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

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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.