Looking at cerebellar malformations through text-mined interactomes of mice and humans.
Looking at cerebellar malformations through text-mined interactomes of mice and humans.
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DOI：
10.1371/journal.pcbi.1000559
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发表时间：
2009-11
影响因子：
4.3
通讯作者：
Rzhetsky A
中科院分区：
文献类型：
--
作者：
Iossifov I;Rodriguez-Esteban R;Mayzus I;Millen KJ;Rzhetsky A
We have generated and made publicly available two very large networks of molecular interactions: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate; 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration. We described and made publicly available the largest existing set of text-mined statements; we also presented its application to an important biological problem. We have extracted and purified two large molecular networks, one for humans and one for mouse. We characterized the data sets, described the methods we used to generate them, and presented a novel biological application of the networks to study the etiology of five cerebellum phenotypes. We demonstrated quantitatively that the development-related malformations differ in their system-level properties from degeneration-related genes. We showed that there is a high degree of overlap among the genes implicated in the developmental malformations, that these genes have a strong tendency to be highly connected within the molecular network, and that they also tend to be clustered together, forming a compact molecular network neighborhood. In contrast, the genes involved in malformations due to degeneration do not have a high degree of connectivity, are not strongly clustered in the network, and do not overlap significantly with the development related genes. In addition, taking into account the above-mentioned system-level properties and the gene-specific network interactions, we made highly confident predictions about novel genes that are likely also involved in the etiology of the analyzed phenotypes.
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