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Genetic variants in mRNA untranslated regions

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Genome Wide Association Studies (GWAS) have mapped thousands of genetic variants associated with complex disease risk and regulating quantitative traits, thus exploiting an unprecedented high‐resolution genetic characterization of the human genome. A small fraction (3.7%) of the identified associations is located in untranslated regions (UTRs), and the molecular mechanism has been elucidated for few of them. Genetic variations at UTRs may modify regulatory elements affecting the interaction of the UTRs with proteins and microRNAs. The overall functional consequences include modulation of messenger RNA (mRNA) transcription, secondary structure, stability, localization, translation, and access to regulators like microRNAs (miRNAs) and RNA‐binding proteins (RBPs). Alterations of these regulatory mechanisms are known to modify molecular pathways and cellular processes, potentially leading to disease processes. Here, we analyze some examples of genetic risk variants mapping in the UTR regulatory elements. We describe a recently identified genetic variant localized in the 3′UTR of the TNFSF13B gene, associated with autoimmunity risk and responsible of an increased stability and translation of TNFSF13B mRNA. We discuss how the correct use and interpretation of public GWAS repositories could lead to a better understanding of etiopathogenetic mechanisms and the generation of robust biological hypothesis as starting point for further functional studies. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry RNA Evolution and Genomics > Computational Analyses of RNA RNA in Disease and Development > RNA in Disease
Distribution of UTR variants among associated diseases and quantitative traits. Representation of UTR variants distributed among associated diseases and quantitative traits, as reported in GWAS Catalog. Variants are considered at 5′UTR and 3′UTR jointly (indicated as “total”), and separately. Diseases are categorized in seven non‐overlapping classes (panel a), while quantitative traits in nine categories (panel b). In each panel, the percentage of variants associated with phenotypes in the defined categories is reported
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BAFF‐var effects at the transcription, protein and cellular level. Representation of the localization of BAFF‐var within TNFSF13B and its effects on the generation of mRNAs with different 3′UTR lengths. The number and location of microRNA sites are reported. BAFF‐var creates an alternative polyadenylation signal that generates a shorter 3′UTR transcript lacking a miRNA binding site. In contrast to the wild type allele which produces only long 3′UTR, BAFF‐var leads to a mixed population of mRNAs with long and short 3′UTRs, resulting in higher production of sBAFF. In turn, the increased sBAFF leads to higher numbers of B cells and immunoglobulins, reduced levels of monocytes, and increased risk for autoimmunity
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Alternative annotations of 5′UTR variants. The pie graph summarizes the 5′UTR variants reported in the GWAS Catalog and shows their alternative predicted localization due to the presence of gene isoforms
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RNA in Disease and Development > RNA in Disease
RNA Evolution and Genomics > Computational Analyses of RNA
RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry

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