IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-465 Porto, Portugal.
BMC Genomics. 2010 Feb 1;11:82. doi: 10.1186/1471-2164-11-82.
X monosomic mice (39,XO) have a remarkably mild phenotype when compared to women with Turner syndrome (45,XO). The generally accepted hypothesis to explain this discrepancy is that the number of genes on the mouse X chromosome which escape X inactivation, and thus are expressed at higher levels in females, is very small. However this hypothesis has never been tested and only a small number of genes have been assayed for their X-inactivation status in the mouse. We performed a global expression analysis in four somatic tissues (brain, liver, kidney and muscle) of adult 40,XX and 39,XO mice using the Illumina Mouse WG-6 v1_1 Expression BeadChip and an extensive validation by quantitative real time PCR, in order to identify which genes are expressed from both X chromosomes.
We identified several genes on the X chromosome which are overexpressed in XX females, including those previously reported as escaping X inactivation, as well as new candidates. However, the results obtained by microarray and qPCR were not fully concordant, illustrating the difficulty in ascertaining modest fold changes, such as those expected for genes escaping X inactivation. Remarkably, considerable variation was observed between tissues, suggesting that inactivation patterns may be tissue-dependent. Our analysis also exposed several autosomal genes involved in mitochondrial metabolism and in protein translation which are differentially expressed between XX and XO mice, revealing secondary transcriptional changes to the alteration in X chromosome dosage.
Our results support the prediction that the mouse inactive X chromosome is largely silent, while providing a list of the genes potentially escaping X inactivation in rodents. Although the lower expression of X-linked genes in XO mice may not be relevant in the particular tissues/systems which are affected in human X chromosome monosomy, genes deregulated in XO mice are good candidates for further study in an involvement in Turner Syndrome phenotype.
与特纳综合征(45,XO)女性相比,X 单体型(39,XO)小鼠的表型非常轻微。解释这种差异的普遍接受的假设是,在雌性中,逃避 X 失活并因此表达水平更高的小鼠 X 染色体上的基因数量非常少。然而,这个假设从未被验证过,只有少数基因在小鼠中被检测到其 X 失活状态。我们使用 Illumina Mouse WG-6 v1_1 Expression BeadChip 在成年 40,XX 和 39,XO 小鼠的四个体组织(大脑、肝脏、肾脏和肌肉)中进行了全局表达分析,并通过定量实时 PCR 进行了广泛验证,以确定哪些基因从两条 X 染色体表达。
我们在 XX 雌性中鉴定出了几个 X 染色体上过度表达的基因,包括以前报道为逃避 X 失活的基因,以及新的候选基因。然而,微阵列和 qPCR 的结果并不完全一致,这说明了确定适度倍数变化(如逃避 X 失活的基因所预期的变化)的困难。值得注意的是,组织之间存在相当大的差异,这表明失活模式可能依赖于组织。我们的分析还暴露了几个参与线粒体代谢和蛋白质翻译的常染色体基因,它们在 XX 和 XO 小鼠之间表达不同,揭示了 X 染色体剂量改变后的转录二次变化。
我们的结果支持了这样的预测,即小鼠的失活 X 染色体基本上是沉默的,同时提供了一个潜在逃避啮齿动物 X 失活的基因列表。尽管 XO 小鼠中 X 连锁基因的低表达在受人类 X 染色体单体性影响的特定组织/系统中可能并不相关,但在 XO 小鼠中失调的基因是进一步研究特纳综合征表型的良好候选基因。