Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs.
Ancient human miRNAs are more likely to have broad functions and disease associations than young miRNAs.
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DOI：
10.1186/s12864-017-4073-z
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发表时间：
2017-08-31
期刊：
影响因子：
4.4
通讯作者：
Capra JA
中科院分区：
文献类型：
--
作者：
Patel VD;Capra JA
microRNA（miRNAs）是真核生物基因表达调控的关键，miRNAs的不当表达导致了数百种疾病。尽管miRNAs具有重要的功能，但它们如何整合到现有基因调控和功能网络中的进化动力学尚未得到很好的理解。基因的起源和进化历史的知识已被证明是关于其功能和疾病关联的信息;我们假设将miRNA的进化起源纳入分析将有助于解决其功能动力学的差异以及它们如何影响疾病。我们计算了146个物种中miRNA的系统发育年龄，并量化了人类miRNA年龄与几个功能属性之间的关系。较老的miRNAs比年轻的miRNAs更可能与疾病相关，并且相关疾病的数量随着年龄的增长而增加。正如对基因所观察到的那样，与不同疾病相关的miRNA具有不同的年龄特征。例如，与癌症有关的人类miRNA在动物多细胞性的黎明附近富集。随着年龄的增长，miRNA对疾病的贡献越来越大，与年轻的miRNA相比，年长的miRNA靶向更多的基因，并且年长的miRNA在更多的组织中表达。此外，所有年龄段的miRNA都表现出对靶向较老基因的强烈偏好; 93%的经验证的miRNA基因靶点存在于靶向miRNA的起源处。最后，我们发现在进化上相关的家族中的人类miRNAs在它们的靶点和表达谱上比不相关的miRNAs更相似。考虑miRNA的进化起源和历史为分析其功能提供了有用的背景。与最近在果蝇中的工作一致，我们的结果支持一个模型，在该模型中，随着进化时间的推移，miRNAs增加了它们的表达和功能调节相互作用，因此较老的miRNAs增加了导致疾病的可能性。我们预计这些模式在哺乳动物物种中也存在;然而，全面评估它们将需要在不同物种中完善miRNA注释并收集非人类系统中的功能数据。本文的在线版本（doi：10.1186/s12864-017-4073-z）包含补充材料，可供授权用户使用。
microRNAs (miRNAs) are essential to the regulation of gene expression in eukaryotes, and improper expression of miRNAs contributes to hundreds of diseases. Despite the essential functions of miRNAs, the evolutionary dynamics of how they are integrated into existing gene regulatory and functional networks is not well understood. Knowledge of the origin and evolutionary history a gene has proven informative about its functions and disease associations; we hypothesize that incorporating the evolutionary origins of miRNAs into analyses will help resolve differences in their functional dynamics and how they influence disease. We computed the phylogenetic age of miRNAs across 146 species and quantified the relationship between human miRNA age and several functional attributes. Older miRNAs are significantly more likely to be associated with disease than younger miRNAs, and the number of associated diseases increases with age. As has been observed for genes, the miRNAs associated with different diseases have different age profiles. For example, human miRNAs implicated in cancer are enriched for origins near the dawn of animal multicellularity. Consistent with the increasing contribution of miRNAs to disease with age, older miRNAs target more genes than younger miRNAs, and older miRNAs are expressed in significantly more tissues. Furthermore, miRNAs of all ages exhibit a strong preference to target older genes; 93% of validated miRNA gene targets were in existence at the origin of the targeting miRNA. Finally, we find that human miRNAs in evolutionarily related families are more similar in their targets and expression profiles than unrelated miRNAs. Considering the evolutionary origin and history of a miRNA provides useful context for the analysis of its function. Consistent with recent work in Drosophila, our results support a model in which miRNAs increase their expression and functional regulatory interactions over evolutionary time, and thus older miRNAs have increased potential to cause disease. We anticipate that these patterns hold across mammalian species; however, comprehensively evaluating them will require refining miRNA annotations across species and collecting functional data in non-human systems. The online version of this article (doi:10.1186/s12864-017-4073-z) contains supplementary material, which is available to authorized users.
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影响因子：
11.4
作者：
Capra, John A.;Stolzer, Maureen;Durand, Dannie;Pollard, Katherine S.
通讯作者：
Pollard, Katherine S.
影响因子：
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