A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes
A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes
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DOI：
10.1073/pnas.0810772105
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发表时间：
2008-12-30
影响因子：
11.1
通讯作者：
Brunak, Soren
中科院分区：
文献类型：
--
作者：
Lage, Kasper;Hansen, Niclas Tue;Brunak, Soren
遗传性疾病是由生殖系突变引起的，尽管存在于组织范围内，但通常会导致组织特异性病理学。在这里，我们对组织特异性基因表达与许多人类疾病和癌症的病理表现之间的联系进行了系统的分析。将疾病系统地映射到PubMed中疾病相关文献中受其影响的组织，以创建> 1，000种疾病与73种组织的高置信度关联的疾病-组织协变矩阵。通过检索超过2,000个已知的疾病基因，并产生1,500个疾病相关蛋白复合物，我们分析了与特定疾病相关的基因或复合物在受疾病影响的组织中与未受影响的组织相比的差异表达。当这种分析扩展到我们数据集中的所有疾病时，疾病基因和复合物在缺陷导致病理的正常组织中过度表达的趋势很明显。相反，癌基因和复合物在肿瘤产生的组织中没有过表达。我们特别确定了一个复杂的XY性逆转，是睾丸特异性和卵巢下调。我们还发现帕金森病、心肌病和肌营养不良综合征中的复合物具有相似的组织特异性。我们的方法代表了一个概念性的支架跨越生物体的分析，并揭示了广泛的组织特异性草案分子途径，已知的和意想不到的，可能会被破坏的疾病。
Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease-tissue covariation matrix of high-confidence associations of > 1,000 diseases to 73 tissues. By retrieving > 2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease.