Genetic architecture predisposes regions of the human genome to copy-number variants, which confer substantial disease risk, most prominently towards neurodevelopmental disorders. These variants typically contain multiple genes and are often associated with extensive pleiotropy and variable phenotypic expressivity. Despite the expansion of the fidelity of CNV detection, and the study of such lesions at the population level, understanding causal mechanisms for CNV phenotypes will require biological testing of constituent genes and their interactions. In this regard, model systems amenable to high-throughput phenotypic analysis of dosage-sensitive genes (and combinations thereof) are beginning to offer improved granularity of CNV-driven pathology. Here, we review the utility of Drosophila and zebrafish models for pathogenic CNV regions, highlight the advances made in discovery of single gene drivers and genetic interactions that determine specific CNV phenotypes, and argue for their validity in dissecting conserved developmental mechanisms associated with CNVs.

中文翻译：

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剖析 CNV 致病性的复杂性：来自果蝇和斑马鱼模型的见解。

遗传结构使人类基因组的区域易于产生拷贝数变异，这会带来很大的疾病风险，最突出的是神经发育障碍。这些变体通常包含多个基因，并且通常与广泛的多效性和可变的表型表达相关。尽管 CNV 检测的保真度得到了扩展，并且在人群水平上对此类病变进行了研究，但了解 CNV 表型的因果机制将需要对组成基因及其相互作用进行生物学测试。在这方面，适用于剂量敏感基因（及其组合）的高通量表型分析的模型系统开始提供改进的 CNV 驱动病理学粒度。在这里，我们回顾了果蝇和斑马鱼模型对致病性 CNV 区域的效用，