Genetic variants in mRNA untranslated regions

Overview

Valeria Orrù, Michael B. Whalen, M. Laura Idda, Maristella Steri

Published Online: Mar 26 2018

DOI: 10.1002/wrna.1474

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

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

[ Normal View | Magnified View ]

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

[ Normal View | Magnified View ]

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

[ Normal View | Magnified View ]

References

Araujo,, P. R., Yoon,, K., Ko,, D., Smith,, A. D., Qiao,, M., Suresh,, U., … Penalva,, L. O. (2012). Before it gets started: Regulating translation at the 5′UTR. Comparative and Functional Genomics, 2012, 475731–475738. https://doi.org/10.1155/2012/475731
Auweter,, S. D., Oberstrass,, F. C., & Allain,, F. H. (2006). Sequence‐specific binding of single‐stranded RNA: Is there a code for recognition? Nucleic Acids Research, 34(17), 4943–4959.
Bach,, J. F. (2002). The effect of infections on susceptibility to autoimmune and allergic diseases. The New England Journal of Medicine, 347(12), 911–920.
Banihashemi,, L., Wilson,, G. M., Das,, N., & Brewer,, G. (2006). Upf1/Upf2 regulation of 3′ untranslated region splice variants of AUF1 links nonsense‐mediated and A+U‐rich element‐mediated mRNA decay. Molecular and Cellular Biology, 26(23), 8743–8754.
Barbosa,, C., Peixeiro,, I., & Romão,, L. (2013). Gene expression regulation by upstream open reading frames and human disease. PLoS Genetics, 9(8), e1003529. https://doi.org/10.1371/journal.pgen.1003529
Bendl,, J., Musil,, M., Štourač,, J., Zendulka,, J., Damborský,, J., & Brezovský,, J. (2016). PredictSNP2: A unified platform for accurately evaluating SNP effects by exploiting the different characteristics of variants in distinct genomic regions. PLoS Computational Biology, 12(5), e1004962. https://doi.org/10.1371/journal.pcbi.1004962
Bennett,, C. L., Brunkow,, M. E., Ramsdell,, F., O`Briant,, K. C., Zhu,, Q., Fuleihan,, R. L., … Chance,, P. F. (2001). A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA‐‐%3EAAUGAA) leads to the IPEX syndrome. Immunogenetics, 53(6), 435–439.
Bindewald,, E., & Shapiro,, B. A. (2006). RNA secondary structure prediction from sequence alignments using a network of k‐nearest neighbor classifiers. RNA, 12(3), 342–352.
Bohnsack,, M. T., Czaplinski,, K., & Gorlich,, D. (2004). Exportin 5 is a RanGTP‐dependent dsRNA‐binding protein that mediates nuclear export of pre‐miRNAs. RNA, 10(2), 185–191.
Brodie,, A., Azaria,, J. R., & Ofran,, Y. (2016). How far from the SNP may the causative genes be? Nucleic Acids Research, 44(13), 6046–6054. https://doi.org/10.1093/nar/gkw500
Brookes,, A. J. (1999). The essence of SNPs. Gene, 234(2), 177–186.
Calvo,, S. E., Pagliarini,, D. J., & Mootha,, V. K. (2009). Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proceedings of the National Academy of Sciences of the United States of America, 106(18), 7507–7512. https://doi.org/10.1073/pnas.0810916106
Carninci,, P., Kasukawa,, T., Katayama,, S., Gough,, J., Frith,, M. C., Maeda,, N., … Genome Network Project Core Group. (2005). The transcriptional landscape of the mammalian genome. Science, 309(5740), 1559–1563 Erratum in: Science 2006, 311, 1713.
Caussy,, C., Charrière,, S., Marçais,, C., Di Filippo,, M., Sassolas,, A., Delay,, M., … Moulin,, P. (2014). An APOA5 3′UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR‐485‐5p binding site. American Journal of Human Genetics, 94(1), 129–134. https://doi.org/10.1016/j.ajhg.2013.12.001
Cenik,, C., Derti,, A., Mellor,, J. C., Berriz,, G. F., & Roth,, F. P. (2010). Genome‐wide functional analysis of human 5′ untranslated region introns. Genome Biology, 11(3), R29. https://doi.org/10.1186/gb-2010-11-3-r29
Chang,, Y. F., Imam,, J. S., & Wilkinson,, M. F. (2007). The nonsense‐mediated decay RNA surveillance pathway. Annual Review of Biochemistry, 76, 51–74.
Chen,, G. L., Vallender,, E. J., & Miller,, G. M. (2008). Functional characterization of the human TPH2 5′ regulatory region: Untranslated region and polymorphisms modulate gene expression in vitro. Human Genetics, 122(6), 645–657.
Chen,, K., & Rajewsky,, N. (2006). Natural selection on human microRNA binding sites inferred from SNP data. Nature Genetics, 38(12), 1452–1456.
Chi,, S., Teng,, L., Song,, J. H., Zhou,, C., Pan,, W. H., Zhao,, R. L., & Zhang,, C. (2013). Tryptophan hydroxylase 2 gene polymorphisms and poststroke anxiety disorders. Journal of Affective Disorders, 144(1–2), 179–182. https://doi.org/10.1016/j.jad.2012.05.017
Cobbold,, L. C., Wilson,, L. A., Sawicka,, K., King,, H. A., Kondrashov,, A. V., Spriggs,, K. A., … Willis,, A. E. (2010). Upregulated c‐myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB‐1 and YB‐1. Oncogene, 29(19), 2884–2891. https://doi.org/10.1038/onc.2010.31
Condit,, C. M., Achter,, P. J., Lauer,, I., & Sefcovic,, E. (2002). The changing meanings of "mutation:" a contextualized study of public discourse. Human Mutation, 19(1), 69–75.
Cortes,, A., & Brown,, M. A. (2011). Promise and pitfalls of the Immunochip. Arthritis Research %26 Therapy, 13(1), 101. https://doi.org/10.1186/ar3204
Cullen,, L. M., Prat,, L., & Cox,, D. W. (2003). Genetic variation in the promoter and 5′ UTR of the copper transporter, ATP7B, in patients with Wilson disease. Clinical Genetics, 64(5), 429–432.
De Angioletti,, M., Lacerra,, G., Sabato,, V., & Carestia,, C. (2004). Beta+45 G ‐‐%3E C: A novel silent beta‐thalassaemia mutation, the first in the Kozak sequence. British Journal of Haematology, 124(2), 224–231.
Dekker,, J., Rippe,, K., Dekker,, M., & Kleckner,, N. (2002). Capturing chromosome conformation. Science, 295(5558), 1306–1311. https://doi.org/10.1126/science.1067799
Di Giammartino,, D. C., Nishida,, K., & Manley,, J. L. (2011). Mechanisms and consequences of alternative polyadenylation. Molecular Cell, 43(6), 853–866. https://doi.org/10.1016/j.molcel.2011.08.017
Di Marco,, S., Hel,, Z., Lachance,, C., Furneaux,, H., & Radzioch,, D. (2001). Polymorphism in the 3′‐untranslated region of TNFalpha mRNA impairs binding of the post‐transcriptional regulatory protein HuR to TNFalpha mRNA. Nucleic Acids Research, 29(4), 863–871.
Felekkis,, K., Touvana,, E., Stefanou,, C., & Deltas,, C. (2010). microRNAs: A newly described class of encoded molecules that play a role in health and disease. Hippokratia, 14(4), 236–240.
Fisher,, R. (1918). XV.—The correlation between relatives on the supposition of Mendelian inheritance. Transactions of the Royal Society of Edinburgh, 52(2), 399–433. https://doi.org/10.1017/S0080456800012163
Gao,, T., He,, B., Liu,, S., Zhu,, H., Tan,, K., & Qian,, J. (2016). EnhancerAtlas: A resource for enhancer annotation and analysis in 105 human cell/tissue types. Bioinformatics, 32(23), 3543–3551.
Ghanbari,, M., Ikram,, M. A., de Looper,, H. W., Hofman,, A., Erkeland,, S. J., Franco,, O. H., & Dehghan,, A. (2016). Genome‐wide identification of microRNA‐related variants associated with risk of Alzheimer`s disease. Scientific Reports, 6, 28387. https://doi.org/10.1038/srep28387
Glisovic,, T., Bachorik,, J. L., Yong,, J., & Dreyfuss,, G. (2008). RNA‐binding proteins and post‐transcriptional gene regulation. FEBS Letters, 582(14), 1977–1986. https://doi.org/10.1016/j.febslet.2008.03.004
Gratacós,, F. M., & Brewer,, G. (2010). The role of AUF1 in regulated mRNA decay. WIREs RNA, 1(3), 457–473. https://doi.org/10.1002/wrna.26
GTEx Consortium, Laboratory, Data Analysis %26 Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, Enhancing GTEx (eGTEx) groups, NIH Common Fund, NIH/NCI, … Montgomery,, S. B. (2017). Genetic effects on gene expression across human tissues. Nature, 550(7675), 204–213. https://doi.org/10.1038/nature24277
Halvorsen,, M., Martin,, J. S., Broadaway,, S., & Laederach,, A. (2010). Disease‐associated mutations that alter the RNA structural ensemble. PLoS Genetics, 6(8), e1001074. https://doi.org/10.1371/journal.pgen.1001074
Han,, J., Lee,, Y., Yeom,, K. H., Kim,, Y. K., Jin,, H., & Kim,, V. N. (2004). The Drosha‐DGCR8 complex in primary microRNA processing. Genes %26 Development, 18(24), 3016–3027.
Hariharan,, M., Scaria,, V., & Brahmachari,, S. K. (2009). dbSMR: A novel resource of genome‐wide SNPs affecting microRNA mediated regulation. BMC Bioinformatics, 10, 108. https://doi.org/10.1186/1471-2105-10-108
He,, F., Krans,, A., Freibaum,, B. D., Taylor,, J. P., & Todd,, P. K. (2014). TDP‐43 suppresses CGG repeat‐induced neurotoxicity through interactions with HnRNP A2/B1. Human Molecular Genetics, 23(19), 5036–5051. https://doi.org/10.1093/hmg/ddu216
Higgs,, D. R., Goodbourn,, S. E., Lamb,, J., Clegg,, J. B., Weatherall,, D. J., & Proudfoot,, N. J. (1983). Alpha‐thalassaemia caused by a polyadenylation signal mutation. Nature, 306(5941), 398–400.
Hindorff,, L. A., Sethupathy,, P., Junkins,, H. A., Ramos,, E. M., Mehta,, J. P., Collins,, F. S., & Manolio,, T. A. (2009). Potential etiologic and functional implications of genome‐wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the United States of America, 106, 9362–9367.
Hofacker,, I. L., & Stadler,, P. F. (2006). Memory efficient folding algorithms for circular RNA secondary structures. Bioinformatics, 22(10), 1172–1176.
Hong,, X., Scofield,, D. G., & Lynch,, M. (2006). Intron size, abundance, and distribution within untranslated regions of genes. Molecular Biology and Evolution, 23(12), 2392–2404 Epub 2006 Sep 15.
Hu,, Z., Yau,, C., & Ahmed,, A. A. (2017). A pan‐cancer genome‐wide analysis reveals tumour dependencies by induction of nonsense‐mediated decay. Nature Communications, 8, 15943. https://doi.org/10.1038/ncomms15943
Hudder,, A., & Werner,, R. (2000). Analysis of a Charcot‐Marie‐tooth disease mutation reveals an essential internal ribosome entry site element in the connexin‐32 gene. The Journal of Biological Chemistry, 275(44), 34586–34591.
Jansen,, R. P. (2001). mRNA localization: Message on the move. Nature Reviews. Molecular Cell Biology, 2(4), 247–256.
Javierre,, B. M., Burren,, O. S., Wilder,, S. P., Kreuzhuber,, R., Hill,, S. M., Sewitz,, S., … Fraser,, P. (2016). Lineage‐specific genome architecture links enhancers and non‐coding disease variants to target gene promoters. Cell, 167, 1369–1384.e19. https://doi.org/10.1016/j.cell.2016.09.037
Jin,, Y., & Lee,, C. G. (2013). Single nucleotide polymorphisms associated with microRNA regulation. Biomolecules, 3(2), 287–302. https://doi.org/10.3390/biom3020287
Kim,, K. M., Cho,, H., & Kim,, Y. K. (2012). The upstream open reading frame of cyclin‐dependent kinase inhibitor 1A mRNA negatively regulates translation of the downstream main open reading frame. Biochemical and Biophysical Research Communications, 424(3), 469–475. https://doi.org/10.1016/j.bbrc.2012.06.135
Kim,, V. N., Han,, J., & Siomi,, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews. Molecular Cell Biology, 10(2), 126–139. https://doi.org/10.1038/nrm2632
Kim,, Y. K., Kim,, B., & Kim,, V. N. (2016). Re‐evaluation of the roles of DROSHA, export in 5, and DICER in microRNA biogenesis. Proceedings of the National Academy of Sciences of the United States of America, 113(13), E1881–E1889. https://doi.org/10.1073/pnas.1602532113
Kircher,, M., Witten,, D. M., Jain,, P., O`Roak,, B. J., Cooper,, G. M., & Shendure,, J. (2014). A general framework for estimating the relative pathogenicity of human genetic variants. Nature Genetics.
Klein,, R. J., Zeiss,, C., Chew,, E. Y., Tsai,, J. Y., Sackler,, R. S., Haynes,, C., … Hoh,, J. (2005). Complement factor H polymorphism in age‐related macular degeneration. Science, 308(5720), 385–389.
Kozak,, M. (1987). At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. Journal of Molecular Biology, 196(4), 947–950.
Kraja,, A. T., Vaidya,, D., Pankow,, J. S., Goodarzi,, M. O., Assimes,, T. L., Kullo,, I. J., … Borecki,, I. B. (2011). A bivariate genome‐wide approach to metabolic syndrome: STAMPEED consortium. Diabetes, 60(4), 1329–1339. https://doi.org/10.2337/db10-1011
Kumar,, S., Ambrosini,, G., & Bucher,, P. (2017). SNP2TFBS ‐ A database of regulatory SNPs affecting predicted transcription factor binding site affinity. Nucleic Acids Research, 45(D1), D139–D144. https://doi.org/10.1093/nar/gkw1064
Kutchko,, K. M., Sanders,, W., Ziehr,, B., Phillips,, G., Solem,, A., Halvorsen,, M., … Laederach,, A. (2015). Multiple conformations are a conserved and regulatory feature of the RB1 5′UTR. RNA, 21(7), 1274–1285. https://doi.org/10.1261/rna.049221.114
Li,, S., Hua,, Y., Jin,, J., Wang,, H., Du,, M., Zhu,, L., … Wang,, M. (2016). Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population. Oncotarget, 7(18), 25470–25477. https://doi.org/10.18632/oncotarget.8330
Li,, W., Notani,, D., & Rosenfeld,, M. G. (2016). Enhancers as non‐coding RNA transcription units: Recent insights and future perspectives. Nature Reviews. Genetics, 17(4), 207–223. https://doi.org/10.1038/nrg.2016.4
Li,, Y., Willer,, C., Sanna,, S., & Abecasis,, G. (2009). Genotype imputation. Annual Review of Genomics and Human Genetics, 10, 387–406. https://doi.org/10.1146/annurev.genom.9.081307.164242
Lianoglou,, S., Garg,, V., Yang,, J. L., Leslie,, C. S., & Mayr,, C. (2013). Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue‐specific expression. Genes %26 Development, 27(21), 2380–2396. https://doi.org/10.1101/gad.229328.113
Liu,, X. Q., Stacey,, K. J., Horne‐Debets,, J. M., Cridland,, J. A., Fischer,, K., Narum,, D., … Wykes,, M. N. (2012). Malaria infection alters the expression of B‐cell activating factor resulting in diminished memory antibody responses and survival. European Journal of Immunology, 42(12), 3291–3301. https://doi.org/10.1002/eji.201242689
Lu,, J., & Clark,, A. G. (2012). Impact of microRNA regulation on variation in human gene expression. Genome Research, 22(7), 1243–1254. https://doi.org/10.1101/gr.132514.111
Lunde,, B. M., Moore,, C., & Varani,, G. (2007). RNA‐binding proteins: Modular design for efficient function. Nature Reviews. Molecular Cell Biology, 8(6), 479–490.
MacArthur,, J., Bowler,, E., Cerezo,, M., Gil,, L., Hall,, P., Hastings,, E., … Parkinson,, H. (2017). The new NHGRI‐EBI catalog of published genome‐wide association studies (GWAS catalog). Nucleic Acids Research, 45(Database issue), D896–D901.
Mackay,, F., & Schneider,, P. (2009). Cracking the BAFF code. Nature Reviews. Immunology, 9(7), 491–502. https://doi.org/10.1038/nri2572
Martin,, J. S., Halvorsen,, M., Davis‐Neulander,, L., Ritz,, J., Gopinath,, C., Beauregard,, A., & Laederach,, A. (2012). Structural effects of linkage disequilibrium on the transcriptome. RNA, 18(1), 77–87. https://doi.org/10.1261/rna.029900.111
Martínez‐Salas,, E., Piñeiro,, D., & Fernández,, N. (2012). Alternative mechanisms to initiate translation in eukaryotic RNAs. Comparative and Functional Genomics, 2012, 391546–391512. https://doi.org/10.1155/2012/391546
Mayr,, C., & Bartel,, D. P. (2009). Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell, 138(4), 673–684. https://doi.org/10.1016/j.cell.2009.06.016
McCarthy,, S., Das,, S., Kretzschmar,, W., Delaneau,, O., Wood,, A. R., Teumer,, A., … Haplotype Reference Consortium. (2016). A reference panel of 64,976 haplotypes for genotype imputation. Nature Genetics, 48(10), 1279–1283. https://doi.org/10.1038/ng.3643
McLaren,, W., Gil,, L., Hunt,, S. E., Riat,, H. S., Ritchie,, G. R., Thormann,, A., … Cunningham,, F. (2016). The ensembl variant effect predictor. Genome Biology, 17(1), 122.
Mignone,, F., Gissi,, C., Liuni,, S., & Pesole,, G. (2002). Untranslated regions of mRNAs. Genome Biology, 3(3), REVIEWS0004 Epub 2002 Feb 28.
Mironov,, A. S., Gusarov,, I., Rafikov,, R., Lopez,, L. E., Shatalin,, K., Kreneva,, R. A., … Nudler,, E. (2002). Sensing small molecules by nascent RNA: A mechanism to control transcription in bacteria. Cell, 111(5), 747–756.
Mitchell,, S. F., Walker,, S. E., Algire,, M. A., Park,, E. H., Hinnebusch,, A. G., & Lorsch,, J. R. (2010). The 5′‐7‐methylguanosine cap on eukaryotic mRNAs serves both to stimulate canonical translation initiation and to block an alternative pathway. Molecular Cell, 39(6), 950–962. https://doi.org/10.1016/j.molcel.2010.08.021
Moore,, L. D., Le,, T., & Fan,, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38(1), 23–38. https://doi.org/10.1038/npp.2012.112
Nahvi,, A., Sudarsan,, N., Ebert,, M. S., Zou,, X., Brown,, K. L., & Breaker,, R. R. (2002). Genetic control by a metabolite binding mRNA. Chemistry %26 Biology, 9(9), 1043–1049.
Nasif,, S., Contu,, L., & Mühlemann,, O. (2017). Beyond quality control: The role of nonsense‐mediated mRNA decay (NMD) in regulating gene expression. Seminars in Cell %26 Developmental Biology. https://doi.org/10.1016/j.semcdb.2017.08.053
Navarra,, S. V., Guzmán,, R. M., Gallacher,, A. E., Hall,, S., Levy,, R. A., Jimenez,, R. E., … BLISS‐52 Study Group. (2011). Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: A randomised, placebo‐controlled, phase 3 trial. Lancet, 377(9767), 721–731. https://doi.org/10.1016/S0140-6736(10)61354-2
Nickless,, A., Bailis,, J. M., & You,, Z. (2017). Control of gene expression through the nonsense‐mediated RNA decay pathway. Cell %26 Bioscience, 7, 26. https://doi.org/10.1186/s13578-017-0153-7
Niesler,, B., Flohr,, T., Nöthen,, M. M., Fischer,, C., Rietschel,, M., Franzek,, E., … Rappold,, G. A. (2001). Association between the 5′ UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Pharmacogenetics, 11(6), 471–475.
Orkin,, S. H., Cheng,, T. C., Antonarakis,, S. E., & Kazazian, Jr., H. H. (1985). Thalassemia due to a mutation in the cleavage‐polyadenylation signal of the human beta‐globin gene. The EMBO Journal, 4(2), 453–456.
Pelletier,, J., & Sonenberg,, N. (1988). Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature, 334(6180), 320–325.
Peng,, S. S., Chen,, C. Y., Xu,, N., & Shyu,, A. B. (1998). RNA stabilization by the AU‐rich element binding protein, HuR, an ELAV protein. The EMBO Journal, 17(12), 3461–3470.
Pesole,, G., Mignone,, F., Gissi,, C., Grillo,, G., Licciulli,, F., & Liuni,, S. (2001). Structural and functional features of eukaryotic mRNA untranslated regions. Gene, 276(1–2), 73–81.
Pichon,, X., Wilson,, L. A., Stoneley,, M., Bastide,, A., King,, H. A., Somers,, J., & Willis,, A. E. (2012). RNA binding protein/RNA element interactions and the control of translation. Current Protein %26 Peptide Science, 13(4), 294–304.
Plomin,, R., Haworth,, C. M., & Davis,, O. S. (2009). Common disorders are quantitative traits. Nature Reviews. Genetics, 10(12), 872–878. https://doi.org/10.1038/nrg2670
Pullmann, Jr., R., Abdelmohsen,, K., Lal,, A., Martindale,, J. L., Ladner,, R. D., & Gorospe,, M. (2006). Differential stability of thymidylate synthase 3′‐untranslated region polymorphic variants regulated by AUF1. The Journal of Biological Chemistry, 281(33), 23456–23463.
Qiu,, F., Tang,, R., Zuo,, X., Shi,, X., Wei,, Y., Zheng,, X., … Ma,, X. (2017). A genome‐wide association study identifies six novel risk loci for primary biliary cholangitis. Nature Communications, 8, 14828. https://doi.org/10.1038/ncomms14828
Rapley,, E. A., Turnbull,, C., Al Olama,, A. A., Dermitzakis,, E. T., Linger,, R., Huddart,, R. A., … Stratton,, M. R. (2009). A genome‐wide association study of testicular germ cell tumor. Nature Genetics, 41(7), 807–810. https://doi.org/10.1038/ng.394
Rhinn,, H., Qiang,, L., Yamashita,, T., Rhee,, D., Zolin,, A., Vanti,, W., & Abeliovich,, A. (2012). Alternative α‐synuclein transcript usage as a convergent mechanism in Parkinson`s disease pathology. Nature Communications, 3, 1084. https://doi.org/10.1038/ncomms2032
Richardson,, K., Lai,, C. Q., Parnell,, L. D., Lee,, Y. C., & Ordovas,, J. M. (2011). A genome‐wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS. BMC Genomics, 12, 504. https://doi.org/10.1186/1471-2164-12-504
Ritz,, J., Martin,, J. S., & Laederach,, A. (2012). Evaluating our ability to predict the structural disruption of RNA by SNPs. BMC Genomics, 13(Suppl 4), S6. https://doi.org/10.1186/1471-2164-13-S4-S6
Romo,, L., Ashar‐Patel,, A., Pfister,, E., & Aronin,, N. (2017). Alterations in mRNA 3′ UTR isoform abundance accompany gene expression changes in human Huntington`s disease brains. Cell Reports, 20(13), 3057–3070. https://doi.org/10.1016/j.celrep.2017.09.009
Ruark,, E., Seal,, S., McDonald,, H., Zhang,, F., Elliot,, A., Lau,, K., … Turnbull,, C. (2013). Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nature Genetics, 45(6), 686–689. https://doi.org/10.1038/ng.2635
Rund,, D., Dowling,, C., Najjar,, K., Rachmilewitz,, E. A., Kazazian, Jr., H. H., & Oppenheim,, A. (1992). Two mutations in the beta‐globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites. Proceedings of the National Academy of Sciences of the United States of America, 89(10), 4324–4328.
Sampson,, J. N., Jacobs,, K., Wang,, Z., Yeager,, M., Chanock,, S., & Chatterjee,, N. (2012). A two‐platform design for next generation genome‐wide association studies. Genetic Epidemiology, 36(4), 400–408. https://doi.org/10.1002/gepi.21634
Scofield,, D. G., Hong,, X., & Lynch,, M. (2007). Position of the final intron in full‐length transcripts: Determined by NMD? Molecular Biology and Evolution, 24(4), 896–899 Epub 2007 Jan 22.
Serretti,, A., Liappas,, I., Mandelli,, L., Albani,, D., Forloni,, G., Malitas,, P., … Kalofoutis,, A. (2009). TPH2 gene variants and anxiety during alcohol detoxification outcome. Psychiatry Research, 167(1–2), 106–114. https://doi.org/10.1016/j.psychres.2007.12.006
Sidore,, C., Busonero,, F., Maschio,, A., Porcu,, E., Naitza,, S., Zoledziewska,, M., … Abecasis,, G. R. (2015). Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nature Genetics, 47(11), 1272–1281. https://doi.org/10.1038/ng.3368
Slatkin,, M. (2008). Linkage disequilibrium‐‐understanding the evolutionary past and mapping the medical future. Nature Reviews. Genetics, 9(6), 477–485. https://doi.org/10.1038/nrg2361
Smibert,, P., Miura,, P., Westholm,, J. O., Shenker,, S., May,, G., Duff,, M. O., … Lai,, E. C. (2012). Global patterns of tissue‐specific alternative polyadenylation in Drosophila. Cell Reports, 1(3), 277–289 Erratum in: Cell Reports 2013, 3, 969.
Smola,, M. J., Rice,, G. M., Busan,, S., Siegfried,, N. A., & Weeks,, K. M. (2015). Selective 2′‐hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE‐MaP) for direct, versatile and accurate RNA structure analysis. Nature Protocols, 10(11), 1643–1669. https://doi.org/10.1038/nprot.2015.103
St Laurent,, H., Vyatkin,, Y., & Kapranov,, P. (2014). Dark matter RNA illuminates the puzzle of genome‐wide association studies. BMC Medicine, 12, 97. https://doi.org/10.1186/1741-7015-12-97
Steri,, M., Orrù,, V., Idda,, M. L., Pitzalis,, M., Pala,, M., Zara,, I., … Cucca,, F. (2017). Overexpression of the cytokine BAFF and autoimmunity risk. The New England Journal of Medicine, 376(17), 1615–1626. https://doi.org/10.1056/NEJMoa1610528
Tang,, G. (2005). siRNA and miRNA: An insight into RISCs. Trends in Biochemical Sciences, 30(2), 106–114.
Tang,, W., Teichert,, M., Chasman,, D. I., Heit,, J. A., Morange,, P. E., Li,, G., … Smith,, N. L. (2013). A genome‐wide association study for venous thromboembolism: The extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Genetic Epidemiology, 37(5), 512–521. https://doi.org/10.1002/gepi.21731
Tanikawa,, C., Urabe,, Y., Matsuo,, K., Kubo,, M., Takahashi,, A., Ito,, H., … Matsuda,, K. (2012). A genome‐wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population. Nature Genetics, 44(4), 430–434, S1‐2. https://doi.org/10.1038/ng.1109
Telenti,, A., Pierce,, L. C., Biggs,, W. H., di Iulio,, J., Wong,, E. H., Fabani,, M. M., … Venter,, J. C. (2016). Deep sequencing of 10,000 human genomes. Proceedings of the National Academy of Sciences of the United States of America, 113(42), 11901–11906.
The 1000 Genomes Project Consortium,, G. P., Auton,, A., Brooks,, L. D., Durbin,, R. M., Garrison,, E. P., Kang,, H. M., … Abecasis,, G. R. (2015). A global reference for human genetic variation. Nature, 526(7571), 68–74. https://doi.org/10.1038/nature15393
Tognotti,, E. (2009). Program to eradicate malaria in Sardinia, 1946‐1950. Emerging Infectious Diseases, 15(9), 1460–1466. https://doi.org/10.3201/eid1509.081317
Vaishnavi,, V., Manikandan,, M., & Munirajan,, A. K. (2014). Mining the 3′UTR of autism‐implicated genes for SNPs perturbing microRNA regulation. Genomics, Proteomics %26 Bioinformatics, 12(2), 92–104. https://doi.org/10.1016/j.gpb.2014.01.003
Voight,, B. F., Kang,, H. M., Ding,, J., Palmer,, C. D., Sidore,, C., Chines,, P. S., … Boehnke,, M. (2012). The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genetics, 8(8), e1002793. https://doi.org/10.1371/journal.pgen.1002793 Epub 2012 Aug 2. Erratum in: PLoS Genetics 2013, 9, 4. https://doi.org/10.1371/annotation/0b4e9c8b-35c5-4dbd-b95b-0640250fbc87
Wan,, Y., Qu,, K., Zhang,, Q. C., Flynn,, R. A., Manor,, O., Ouyang,, Z., … Chang,, H. Y. (2014). Landscape and variation of RNA secondary structure across the human transcriptome. Nature, 505(7485), 706–709. https://doi.org/10.1038/nature12946
Wang,, Y., Huang,, H. Y., Bian,, G. L., Yu,, Y. S., Ye,, W. X., Hua,, F., … Shen,, Z. Y. (2017). A functional variant of SMAD4 enhances thoracic aortic aneurysm and dissection risk through promoting smooth muscle cell apoptosis and proteoglycan degradation. eBioMedicine, 21, 197–205. https://doi.org/10.1016/j.ebiom.2017.06.022
Wellcome Trust Case Control Consortium, Australo‐Anglo‐American Spondylitis Consortium (TASC), Burton,, P. R., Clayton,, D. G., Cardon,, L. R., Craddock,, N., … Brown,, M. (2007). Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genetics, 39(11), 1329–1337.
Wen,, Y., Liu,, Y., Xu,, Y., Zhao,, Y., Hua,, R., Wang,, K., … Zhang,, X. (2009). Loss‐of‐function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nature Genetics, 41(2), 228–233. https://doi.org/10.1038/ng.276
Wethmar,, K., Smink,, J. J., & Leutz,, A. (2010). Upstream open reading frames: Molecular switches in (patho)physiology. BioEssays, 32(10), 885–893. https://doi.org/10.1002/bies.201000037
Witt,, H., Luck,, W., Hennies,, H. C., Classen,, M., Kage,, A., Lass,, U., … Becker,, M. (2000). Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature Genetics, 25(2), 213–216.
Wongfieng,, W., Jumnainsong,, A., Chamgramol,, Y., Sripa,, B., & Leelayuwat,, C. (2017). 5`‐UTR and 3`‐UTR regulation of MICB expression in human cancer cells by novel microRNAs. Genes (Basel), 8(9), E213. https://doi.org/10.3390/genes8090213
Xia,, J., Bogardus,, C., & Prochazka,, M. (1999). A type 2 diabetes‐associated polymorphic ARE motif affecting expression of PPP1R3 is involved in RNA‐protein interactions. Molecular Genetics and Metabolism, 68(1), 48–55.
Yang,, W., Shen,, N., Ye,, D. Q., Liu,, Q., Zhang,, Y., Qian,, X. X., … Asian Lupus Genetics Consortium (ALGC). (2010). Genome‐wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genetics, 6(2), e1000841. https://doi.org/10.1371/journal.pgen.1000841
Zhang,, S., Hou,, C., Li,, G., Zhong,, Y., Zhang,, J., Guo,, X., … Shao,, M. (2016). A single nucleotide polymorphism in the 3′‐untranslated region of the KRAS gene disrupts the interaction with let‐7a and enhances the metastatic potential of osteosarcoma cells. International Journal of Molecular Medicine, 38(3), 919–926. https://doi.org/10.3892/ijmm.2016.2661
Zhou,, L., He,, M., Mo,, Z., Wu,, C., Yang,, H., Yu,, D., … Wu,, T. (2013). A genome wide association study identifies common variants associated with lipid levels in the Chinese population. PLoS One, 8(12), e82420. https://doi.org/10.1371/journal.pone.0082420
Zhou,, Y., Kumari,, D., Sciascia,, N., & Usdin,, K. (2016). CGG‐repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell‐derived neurons. Molecular Autism, 7, 42.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Genetic variants in mRNA untranslated regions

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox