Sensitive measurement of single-nucleotide polymorphism-induced changes of RNA conformation: application to disease studies.
Sensitive measurement of single-nucleotide polymorphism-induced changes of RNA conformation: application to disease studies.
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DOI：
10.1093/nar/gks1009
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发表时间：
2013-01-07
影响因子：
14.9
通讯作者：
Przytycka TM
中科院分区：
文献类型：
--
作者：
Salari R;Kimchi-Sarfaty C;Gottesman MM;Przytycka TM
单核苷酸多态(SNPs)通常与疾病或对疫苗、药物和环境因素的反应等关键表型有关。然而，因果SNP作用的具体分子机制通常并不明显。RNA二级结构的变化是一种可能的解释，需要开发方法来衡量单核苷酸变异对RNA结构的影响。尽管人们认识到在这种情况下考虑RNA构象的Boltzmann系综变化的重要性，但缺乏直接进行这种比较的正式方法。在这里，我们解决了这个问题，并设计了一种有效的方法来计算天然结构和突变结构的Boltzmann系综之间的相对熵。在这一理论进展的基础上，我们开发了一个软件工具remuRNA，并调查了它的应用实例。比较自然发生在人群中的常见SNPs和随机点突变的影响，我们发现普通SNPs带来的结构变化比随机点突变带来的结构变化要小。这表明针对显著改变RNA结构的突变是一种自然选择，并令人惊讶地证明，随机插入的点突变不能充分估计随机突变的影响。随后，我们应用remuRNA来确定哪些与疾病相关的非编码SNP可能与RNA结构变化有关。
Single-nucleotide polymorphisms (SNPs) are often linked to critical phenotypes such as diseases or responses to vaccines, medications and environmental factors. However, the specific molecular mechanisms by which a causal SNP acts is usually not obvious. Changes in RNA secondary structure emerge as a possible explanation necessitating the development of methods to measure the impact of single-nucleotide variation on RNA structure. Despite the recognition of the importance of considering the changes in Boltzmann ensemble of RNA conformers in this context, a formal method to perform directly such comparison was lacking. Here, we solved this problem and designed an efficient method to compute the relative entropy between the Boltzmann ensembles of the native and a mutant structure. On the basis of this theoretical progress, we developed a software tool, remuRNA, and investigated examples of its application. Comparing the impact of common SNPs naturally occurring in populations with the impact of random point mutations, we found that structural changes introduced by common SNPs are smaller than those introduced by random point mutations. This suggests a natural selection against mutations that significantly change RNA structure and demonstrates, surprisingly, that randomly inserted point mutations provide inadequate estimation of random mutations effects. Subsequently, we applied remuRNA to determine which of the disease-associated non-coding SNPs are potentially related to RNA structural changes.
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影响因子：
2.9
作者：
MCCASKILL, JS
通讯作者：
MCCASKILL, JS
UCSC基因组浏览器数据库：更新2010。
影响因子：
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Bartoszewski, Rafal A.;Jablonsky, Michael;Bebok, Zsuzsa
通讯作者：
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