Inference of miRNA targets using evolutionary conservation and pathway analysis.
Inference of miRNA targets using evolutionary conservation and pathway analysis.
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DOI：
10.1186/1471-2105-8-69
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发表时间：
2007-03-01
影响因子：
3
通讯作者：
Zavolan M
中科院分区：
文献类型：
--
作者：
Gaidatzis D;van Nimwegen E;Hausser J;Zavolan M
MicroRNA已成为多种细胞过程中的重要调控基因，近年来，在动物中发现了数百个这样的基因。相比之下，功能注释仅可用于这些miRNA的非常小的部分，并且即使在这些情况下也仅部分可用。我们开发了一种通用的贝叶斯方法来推断miRNA的靶位点，其中，对于每个miRNA，我们明确地模拟了一组相关物种中的正向靶位点的进化。使用这种方法，我们预测了苍蝇，蠕虫，鱼类和哺乳动物中所有已知的miRNA的靶位点。通过将我们在苍蝇中的预测与实验测试的miRNA-mRNA相互作用的参考集进行比较，我们表明我们的一般方法至少与迄今为止最准确的方法一样好，包括专门针对苍蝇中的目标预测的方法。我们的模型的一个重要的新特征是，它明确地推断出功能性靶位点的系统发育分布，独立于每个miRNA。这使我们能够推断物种特异性和进化枝特异性miRNA靶向。我们还发现，在长的人类3'UTR中，miRNA靶位点优先出现在3' UTR的开始和结束附近。为了表征超出预测目标列表的miRNA功能，我们进一步提出了一种方法来推断针对单个miRNA预测的目标集与特定生化途径（特别是KEGG途径数据库的那些）之间的显著关联。我们表明，这种方法检索几个已知的功能miRNA-mRNA协会，并预测新的功能，已知的miRNA在细胞生长和发育。我们提出了一个贝叶斯目标预测算法，没有任何可调参数，可以应用于任何进化枝的物种序列。该算法自动推断每个miRNA的功能位点的系统发育分布，并为每个推定的靶位点分配后验概率。这里呈现的结果表明，我们的通用方法在预测miRNA靶位点方面实现了非常好的性能，同时提供了对单个miRNA靶位点进化的见解。此外，通过结合我们的预测和途径分析，我们提出了特定的miRNAs在神经系统发育，细胞间通讯和细胞生长中的功能。完整的靶位点预测以及miRNA/通路关联可在ElMMo Web服务器上访问。
MicroRNAs have emerged as important regulatory genes in a variety of cellular processes and, in recent years, hundreds of such genes have been discovered in animals. In contrast, functional annotations are available only for a very small fraction of these miRNAs, and even in these cases only partially. We developed a general Bayesian method for the inference of miRNA target sites, in which, for each miRNA, we explicitly model the evolution of orthologous target sites in a set of related species. Using this method we predict target sites for all known miRNAs in flies, worms, fish, and mammals. By comparing our predictions in fly with a reference set of experimentally tested miRNA-mRNA interactions we show that our general method performs at least as well as the most accurate methods available to date, including ones specifically tailored for target prediction in fly. An important novel feature of our model is that it explicitly infers the phylogenetic distribution of functional target sites, independently for each miRNA. This allows us to infer species-specific and clade-specific miRNA targeting. We also show that, in long human 3' UTRs, miRNA target sites occur preferentially near the start and near the end of the 3' UTR. To characterize miRNA function beyond the predicted lists of targets we further present a method to infer significant associations between the sets of targets predicted for individual miRNAs and specific biochemical pathways, in particular those of the KEGG pathway database. We show that this approach retrieves several known functional miRNA-mRNA associations, and predicts novel functions for known miRNAs in cell growth and in development. We have presented a Bayesian target prediction algorithm without any tunable parameters, that can be applied to sequences from any clade of species. The algorithm automatically infers the phylogenetic distribution of functional sites for each miRNA, and assigns a posterior probability to each putative target site. The results presented here indicate that our general method achieves very good performance in predicting miRNA target sites, providing at the same time insights into the evolution of target sites for individual miRNAs. Moreover, by combining our predictions with pathway analysis, we propose functions of specific miRNAs in nervous system development, inter-cellular communication and cell growth. The complete target site predictions as well as the miRNA/pathway associations are accessible on the ElMMo web server.
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影响因子：
10.5
作者：
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通讯作者：
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