Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases.
Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases.
复制标题
DOI：
10.1371/journal.pcbi.1003632
复制
发表时间：
2014-06
影响因子：
4.3
通讯作者：
Yeger-Lotem E
中科院分区：
文献类型：
--
作者：
Barshir R;Shwartz O;Smoly IY;Yeger-Lotem E
人类遗传学中的一个悬而未决的问题是遗传性疾病的组织特异性表现的基础是什么，遗传性疾病是由人体细胞中存在的基因组畸变引起的。在这里，我们通过比较网络分析分析了300多种遗传性疾病的这种现象。我们通过整合组织间基因和蛋白质表达的最新数据与蛋白质-蛋白质相互作用（PPI）的数据，创建了16种主要人体组织中蛋白质表达和相互作用的广泛资源。由此产生的组织相互作用网络（interactomes）共享大部分蛋白质和PPI，只有一小部分是组织特异性的。将这一资源应用于遗传性疾病，我们首先表明，大多数致病基因在组织中广泛表达，但神秘的是，仅在少数组织中引起疾病表型。在测试可能导致组织特异性脆弱性的因素后，我们发现，与未受影响的组织相比，致病基因往往在其疾病组织中具有升高的转录水平和增加的组织特异性PPI数量。我们通过几个例子证明，这些组织特异性PPI可以突出疾病机制，因此，由于其数量少，提供了一个强大的过滤器询问疾病病因。由于三分之二的遗传性疾病与这些因素有关，比较组织分析提供了一个有意义的和有效的框架，以提高对遗传性疾病的分子基础的理解。人类遗传学中的一个悬而未决的问题是遗传性疾病的组织特异性表现的基础是什么，遗传性疾病是由整个人体细胞中存在的基因组畸变引起的。为了回答这个问题，我们在16种主要人体组织中创建了广泛的蛋白质表达和相互作用资源。利用这一资源，我们首先表明，数百种遗传性疾病的基因在组织中广泛表达，但神秘的是，仅在少数组织中引起疾病表型。然后，我们确定了两个不同的，具有重要意义的因素，可能会导致组织特异性的脆弱性，面对这种广泛的表达：（i）许多致病基因在其疾病组织中的表达水平升高，（ii）致病基因在其疾病组织中具有明显更高的组织特异性相互作用的倾向。正如我们所展示的几个致病基因，这些组织特异性相互作用突出了疾病机制，并为询问疾病的分子基础提供了有效的过滤器。我们确定的这两个因素与多达三分之二的组织特异性遗传性疾病有关。因此，我们的比较组织分析提供了一个有意义的和有效的框架，以提高遗传性疾病的分子基础的理解。
An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases. An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the entire human body. In order to answer this question, we created an extensive resource of protein expression and interactions across 16 main human tissues. Using this resource, we first show that the genes underlying hundreds of hereditary diseases are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. We then identify two distinct, statistically-significant factors that could lead to tissue-specific vulnerability in the face of this broad expression: (i) many disease-causing genes have elevated expression levels in their disease tissues, and (ii) disease-causing genes have a significantly higher tendency for tissue-specific interactions in their disease tissues. As we show for several disease-causing genes, these tissue-specific interactions highlight disease mechanisms and provide an efficient filter for interrogating the molecular basis of diseases. Together the two factors we identified are relevant for as many as two thirds of the tissue-specific hereditary diseases. Our comparative tissue analysis therefore provides a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.
登录
查看更多内容
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.3
作者：
Guan Y;Gorenshteyn D;Burmeister M;Wong AK;Schimenti JC;Handel MA;Bult CJ;Hibbs MA;Troyanskaya OG
通讯作者：
Troyanskaya OG
人类基因表达的组织特异性的综合功能分析。
影响因子：
5.4
作者：
Dezso Z;Nikolsky Y;Sviridov E;Shi W;Serebriyskaya T;Dosymbekov D;Bugrim A;Rakhmatulin E;Brennan RJ;Guryanov A;Li K;Blake J;Samaha RR;Nikolskaya T
通讯作者：
Nikolskaya T
影响因子：
4.5
作者：
Nassoury, Nasha;Blasiole, Daniel A.;Seidah, Nabil G.
通讯作者：
Seidah, Nabil G.
影响因子：
5.8
作者：
Correa, RV;Domenice, S;Mendonca, BB
通讯作者：
Mendonca, BB