzhou, Zhejiang , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Gao","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Biostatistics and Bioinformatics, , Buffalo, NY , USA"},{"name":"Bioinformatics, OmniSeq Inc. , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Pao","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center The Children\u2019s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jidong","family":"Shan","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Molecular Cytogenetics Core, , Bronx, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Song","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine Molecular Cytogenetics Core, , Bronx, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Perez","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yu","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center The Children\u2019s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max R","family":"Highsmith","sequence":"additional","affiliation":[{"name":"University of Missouri Department of Electric Engineering and Computer Science, , Columbia, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frimpong","family":"Boadu","sequence":"additional","affiliation":[{"name":"University of Missouri Department of Electric Engineering and Computer Science, , Columbia, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M","family":"Conroy","sequence":"additional","affiliation":[{"name":"OmniSeq Inc. Research and Development, , Buffalo, NY , USA"},{"name":"Roswell Park Comprehensive Cancer Center Research Support Services, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant K","family":"Singh","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei V","family":"Bakin","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlin","family":"Cheng","sequence":"additional","affiliation":[{"name":"University of Missouri Department of Electric Engineering and Computer Science, , Columbia, MO , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Duan","sequence":"additional","affiliation":[{"name":"University of Washington Institute for Stem Cell and Regenerative Medicine, , Seattle, WA , USA"},{"name":"University of Washington Division of Hematology, Department of Medicine, , Seattle, WA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmin","family":"Wang","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Biostatistics and Bioinformatics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Liu","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center Department of Biostatistics and Bioinformatics, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Tycko","sequence":"additional","affiliation":[{"name":"Hackensack-Meridian Health Center for Discovery and Innovation , Nutley, NJ , USA"},{"name":"Hackensack University Medical Center John Theurer Cancer Center, , Hackensack, NJ , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y Eugene","family":"Yu","sequence":"additional","affiliation":[{"name":"Roswell Park Comprehensive Cancer Center The Children\u2019s Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, , Buffalo, NY , USA"},{"name":"State University of New York at Buffalo Genetics, Genomics and Bioinformatics Program, , Buffalo, NY , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,4]]},"reference":[{"key":"2023062021513213200_ref1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nrg.2016.154","article-title":"Down syndrome and the complexity of genome dosage imbalance","volume":"18","author":"Antonarakis","year":"2017","journal-title":"Nat. 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Genet."},{"key":"2023062021513213200_ref5","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/ana.410430316","article-title":"Molecular mapping of Alzheimer-type dementia in Down's syndrome","volume":"43","author":"Prasher","year":"1998","journal-title":"Ann. Neurol."},{"key":"2023062021513213200_ref6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.neuron.2006.05.022","article-title":"Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration","volume":"51","author":"Salehi","year":"2006","journal-title":"Neuron"},{"key":"2023062021513213200_ref7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s00335-021-09930-z","article-title":"Mouse models of aneuploidy to understand chromosome disorders","volume":"33","author":"Tosh","year":"2022","journal-title":"Mamm. 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Rep."},{"key":"2023062021513213200_ref13","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3390\/ijms22031259","article-title":"Nuclear reorganization in hippocampal granule cell neurons from a mouse model of Down syndrome: changes in chromatin configuration, nucleoli and Cajal bodies","volume":"22","author":"Puente-Bedia","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2023062021513213200_ref14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41556-018-0243-8","article-title":"The diverse consequences of aneuploidy","volume":"21","author":"Chunduri","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"2023062021513213200_ref15","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/ajmg.1320050411","article-title":"Anatomical analysis of the developmental effects of aneuploidy in man: the Down syndrome","volume":"5","author":"Bersu","year":"1980","journal-title":"Am. J. Med. Genet."},{"key":"2023062021513213200_ref16","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/MOP.0b013e3283595031","article-title":"Perspectives on the care and management of infants with trisomy 18 and trisomy 13: striving for balance","volume":"24","author":"Carey","year":"2012","journal-title":"Curr. Opin. Pediatr."},{"key":"2023062021513213200_ref17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/1750-1172-7-81","article-title":"The trisomy 18 syndrome","volume":"7","author":"Cereda","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"2023062021513213200_ref18","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/pd.3920","article-title":"Posterior brain in fetuses with trisomy 18, trisomy 13 and triploidy at 11 to 13 weeks' gestation","volume":"32","author":"Ferreira","year":"2012","journal-title":"Prenat. Diagn."},{"key":"2023062021513213200_ref19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1891\/0730-0832.35.1.31","article-title":"Trisomy 13: changing perspectives","volume":"35","author":"Macias","year":"2016","journal-title":"Neonatal Netw."},{"key":"2023062021513213200_ref20","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.pediatrneurol.2019.03.015","article-title":"Structural magnetic resonance imaging-based brain morphology study in infants and toddlers with Down syndrome: the effect of comorbidities","volume":"100","author":"Shiohama","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"2023062021513213200_ref21","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S1053-8119(03)00273-8","article-title":"A voxel-based morphometric study of nondemented adults with Down syndrome","volume":"20","author":"White","year":"2003","journal-title":"NeuroImage"},{"key":"2023062021513213200_ref22","first-page":"263","article-title":"Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome","volume":"360","author":"Davisson","year":"1990","journal-title":"Prog. Clin. Biol. Res."},{"key":"2023062021513213200_ref23","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1242\/dmm.029728","article-title":"Rodent models in Down syndrome research: impact and future opportunities","volume":"10","author":"Herault","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"2023062021513213200_ref24","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1093\/hmg\/ddm086","article-title":"Duplication of the entire 22.9-Mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities","volume":"16","author":"Li","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"2023062021513213200_ref25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/ng1095-177","article-title":"A mouse model for Down syndrome exhibits learning and behaviour deficits","volume":"11","author":"Reeves","year":"1995","journal-title":"Nat. Genet."},{"key":"2023062021513213200_ref26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1093\/bmb\/ldw040","article-title":"Mouse-based genetic modeling and analysis of Down syndrome","volume":"120","author":"Xing","year":"2016","journal-title":"Br. Med. Bull."},{"key":"2023062021513213200_ref27","doi-asserted-by":"crossref","first-page":"dmm031013","DOI":"10.1242\/dmm.031013","article-title":"Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1\/Yey mouse models of Down syndrome","volume":"11","author":"Aziz","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"2023062021513213200_ref28","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1182\/blood-2007-04-085670","article-title":"Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome","volume":"111","author":"Kirsammer","year":"2008","journal-title":"Blood"},{"key":"2023062021513213200_ref29","doi-asserted-by":"crossref","first-page":"4773","DOI":"10.18632\/oncotarget.23463","article-title":"Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors","volume":"9","author":"Liu","year":"2018","journal-title":"Oncotarget"},{"key":"2023062021513213200_ref30","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1007\/s00335-006-0032-8","article-title":"Postnatal lethality and cardiac anomalies in the Ts65Dn Down syndrome mouse model","volume":"17","author":"Moore","year":"2006","journal-title":"Mamm. 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Genet."},{"key":"2023062021513213200_ref42","first-page":"35","article-title":"Survey of embryonic stem cell line source strains in the water maze reveals superior reversal learning of 129S6\/SvEvTac mice","volume":"152","author":"Clapcote","year":"2004","journal-title":"Behav. Brain Res."},{"key":"2023062021513213200_ref43","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0306-4522(96)00224-2","article-title":"Mildly impaired water maze performance in male Fmr1 knockout mice","volume":"76","author":"D'Hooge","year":"1997","journal-title":"Neuroscience"},{"key":"2023062021513213200_ref44","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.nbd.2011.04.011","article-title":"Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of beta1-adrenergic receptor by xamoterol as a potential cognitive enhancer","volume":"43","author":"Faizi","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"2023062021513213200_ref45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/467251","article-title":"Adult-onset fluoxetine treatment does not improve behavioral impairments and may have adverse effects on the Ts65Dn mouse model of Down syndrome","volume":"2012","author":"Heinen","year":"2012","journal-title":"Neural Plast."},{"key":"2023062021513213200_ref46","doi-asserted-by":"crossref","first-page":"13333","DOI":"10.1073\/pnas.93.23.13333","article-title":"Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome","volume":"93","author":"Holtzman","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023062021513213200_ref47","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/s41398-019-0495-5","article-title":"Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities","volume":"9","author":"Lauterborn","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"2023062021513213200_ref48","doi-asserted-by":"crossref","first-page":"e114521","DOI":"10.1371\/journal.pone.0114521","article-title":"Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of Down syndrome","volume":"9","author":"Lysenko","year":"2014","journal-title":"PLoS One"},{"key":"2023062021513213200_ref49","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3389\/fnagi.2020.00106","article-title":"Cilostazol, a phosphodiesterase 3 inhibitor, moderately attenuates behaviors depending on sex in the Ts65Dn mouse model of Down syndrome","volume":"12","author":"Tsuji","year":"2020","journal-title":"Front. 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