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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使用小鼠模型研究与精神分裂症和自闭症相关的 CNV 对疾病机制的贡献。

人类遗传学正在为神经精神疾病的潜在机制提供急需的线索。高外显拷贝数变异 (CNV) 是最早与精神分裂症和自闭症谱系障碍 (ASD) 相关的遗传变异之一。尽管结构复杂，但与神经精神疾病相关的 CNV 的高外显率表明其可用于构建细胞和动物模型。携带疾病相关等位基因的人类细胞模型具有研究 CNV 影响的人类遗传背景的优势。然而，研究疾病相关等位基因对活体大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大脑。在这里，我关注携带人类神经精神 CNV 模型的转基因小鼠的转化效用，同时认识到它们作为复杂人类大脑疾病的真实模型的局限性。为了提高翻译效用并避免经常困扰神经精神疾病模型解释的智力死胡同，我最后提出了一个“草案”建议，用更细微和上下文相关的判断来取代当前的构念和表面效度概念。