Impact of gene copy number variation on anesthesia in Drosophila melanogaster.
Impact of gene copy number variation on anesthesia in Drosophila melanogaster.
复制标题
基因拷贝数变异对果蝇麻醉的影响。
DOI：
10.1097/aln.0b013e3181a3276c
复制
发表时间：
2009
期刊：
影响因子：
8.8
通讯作者：
Nash,HowardA
中科院分区：
文献类型：
--
作者：
Alone,DebasmitaP;Rodriguez,JasonC;Noland,CameronL;Nash,HowardA
背景染色体缺失和复制导致基因组拷贝数减半或加倍，是个体间变异的重要来源。通常观察到拷贝数变异的表型效应，但据我们所知，尚未在任何生物体中评估对挥发性麻醉剂敏感性的影响。方法在同源果蝇品系中测定氟烷抑制果蝇翻正反射的效力，每个品系的平均大小约为400 kb的缺失是杂合的。超过200个菌株进行了检查，从而扫描苍蝇基因组的一半。结果尽管绝大多数缺失杂合子与对照组无明显区别，但有8例对氟烷的敏感性发生了显著改变。基因检测支持这一假设，即麻醉剂敏感性的变化是由于拷贝数的减少，而不是菌株中的外源突变。在8个异常值中，氟烷效力的差异范围从增加25%到减少15%。当这些线进行了测试，安氟醚，异氟醚和七氟醚，类似的幅度，但独特的模式的变化被发现。结论基因拷贝数的变化有显着的影响，在果蝇的麻醉敏感性。因此，一些基因的转录水平必须限制对挥发物的正常反应。由于基因拷贝和基因表达之间的耦合是普遍的，因为苍蝇的神经系统的组成部分是高度保守的，我们的工作提供了一个基本原理，研究拷贝数变异的临床影响。
Background Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed but, to our knowledge, effects on sensitivity to volatile anesthetics have not been assessed in any organism. Methods The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which was heterozygous for a deletion of average size ~ 400 kb. Over 200 strains were examined, thereby scanning~half of the fly genome. Results Although the vast majority of deletion heterozygotes were indistinguishable from the control, eight had significantly altered sensitivity to halothane. Genetic tests supported the hypothesis that the change in anesthetic sensitivity was due to reduction in copy number and not adventitious mutations in the strains. Among the eight outliers, the difference in halothane potency ranged from a 25% increase to a 15% decrease. When these lines were tested with enflurane, isoflurane and sevoflurane, changes of similar magnitude but distinctive patterns were found. Conclusions Variation in gene copy number has a significant impact on anesthetic sensitivity in Drosophila melanogaster. The level of transcription of a few genes must thus be limiting for a normal response to volatiles. Since coupling between gene copy and gene expression is universal and since the components of the fly’s nervous system are highly conserved, our work provides a rationale for investigating the clinical impact of copy number variation.