MicroRNA genetic variation: from population analysis to functional implications of three allele variants associated with cancer

Abstract

Nucleotide variants in microRNA regions have been associated with disease; nevertheless, few studies still have addressed the allele-dependent effect of these changes. We studied microRNA genetic variation in human populations and found that while low-frequency variants accumulate indistinctly in microRNA regions, the mature and seed regions tend to be depleted of high-frequency variants, probably as a result of purifying selection. Comparison of pairwise population fixation indexes among regions showed that the seed had higher population fixation indexes than the other regions, suggesting the existence of local adaptation in the seed region. We further performed functional studies of three microRNA variants associated with cancer (rs2910164:C > G in MIR146A, rs11614913:C > T in MIR196A2, and rs3746444:A > G in both MIR499A and MIR499B). We found differences in the expression between alleles and in the regulation of several genes involved in cancer, such as TP53, KIT, CDH1, CLH, and TERT, which may result in changes in regulatory networks related to tumorigenesis. Furthermore, luciferase-based assays showed that MIR499A could be regulating the cadherin CDH1 and the cell adhesion molecule CLH1 in an allele-dependent fashion. A better understanding of the effect of microRNA variants associated with disease could be key in our way to a more personalized medicine.

Contract grant sponsors: Spanish National Institute for Bioinformatics (www.inab.org); "Ministerio de Ciencia e Innovación de España" (BFU2010-18477, CGL2009-09013 and FPI-MINECO); European Union Seventh Framework Programme (PIOF-GA-2009-236836 and PIRSES-GA-2013-612583); "Direcció general de Recerca de la Generalitat de Catalunya; Agencia de Gestió d'Ajuts Universitaris de Recerca" (2014SGR-866, 2014SGR-1311); "Ministerio de Educación, Cultura y Deporte de España" (FPU-MEC, FPU13/06813); FEDER European Regional Development Fund "A way to build Europe"; Ministerio de Economia y Competitividad, Spain (grant no. BFU2013-43726-P).