SNP-INVOLVED, MIRNA-MEDIATED RELATIONSHIPS BETWEEN CIS-SNP GENOTYPES AND TRANSCR

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 背景：在后生动物中，miRNAs主要通过与信使RNA(Messenger RNAs，mRNAs)3‘端非编码区的靶点结合来调节基因表达。基因内或基因附近的顺式变异在解释基因表达测量的可变性方面至关重要。基因3‘端非编码区的单核苷酸多态(SNPs)可以影响miRNAs和mRNAs之间的碱基配对，从而破坏(参考序列中)现有的靶点或产生新的靶点，这为顺式调控基因表达提供了一种有前景的机制。此外，由于有限长度的DNA序列中不同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靶点的变体可能起到将已报道的顺-SNP标记与相关基因的表达联系起来的桥梁作用。 结果：我们对文献记载的顺-SNP标记和位于不同人类基因3‘UTRs上miRNA靶点的群体间SNP进行了关联分析。通过系统整合多种信息源，我们从CEU和YRI群体中发现了58个显著的基因水平的SNP转录后调控模块(SNP-PTRM)，它们以SNP-miRNA-mRNA三联体的形式存在。在这些同源基因中，包括CHL1、CTSB、GNA12、KLF11、LRPAP1、MTRR和P2RY1在内的7个基因与抑郁症、II型糖尿病等多种遗传病有关。此外，我们还发现，在记录的转录本中，约35%的顺式相关SNPs(~950)与位于miRNA靶点的一个或多个SNPs相同或处于连锁不平衡(p0.01)。基于这些关联(或身份)，进一步确定了每个群体的100多个外显子水平的SNP-PTRM。 结论：miRNA靶点内的SNP可能为基因表达测量的个体和群体变异性提供了一个有希望的解释，这些位点变异可能作为连接已有文献记载的顺式SNP标记与相关基因表达的桥梁。我们通过鉴定全基因组SNP参与的淋巴细胞中miRNA介导的转录后调控模块，为这一假说提供了坚实的电子证据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background: In metazoan, miRNAs regulate gene expression primarily through binding to the target sites on the 3' UTR of messenger RNAs (mRNAs). Cis variants within, or close to, a gene are crucial in explaining the variability of the gene expression measures. Single nucleotide polymorphisms (SNPs) in the 3' UTRs of genes can affect the base-pairing between the miRNAs and mRNAs, and hence disrupt existing target sites (in the reference sequence) or create novel target sites, suggesting a promising 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 that, 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. Results: We herein performed an association analysis of the documented cis-SNP markers and the inter-population SNPs located in the miRNA target sites on the 3' UTRs of various human genes. By systematically integrating multiple information sources, we found 58 significant gene-level SNP-involved post-transcriptional regulation modules (SNP-PTRMs) in the form of SNP-miRNA-mRNA triplets from the CEU and YRI populations. Among the cognate genes, seven including CHL1, CTSB, GNA12, KLF11, LRPAP1, MTRR and P2RY1 are related to multiple genetic diseases such as depressive disorder and type-II diabetes. Moreover, we found that ~35% of cis-associated SNPs (~950) within documented transcripts are identical to, or in linkage disequilibrium (LD) (p 0.01) with, one or multiple SNPs located in miRNA target sites. Based on these associations (or identities), over 100 exon-level SNP-PTRMs were further determined for each population. Conclusion: SNPs inside miRNA target sites may provide a promising explanation to the individual and population variability of gene expression measures, and these site variants potentially function as bridges linking the documented cis-SNP markers to the expression of the associated genes. We provided solid in silico evidence for this hypothesis by identifying genome-wide SNP-involved miRNA-mediated post-transcriptional regulation modules in lymphocyte cells.