Somatic mutations that alter miRNA targeting in linkage disequilibrium blocks of association study markers.

a<p>: The number in parentheses below the name of the polymorphism is the distance, in bp, from the germline mutation to the somatic mutation.</p

Frequency of single base substitutions.

<p>The percentage of each class of substitution among somatic mutations in 3′UTRs (black bar) or across the entire genome (white bar) is shown for (A) lung cancer, (B) SCLC, (C) melanoma, and (D) prostate cancer.</p

Location of somatic mutations in 3′UTRs.

<p>For each somatic mutation, the percentage of the distance from the start of the 3′UTR to the somatic mutation compared to the total length of the 3′UTR was calculated. The figure shows the number of mutations in rolling windows of 5% of the 3′UTR length for somatic mutations in (A) all cancer types, (B) lung cancer, (C) SCLC, (D) melanoma, and (E) prostate cancer.</p

Systematic Analysis of microRNA Targeting Impacted by Small Insertions and Deletions in Human Genome

<div><p>MicroRNAs (miRNAs) are small noncoding RNA that play an important role in posttranscriptional regulation of mRNA. Genetic variations in miRNAs or their target sites have been shown to alter miRNA function and have been associated with risk for several diseases. Previous studies have focused on the most abundant type of genetic variations, single nucleotide polymorphisms (SNPs) that affect miRNA-mRNA interactions. Here, we systematically identified small insertions and deletions (indels) in miRNAs and their target sites, and investigated the effects of indels on miRNA targeting. We studied the distribution of indels in miRNAs and their target sites and found that indels in mature miRNAs, experimentally supported miRNA target sites and PAR-CLIP footprints have significantly lower density compared to flanking regions. We identified over 20 indels in the seed regions of miRNAs, which may disrupt the interactions between these miRNAs and their target genes. We also identified hundreds of indels that alter experimentally supported miRNA target sites. We mapped these genes to human disease pathways to identify indels that affect miRNA targeting in these pathways. We also used the results of genome-wide association studies (GWAS) to identify potential links between miRNA-related indels and diseases.</p> </div

Disruption of a target site of miR-378g in the 3′ UTR of <i>DNAJC27</i> by an indel <i>rs34922018</i> that is in linkage disequilibrium with a high-scoring marker <i>rs713586</i> from a body mass index study.

<p>Disruption of a target site of miR-378g in the 3′ UTR of <i>DNAJC27</i> by an indel <i>rs34922018</i> that is in linkage disequilibrium with a high-scoring marker <i>rs713586</i> from a body mass index study.</p

Disruption of miRNA target sites that are in linkage disequilibrium with high scoring markers (purple) from cancer association studies by both germline (blue) and somatic (red) mutations.

<p>(A) Disruption of a target site of miR-125b in the 3′UTR of <i>BMPR1B</i>. (B) Disruption of a target site of miR-210 in the 3′UTR of <i>KLK3</i>. (C) Disruption of a target site of miR-608 in the 3′UTR of <i>SPRY4</i>.</p

Overview of the study.

<p>Somatic mutations within putative miRNA target sites are linked with cancer-related genes and miRNAs as well as the results of cancer association studies.</p

Density of all genetic variants (a) and indels (b) in dbSNP 135 as well as indels (c) from the GATK resource bundle in pre-miRNAs, mature miRNAs, miRNA seed regions, and flanking regions.

<p>Flanking regions 1 and 2 represent successive sequences adjacent to pre-miRNAs that were equal to the length of the pre-miRNA (∼100 bp). Error bars indicate the standard error. The density of all genetic variants (a) in pre-miRNAs was significantly different from the density in flanking regions, mature miRNAs, and seed regions (*p<0.01, **0.01</p

Selected somatic mutations that alter miRNA target sites in cancer-related genes.

a<p>:Mutations in bold type indicate somatic mutations in genes over-expressed in cancers that create or enhance miRNA target sites or somatic mutations in genes under-expressed in cancer that disrupt or hinder miRNA target sites.</p

Indels in miRNAs and miRNA target sites in linkage disequilibrium block for high-scoring markers from association studies.

<p>Indels in miRNAs and miRNA target sites in linkage disequilibrium block for high-scoring markers from association studies.</p