Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy.
Mamm Genome. 2012 Aug;23(7-8):443-53. doi: 10.1007/s00335-012-9401-7. Epub 2012 Jul 7.
Copy number variation (CNV) has been associated increasingly with altered susceptibility to human disease. Large CNVs are likely to incur disease risk or resilience via predictable changes in gene dosage that are relatively straightforward to model using chromosomal engineering in mice. The classical class I major histocompatibility locus (MHC-I) contains a dense set of genes essential for innate immune system function in vertebrates. MHC-I genes are highly polymorphic and genetic variation in the region is associated with altered susceptibility to a wide variety of common diseases. Here we investigated the role of gene dosage within MHC-I on susceptibility to disease by engineering a mouse line carrying a 1.9-Mb duplication of this region [called Dp(MHC-I)]. Extensive phenotypic analysis of heterozygous (3N) Dp(MHC-I) animals did not reveal altered blood and stem cell parameters, susceptibility to high-fat diet, death by cancer, or contact dermatitis. However, several measures of disease severity in a model of atherosclerosis were improved, suggesting dosage-sensitive modulators of cardiovascular disease. Homozygous Dp(MHC-I)/Dp(MHC-I) mice demonstrated embryonic lethality. These mice serve as a model for studying the consequences of targeted gene dosage alteration in MHC-I with functional and evolutionary implications.
拷贝数变异（CNV）与人类疾病易感性的改变越来越相关。大的 CNV 可能会通过基因剂量的可预测变化导致疾病风险或抵抗力，而这种变化在小鼠中使用染色体工程相对容易建模。经典的 I 类主要组织相容性位点（MHC-I）包含一组对脊椎动物固有免疫系统功能至关重要的密集基因。MHC-I 基因高度多态性，该区域的遗传变异与多种常见疾病的易感性改变有关。在这里，我们通过构建携带该区域 1.9Mb 重复的小鼠系（称为 Dp（MHC-I））来研究 MHC-I 内基因剂量对疾病易感性的作用。对杂合子（3N）Dp（MHC-I）动物的广泛表型分析并未揭示血液和干细胞参数的改变、高脂肪饮食易感性、癌症死亡或接触性皮炎。然而，动脉粥样硬化模型中几种疾病严重程度的测量指标有所改善，提示心血管疾病存在剂量敏感的调节因子。纯合子 Dp（MHC-I）/Dp（MHC-I）小鼠表现出胚胎致死性。这些小鼠可作为研究 MHC-I 中靶向基因剂量改变的后果的模型，具有功能和进化意义。
