Department of Computer Science, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
PLoS One. 2012;7(2):e31429. doi: 10.1371/journal.pone.0031429. Epub 2012 Feb 14.
In metazoans, miRNAs regulate gene expression primarily through binding to target sites in the 3' UTRs (untranslated regions) of messenger RNAs (mRNAs). Cis-acting variants within, or close to, a gene are crucial in explaining the variability of gene expression measures. Single nucleotide polymorphisms (SNPs) in the 3' UTRs of genes can affect the base-pairing between miRNAs and mRNAs, and hence disrupt existing target sites (in the reference sequence) or create novel target sites, suggesting a possible mechanism for cis regulation of gene expression. Moreover, because the alleles of different SNPs within a DNA sequence of limited length tend to be in strong linkage disequilibrium (LD), we hypothesize the variants of miRNA target sites caused by SNPs potentially function as bridges linking the documented cis-SNP markers to the expression of the associated genes. A large-scale analysis was herein performed to test this hypothesis. By systematically integrating multiple latest information sources, we found 21 significant gene-level SNP-involved miRNA-mediated post-transcriptional regulation modules (SNP-MPRMs) in the form of SNP-miRNA-mRNA triplets in lymphocyte cell lines for the CEU and YRI populations. Among the cognate genes, six including ALG8, DGKE, GNA12, KLF11, LRPAP1, and MMAB are related to multiple genetic diseases such as depressive disorder and Type-II diabetes. Furthermore, we found that 35% of the documented transcript intensity-related cis-SNPs (950) in a recent publication are identical to, or in significant linkage disequilibrium (LD) (p<0.01) with, one or multiple SNPs located in miRNA target sites. Based on these associations (or identities), 69 significant exon-level SNP-MPRMs and 12 disease genes were further determined for two populations. These results provide concrete in silico evidence for the proposed hypothesis. The discovered modules warrant additional follow-up in independent laboratory studies.
在后生动物中，miRNA 主要通过与信使 RNA（mRNA）的 3'UTR（非翻译区）中的靶位点结合来调节基因表达。基因内或附近的顺式作用变异体对于解释基因表达测量的可变性至关重要。基因 3'UTR 中的单核苷酸多态性（SNPs）可以影响 miRNA 和 mRNA 之间的碱基配对，从而破坏现有靶位点（在参考序列中）或创建新的靶位点，这表明基因表达的顺式调控的一种可能机制。此外，由于有限长度 DNA 序列内的不同 SNPs 的等位基因往往处于强连锁不平衡（LD）状态，我们假设由 SNPs 引起的 miRNA 靶位点变异可能作为桥梁，将已记录的顺式-SNP 标记与相关基因的表达联系起来。本文进行了大规模分析以检验这一假设。通过系统地整合多个最新的信息源，我们在 CEU 和 YRI 人群的淋巴细胞系中以 SNP-miRNA-mRNA 三体的形式发现了 21 个显著的基因水平 SNP 涉及 miRNA 介导的转录后调控模块（SNP-MPRM）。在相应的基因中，包括 ALG8、DGKE、GNA12、KLF11、LRPAP1 和 MMAB 在内的六个基因与多种遗传疾病有关，如抑郁症和 II 型糖尿病。此外，我们发现最近一篇出版物中约 35%的记录转录物强度相关的顺式-SNPs（~950 个）与位于 miRNA 靶位点中的一个或多个 SNPs 相同或处于显著连锁不平衡（LD）（p<0.01）。基于这些关联（或同一性），对于两个群体进一步确定了 69 个显著的外显子水平 SNP-MPRM 和 12 个疾病基因。这些结果为提出的假设提供了具体的计算机证据。发现的模块值得在独立实验室研究中进一步跟进。
