Expression QTL and regulatory network analysis of microtubule-associated protein tau gene.
Expression QTL and regulatory network analysis of microtubule-associated protein tau gene.
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DOI：
10.1016/j.parkreldis.2008.10.010
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发表时间：
2009-08
影响因子：
4.1
通讯作者：
Qin Shen;Xusheng Wang;Ying Chen;Lingli Xu;Xiaodong Wang;Lu Lu-Lu
中科院分区：
文献类型：
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作者：
Qin Shen;Xusheng Wang;Ying Chen;Lingli Xu;Xiaodong Wang;Lu Lu-Lu
大量研究表明微管相关蛋白tau（Mapt）基因在tau蛋白病中起重要作用。然而，人们对基因调控网络知之甚少。在本研究中，我们结合阵列分析和数量性状位点（QTL）定位方法（遗传基因组学）来表征小鼠Mapt的表达变异和调控网络。通过检测探针组的重叠单核苷酸多态性（SNPs），选择了两个没有重叠SNPs的探针组进行QTL定位。区间作图结果表明，Mapt的表达数量性状基因座（eQTL）作图具有27.2的显著连锁得分（LRS）。此外，该QTL被定位到基因本身的位置（Mapt）的3 Mb内作为顺式作用QTL。通过对Mapt的联合调控定位，我们鉴定出22个在Mapt位点附近具有反式调控QTL的转录本/基因。通过进一步排除由于连锁不平衡而导致的相关转录本，结果突出了三个基因作为Mapt的潜在下游基因。表达相关性和遗传网络分析表明，Mapt与许多tau蛋白相关基因，包括Gsk 3b，Falz，Apbb 2，Slc 1a 3，Ntrk 2，Pik 3ca和Ikbkap共变异。这些结果表明，遗传基因组学方法提供了一个强大的工具，用于构建途径，有助于复杂的性状，如神经退行性疾病。
Numerous studies have shown that the microtubule-associated protein tau (Mapt) gene plays an important role in tauopathies. However, little is known about the genetic regulatory network. In this study, we combined array analysis and quantitative trait loci (QTL) mapping approaches (genetical genomics) to characterize the expression variation and the regulatory network of Mapt in mouse. Through examining the probe sets for overlapping single nucleotide polymorphysms (SNPs), two probe sets without overlapping SNPs were selected for QTL mapping. Interval mapping results showed that expression quantitative trait loci (eQTL) mapping for Mapt had a significant linkage score (LRS) of 27.2. Moreover, the QTL was mapped to within 3 Mb of the location of the gene itself (Mapt) as a cis-acting QTL. Through mapping the joint modulation of Mapt, we identified 22 transcripts/genes with trans-regulated QTLs close to the location of Mapt. By further excluding the correlated transcripts due to linkage disequilibrium, the result highlighted three genes as potential downstream genes of Mapt. Expression correlation and genetic network analysis demonstrated that Mapt co-varies with many tauopathies-related genes, including Gsk3b, Falz, Apbb2, Slc1a3, Ntrk2, Pik3ca, and Ikbkap. These results demonstrate that the genetical genomics approach provides a powerful tool for constructing pathways that contribute to complex traits, such as neurodegenerative disorders.