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regQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors

By Gary Wilk (6091568) and Rosemary Braun (217862)

Abstract

<div><p>Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with trait diversity and disease susceptibility, yet their functional properties often remain unclear. It has been hypothesized that SNPs in microRNA binding sites may disrupt gene regulation by microRNAs (miRNAs), short non-coding RNAs that bind to mRNA and downregulate the target gene. While several studies have predicted the location of SNPs in miRNA binding sites, to date there has been no comprehensive analysis of their impact on miRNA regulation. Here we investigate the functional properties of genetic variants and their effects on miRNA regulation of gene expression in cancer. Our analysis is motivated by the hypothesis that distinct alleles may cause differential binding (from miRNAs to mRNAs or from transcription factors to DNA) and change the expression of genes. We previously identified pathways—systems of genes conferring specific cell functions—that are dysregulated by miRNAs in cancer, by comparing miRNA–pathway associations between healthy and tumor tissue. We draw on these results as a starting point to assess whether SNPs on dysregulated pathways are responsible for miRNA dysregulation of individual genes in tumors. Using an integrative regression analysis that incorporates miRNA expression, mRNA expression, and SNP genotype data, we identify functional SNPs that we term “regulatory QTLs (regQTLs)”: loci whose alleles impact the regulation of genes by miRNAs. We apply the method to breast, liver, lung, and prostate cancer data from The Cancer Genome Atlas, and provide a tool to explore the findings.</p></div

Topics: Biophysics, Cell Biology, Genetics, Molecular Biology, Immunology, Cancer, Mental Health, Infectious Diseases, Biological Sciences not elsewhere classified, GWAS, prostate cancer data, microRNA binding sites, gene expression, Single nucleotide polymorphisms, tumors Genome-wide association studies, QTL, DNA, SNP genotype data, Cancer Genome Atlas, miRNA regulation, miRNA binding sites
Year: 2018
DOI identifier: 10.1371/journal.pgen.1007837
OAI identifier: oai:figshare.com:article/7475681
Provided by: FigShare
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