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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子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（mRNAs）3' UTR上的靶位点结合来调控基因表达。基因内或附近的顺式变异在解释基因表达测量的变异性方面是至关重要的。基因3'UTR中的单核苷酸多态性（SNP）可以影响miRNA和mRNA之间的碱基配对，从而破坏现有的靶位点（在参考序列中）或产生新的靶位点，这表明基因表达的顺式调控的有希望的机制。此外，由于有限长度的DNA序列内的不同SNP的等位基因往往处于强连锁不平衡（LD）中，我们假设，由SNP引起的miRNA靶位点的变体潜在地起着将记录的顺式SNP标记与相关基因的表达连接起来的桥梁的作用。 结果如下：我们在本文中对已记录的顺式SNP标记和位于各种人类基因3'UTR上的miRNA靶位点中的群体间SNP进行了关联分析。通过系统地整合多种信息来源，我们发现了58个显著的基因水平SNP参与的转录后调控模块（SNP-PTRM）的SNP-miRNA-mRNA三联体的形式从CEU和YRI人口。在同源基因中，包括CHL 1、CTSB、GNA 12、KLF 11、LRPAP 1、MTRR和P2 RY 1在内的7个基因与抑郁症和II型糖尿病等多种遗传疾病相关。此外，我们发现，在记录的转录本中，约35%的顺式相关SNP（约950个）与位于miRNA靶位点的一个或多个SNP相同或处于连锁不平衡（LD）（p 0.01）。基于这些关联（或身份），进一步确定了每个人群的100多个外显子水平SNP-PTRM。 结论：miRNA靶位点内的SNP可能为基因表达测量的个体和群体变异性提供有希望的解释，并且这些位点变体潜在地充当将记录的顺式SNP标记与相关基因的表达连接的桥梁。我们通过鉴定淋巴细胞中全基因组SNP参与的miRNA介导的转录后调控模块，为这一假设提供了坚实的计算机证据。

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.