Signatures of Purifying and Local Positive Selection in Human miRNAs
Signatures of Purifying and Local Positive Selection in Human miRNAs
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DOI：
10.1016/j.ajhg.2009.01.022
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发表时间：
2009-03-13
影响因子：
9.8
通讯作者：
Quintana-Murci, Lluis
中科院分区：
文献类型：
--
作者：
Quach, Helene;Barreiro, Luis B.;Quintana-Murci, Lluis
MicroRNA (miRNA) 是参与转录后基因抑制的非编码 RNA，它们在多种生理过程中的作用越来越得到认可。然而，很少有人致力于人类 miRNA 的进化研究。了解自然选择如何靶向 miRNA 的方式应该有助于深入了解它们的功能相关性及其作用机制。在这里，我们使用 miRNA 作为模型系统，通过表征来自世界各地不同人群的 117 种人类 miRNA 的全谱自然发生序列变异来研究自然选择对基因调控的影响。我们发现纯化选择全局性地限制了含有miRNA的区域的多样性并且强烈地针对成熟的miRNA。这一观察结果强调，这些分子的突变可能是有害的，因此它们可能对人类健康产生严重的表型后果。更重要的是，我们获得了作用于许多含有 miRNA 的区域的群体特异性正选择事件的证据。值得注意的是，我们的分析表明，在欧洲人和东亚人中，正选择针对的是 14 号染色体上的“富含小 RNA 的岛”，其中包含 miRNA 和小核仁 RNA。这些观察结果支持这样的观点：基因表达的调节有助于种群适应特定环境的过程。这些发现将推动未来的研究，探索选择下的 miRNA 的遗传和功能变异如何影响其 mRNA 靶标的抑制，从而加深我们对基因调控在群体适应和人类疾病中的作用的理解。
MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional gene repression, and their role in diverse physiological processes is increasingly recognized. Yet, few efforts have been devoted to evolutionary studies of human miRNAs. Knowledge about the way in which natural selection has targeted miRNAs should provide insight into their functional relevance as well as their mechanisms of action. Here we used miRNAs as a model system for investigating the influence of natural selection on gene regulation by characterizing the full spectrum of naturally occurring sequence variation of 117 human miRNAs from different populations worldwide. We found that purifying selection has globally constrained the diversity of miRNA-containing regions and has Strongly targeted the mature miRNA. This observation emphasizes that mutations in these molecules are likely to be deleterious, and therefore they can have severe phenotypic consequences on human health. More importantly, we obtained evidence of population-specific events of positive selection acting on a number of miRNA-containing regions. Notably, our analysis revealed that positive selection has targeted a "small-RNA-rich island" on chromosome 14, harboring both miRNAs and small nucleolar RNAs, in Europeans and East Asians. These observations support the notion that the tuning of gene expression contributes to the processes by which populations adapt to specific environments. These findings will fuel future investigations exploring how genetic and functional variation of miRNAs under selection affects the repression of their mRNA targets, increasing our understanding of the role of gene regulation in population adaptation and human disease.