Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we “clone” the 34 MB long arm of HSA21 (HSA21q) as a mouse artificial chromosome (MAC). Through multiple steps of microcell-mediated chromosome transfer, we created a new Tc DS mouse model, Tc(HSA21q;MAC)1Yakaz (“TcMAC21”). TcMAC21 is not mosaic and contains 93% of HSA21q PCGs that are expressed and regulatable. TcMAC21 recapitulates many DS phenotypes including anomalies in heart, craniofacial skeleton and brain, molecular/cellular pathologies, and impairments in learning, memory and synaptic plasticity. TcMAC21 is the most complete genetic mouse model of DS extant and has potential for supporting a wide range of basic and preclinical research.

中文翻译：

---

携带人类 21 号染色体长臂的唐氏综合征非镶嵌转染色体小鼠模型

唐氏综合症 (DS)、人类 21 号染色体 (HSA21) 三体基因或直向同源物的动物模型提供了更好地理解和治疗选择的见解。唯一现有的转染色体 (Tc) 小鼠 DS 模型 Tc1 携带一个 HSA21，其中 50 多个蛋白质编码基因 (PCG) 被破坏。Tc1 是马赛克，影响结果的解释。在这里，我们将 HSA21 (HSA21q) 的 34 MB 长臂“克隆”为小鼠人工染色体 (MAC)。通过微细胞介导的染色体转移的多个步骤，我们创建了一个新的 Tc DS 小鼠模型，Tc(HSA21q;MAC)1Yakaz (“TcMAC21”)。TcMAC21 不是嵌合体，包含 93% 的 HSA21q PCG，这些 PCG 是可表达和可调节的。TcMAC21 概括了许多 DS 表型，包括心脏异常、颅面骨骼和大脑、分子/细胞病变和学习障碍，记忆和突触可塑性。TcMAC21 是现存最完整的 DS 遗传小鼠模型，具有支持广泛的基础和临床前研究的潜力。