Genomic Variants Disrupt miRNA-mRNA Regulation

Abstract

Micro RNA (miRNA) and its regulatory effect on messenger RNA (mRNA) gene expression are a major focus in cancer research. Disruption in the normal miRNA-mRNA regulation network can result in serious cascading biological repercussions. In this study, we curated miRNA-related variants from major genomic consortiums and thoroughly evaluated how these variants could exert their effects by cross-validating with independent functional knowledge bases. Nearly all known variants (more than 664 million) categorized by type (germline, somatic, epigenetic) were mapped to the genomic regions involved in miRNA-mRNA binding (miRNA seeds and miRNA-mRNA 3’-UTR binding sequence). Subsets of miRNA-related variants supported by additional functional evidence, such as expression Quantitative Trait Loci (eQTL) and Genome-Wide Association Study (GWAS), were identified and scrutinized. Our results show that variants in miRNA seeds can substantially alter the composition of a miRNA's target mRNA set. Various functional analyses converged to reveal a post-transcriptional complex regulatory network where miRNA, eQTL, and RNA-binding protein intertwined to disseminate the impact of genomic variants. These results may potentially explain how certain variants affect disease/trait risks in genome wide association studies.