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DS mouse models recapitulate these deficits, including sexual dimorphism in long bone alterations. Historically, Ts65Dn mice provided much of the insight behind DS-related skeletal deficits with \u223c100 trisomic orthologous genes, but there are concerns about the genetic fidelity in this model due to the included triplication of genes not homologous to Hsa21. A new DS model, Ts66Yah, subtracted the non-Hsa21 homologous trisomic genes from Ts65Dn but has not been evaluated for long bone deficits. Comparing skeletal phenotypes between these models can determine the contribution of non-Hsa21 homologous trisomic genes and whether the Ts66Yah mouse is relevant as a model for DS-associated skeletal deficits. After assessing individual densitometric, morphometric, and mechanical variables in male and female Ts66Yah femurs at similar ages to when skeletal deficits were observed in Ts65Dn mice, structural phenotypes were directly compared to those of Ts65Dn mice using a novel multivariate principal components analysis method to generate composite scores. Overall, structural and mechanical bone phenotypes of the femur appeared milder in Ts66Yah compared to Ts65Dn mice. The appearance of developmental trabecular microarchitecture deficits, but not other abnormalities, was evident earlier in Ts65Dn than Ts66Yah mice. Dyrk1a, a gene triplicated in both models, affected skeletal structure differently in each model, likely through differing gene interactions. The novel principal components analysis detected subclinical phenotypes lost in individual analyses, which could be advantageous when determining overall skeletal deficits.<\/jats:p>","DOI":"10.1093\/g3journal\/jkag056","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:11:57Z","timestamp":1772788317000},"source":"Crossref","is-referenced-by-count":1,"title":["Genetic analysis of triplicated genes affecting sex-specific skeletal deficits in Down syndrome model mice"],"prefix":"10.1093","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3552-6085","authenticated-orcid":false,"given":"Kourtney","family":"Sloan","sequence":"first","affiliation":[{"name":"Department of Biology, Indiana University Indianapolis , 723 W Michigan Street, SL306, Indianapolis, IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina M","family":"Piner","sequence":"additional","affiliation":[{"name":"Department of Biology, Indiana University Indianapolis , 723 W Michigan Street, SL306, Indianapolis, IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6317-1216","authenticated-orcid":false,"given":"Pathum Randunu Nawarathna","family":"Kandedura Arachchige","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Missouri University of Science and Technology , 202 Rolla Building, 400 W 12th St, Rolla, MO 65409 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7821-9999","authenticated-orcid":false,"given":"Charles R","family":"Goodlett","sequence":"additional","affiliation":[{"name":"Department of Psychology, Indiana University Indianapolis , 402 N Blackford St, LD124, Indianapolis, IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-6900","authenticated-orcid":false,"given":"Yann","family":"Herault","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine and Neurogenetics, University of Strasbourg, CNRS UMR7104, INSERM U1258, Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC) , 1 Rue Laurent Fries, BP 10142, 64700 Illkirch CEDEX ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayla R","family":"Olbricht","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Missouri University of Science and Technology , 202 Rolla Building, 400 W 12th St, Rolla, MO 65409 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M","family":"Wallace","sequence":"additional","affiliation":[{"name":"Weldon School of Biomedical Engineering, Purdue 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