Human genetics is providing much needed clues to mechanisms underlying neuropsychiatric disorders. Highly penetrant copy number variants (CNVs) were among the first genetic variants confidently associated with schizophrenia and autism spectrum disorders (ASDs). Despite their structural complexity, the high penetrance of CNVs associated with neuropsychiatric disorders suggested utility for construction of cellular and animal models. Human cellular models that carry disease associated alleles have the advantage of human genetic backgrounds against which to study the effects of CNVs. However, investigation of the effects of disease-associated alleles on the structure and function of living brains requires genome engineering of model organisms or introduction of genetic material into their brains by viral vectors. Here I focus on the translational utility of transgenic mice that carry models of human neuropsychiatric CNVs, while recognizing their limitations as veridical models of complex human brain disorders. In order to improve translational utility and avoid the intellectual cul-de-sacs that often bedevil interpretation of neuropsychiatric disease models, I conclude with a 'draft' proposal to replace current concepts of construct and face validity with more nuanced and contextually relevant judgments.

中文翻译：

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使用小鼠模型调查与精神分裂症和自闭症相关的CNV对疾病机制的贡献。

人类遗传学为神经精神疾病的潜在机制提供了急需的线索。高渗透性拷贝数变异（CNV）是与精神分裂症和自闭症谱系障碍（ASD）可靠相关的首批遗传变异之一。尽管其结构复杂，但与神经精神疾病相关的CNV的高渗透性提示可用于构建细胞和动物模型。携带与疾病相关的等位基因的人类细胞模型具有人类遗传背景的优势，可根据其研究CNV的作用。然而，研究与疾病相关的等位基因对活脑结构和功能的影响，需要模型生物的基因组工程或通过病毒载体将遗传物质引入其脑中。在这里，我将重点放在携带人类神经精神CNV模型的转基因小鼠的翻译实用性上，同时认识到它们的局限性是复杂的人类脑部疾病的垂直模型。为了提高翻译的实用性并避免经常困扰神经精神疾病模型的知识盲点，我以“草案”建议作为结束，提出了以较细微的和与上下文相关的判断代替当前的构想和面部有效性的建议。