MicroRNA-Target Interactions Reloaded: Identification of Potentially Functional Sequence Variants Within Validated MicroRNA-Target Interactions.

MicroRNAs (miRNAs) serve as critical regulators of gene expression. However, their binding to target genes can be influenced by genetic variability within the miRNA-target interaction (MTI) sites. We performed an in silico sequence reanalysis to identify novel sequence variants within MTIs with potential functional impacts. A literature search of the PubMed and the Web of Science spanning the years 2008 to April 2018 identified 240 articles reporting MTIs in humans. Sequence reanalysis of reported MTI regions was performed using the Ensembl browser. We found 76 sequence variants within 23 MTIs. We present description of MTIs wherein sequence variants are present within both the mature miRNA seed region and the miRNA target, which we termed miR-gene-target-single nucleotide polymorphism (miR-GenTar-SNP). To the best of our knowledge, this is the first report on copresence of sequence variants within both miRNA gene and the target site. In the course our analyses, the need for extension of current terminology emerged and therefore, novel terminology was introduced: miR-indel, miR-double nucleotide polymorphism (DNP), miR-TS-indel, and miR-TS-DNP. Identification of novel MTI sequence variants is a hitherto understudied, but critical dimension in understanding the complexity of interactions and gene deregulation in various complex diseases. Because such variations might profoundly affect miRNA function, they should be taken into consideration in future research that depends on "variability science" such as precision medicine, human genetics, and genomics in the study of complex diseases. The findings presented herein offer a baseline for further systematic reanalysis of all reported MTIs in human and other species.