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Here, we applied an additive genetic strategy to dissect the Down syndrome critical region (DSCR) by generating 2 complementary mouse models using Cre\/loxP-mediated chromosome engineering that together span the entire DSCR on mouse chromosome 16: Dp(16)5Yey, duplicating the Setd4\u2013Kcnj6 interval, and Dp(16)6Yey, duplicating the Kcnj15\u2013Mx2 interval. In addition, we engineered a third duplication model, Dp(16)7Yey, carrying a selective duplication of the Dyrk1a\u2013Kcnj6 interval containing only these 2 genes. Building upon our previously reported results, cognitive behavioral analyses of these 3 models reveal a complex functional genetic architecture of the DSCR, including dosage-sensitive genetic elements, interactions among these elements, and their contributions to DS-associated cognitive deficits. Together, these findings highlight the complexity of dosage-dependent genetic interactions, which provide important insights into DSCR functional organization and have major implications for the development of effective therapeutic strategies for DS-associated cognitive deficits. In addition, these duplication mouse models represent valuable resources for further genetic dissection of DS phenotypes beyond cognition.<\/jats:p>","DOI":"10.1093\/g3journal\/jkag173","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T15:15:43Z","timestamp":1782918943000},"source":"Crossref","is-referenced-by-count":0,"title":["Duplication-based genetic dissection of the Down syndrome critical region reveals its complex functional organization"],"prefix":"10.1093","volume":"16","author":[{"given":"Xiaoling","family":"Jiang","sequence":"first","affiliation":[{"name":"The Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center , Buffalo, NY 14263 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Liu","sequence":"additional","affiliation":[{"name":"The Children's Guild Foundation Down Syndrome Research 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