Down syndrome (DS), associated with trisomy 21, is the most common genetic cause of developmental delay and intellectual disability, yet the specific dosage-sensitive genes and the associated genetic mechanisms underlying these phenotypes remain incompletely defined. Here, we applied an additive genetic strategy to dissect the Down syndrome critical region (DSCR) by generating two 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-Kcnj6 interval, and Dp(16)6Yey, duplicating the Kcnj15-Mx2 interval. In addition, we engineered a third duplication model, Dp(16)7Yey, carrying a selective duplication of the Dyrk1a-Kcnj6 interval containing only these two genes. Building upon our previously reported results, cognitive behavioral analyses of these three 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.
Jiang et al. (Wed,) studied this question.