自然恢复的遗传变异影响突变人胰岛素基因表达诱导的果蝇眼变性的严重程度
Naturally Occurring Genetic Variation Influences the Severity of Drosophila Eye Degeneration Induced by Expression of a Mutant Human Insulin Gene
摘要：
胰岛素基因的显性负突变是永久性新生儿糖尿病的第二大常见原因。然而，新生儿糖尿病的严重程度和发病率的变化，与其他复杂的遗传疾病一样，不能用已知的疾病突变来解释。在解决这个问题的一种新方法中，我们利用果蝇中可用的遗传工具来模拟C96 Y突变的影响，C96 Y突变是胰岛素蛋白中的半胱氨酸到酪氨酸突变，可导致人类永久性新生儿糖尿病。这种突变破坏了胰岛素原分子中的二硫键，已被证明会导致部分蛋白质在内质网中展开和聚集。它被认为通过内质网应激介导的细胞凋亡诱导人和小鼠的β细胞死亡。我们采用UAS/GAL 4系统在果蝇眼睛中产生表达具有C96 Y突变（INSC 96 Y）的人胰岛素的稳定的果蝇实验室原种。我们将这些转基因INSC 96 Y果蝇与来自野生种群的36个等基因系杂交。F1代果蝇表现出眼发育表型紊乱，眼大小减小，小眼不规则，且随性别和品系而异。通过将F1后代与其野生亲本回交，我们能够分析野生第三染色体杂合和纯合果蝇中自然发生的遗传变异对INSC 96 Y表型的影响。我们观察到的显着差异线之间的眼睛大小，眼睛形状，病变的存在或不存在，以及存在的小眼结构的程度，表明一种方法，考虑到遗传背景中的定量变异可以产生有价值的见解的表型严重程度和复杂的遗传疾病的发病率。
英文摘要：
Dominant negative mutations in the insulin gene are the second most common cause of permanent neonatal diabetes. However, variation in severity and penetrance of neonatal diabetes, as in other complex genetic diseases, cannot be accounted for by known disease mutations. In a novel approach to this problem, we have utilized the genetic tools available in Drosophila to model the effects of the C96Y mutation, a cysteine to tyrosine mutation in the insulin protein that can cause permanent neonatal diabetes in humans. This mutation, which disrupts a disulfide bridge in the proinsulin molecule, has been shown to lead to partial protein unfolding and aggregation in the endoplasmic reticulum. It is thought to induce beta cell death in humans and mice through endoplasmic reticulum stress-mediated apoptosis. We employed the UAS/GAL4 system to create a stable fly laboratory stock expressing human insulin with the C96Y mutation (INSC96Y) in the Drosophila eye. We crossed these transgenic INSC96Y flies to 36 isogenic lines derived from a wild population. The F1 flies displayed a disrupted eye development phenotype, with both reduced eye size and irregularity in ommatidia, which varied between lines and with sex. By backcrossing F1 offspring to their wild parents, we were able to analyze the effects of naturally occurring genetic variation on the INSC96Y phenotype in flies both heterozygous and homozygous for wild third chromosomes. We observed significant differences between lines in terms of eye size, eye shape, the presence or absence of lesions, and degree of ommatidial structure present, indicating that an approach that takes into account quantitative variation in the genetic background can yield valuable insights into the phenotypic severity and penetrance of a complex genetic disease.
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