title: 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.
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Torruella-Loran
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.|Departament de Genètica i de Microbiologia, Grup de Biologia Evolutiva (GBE), Universitat Autonòma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Hafid
authors.initials: H
authors.lastname: Laayouni
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Dobon
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gallego
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Balcells
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Garcia-Ramallo
authors.affiliation: Department of Experimental and Health Sciences, IBE, Institute of Evolutionary Biology, (Universitat Pompeu Fabra-CSIC), Barcelona, Catalonia, Spain. yolespinosa@gmail.com.|School of Medicine, University of Magallanes, Punta Arenas, Chile. yolespinosa@gmail.com.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Espinosa-Parrilla
mesh_terms: D020413:3' Untranslated Regions; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D057285:Precision Medicine
chemical_list: D020413:3' Untranslated Regions; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C542542:MIRN146 microRNA, human; C542543:MIRN196 microRNA, human; C548683:MIRN499 microRNA, human; D035683:MicroRNAs
keywords: cancer; functional allele variant; genetic association; microRNA