- Research Article
- Open access
- Published:
Searching for potential microRNA-binding site mutations amongst known disease-associated 3′ UTR variants
Genomic Medicine volume 1, pages 29–33 (2007)
Abstract
The 3′ untranslated regions (3′ UTRs) of human protein-coding genes play a pivotal role in the regulation of mRNA 3′ end formation, stability/degradation, nuclear export, subcellular localisation and translation, and hence are particularly rich in cis-acting regulatory elements. One recent addition to the already large repertoire of known cis-acting regulatory elements are the microRNA (miRNA) target sites that are present in the 3′ UTRs of many human genes. miRNAs post-transcriptionally down-regulate gene expression by binding to complementary sequences on their cognate target mRNAs, thereby inducing either mRNA degradation or translational repression. To date, only one disease-associated 3′ UTR variant (in the SLITRK1 gene) has been reported to occur within a bona fide miRNA binding site. By means of sequence complementarity, we have performed the first systematic search for potential miRNA-target site mutations within a set of 79 known disease-associated 3′ UTR variants. Since no variants were found that either disrupted or created binding sites for known human miRNAs, we surmise that miRNA-target site mutations are not likely to represent a frequent cause of human genetic disease.
Abbreviations
- LAS:
-
Left arm of the ‹spacer’ sequence between the upstream core polyadenylation signal and the pre-mRNA cleavage site
- miRNA:
-
MicroRNA
- UCPAS:
-
Upstream core polyadenylation signal
- USS:
-
Upstream sequence between the translational termination codon and the UCPAS
- 3′ UTR:
-
3′ Untranslated region
References
Abelson JF, Kwan KY, O’Roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Spertus JA, Leckman JF, Dure LS 4th, Kurlan R, Singer HS, Gilbert DL, Farhi A, Louvi A, Lifton RP, Sestan N, State MW (2005) Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310:317–320
Alvarez-Garcia I, Miska EA (2005) MicroRNA functions in animal development and human disease. Development 132:4653–4662
Bentwich I (2005) Prediction and validation of microRNAs and their targets. FEBS Lett 579:5904–5910
Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, Sharon E, Spector Y, Bentwich Z (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770
Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3:e85
Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F (2004) Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis 25:229–235
Chen JM, Férec C, Cooper DN (2006a) A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes I: general principles and overview. Hum Genet 120:1–21
Chen JM, Férec C, Cooper DN (2006b) A systematic analysis of disease-associated variants in the 3′ regulatory regions of human protein-coding genes II: the importance of mRNA secondary structure in assessing the functionality of 3′ UTR variants. Hum Genet 120:301–333
Cox DG, Pontes C, Guino E, Navarro M, Osorio A, Canzian F, Moreno V, Bellvitge Colorectal Cancer Study Group (2004) Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer. Br J Cancer 91:339–343
Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB, Bartel DP (2005) The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310:1817–1821
Garner C, Best S, Menzel S, Rooks H, Spector TD, Thein SL (2005) Two candidate genes for low platelet count identified in an Asian Indian kindred by genome-wide linkage analysis: glycoprotein IX and thrombopoietin. Eur J Hum Genet 14:101–108
Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34:D140–D144
Grun D, Wang YL, Langenberger D, Gunsalus KC, Rajewsky N (2005) microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput Biol 1:e13
Hong LE, Wonodi I, Avila MT, Buchanan RW, McMahon RP, Mitchell BD, Stine OC, Carpenter WT Jr, Thaker GK (2005) Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia. Am J Med Genet B Neuropsychiatr Genet 136:8–11
Jankovic L, Dimovski AJ, Kollia P, Karageorga M, Loukopoulos D, Huisman TH (1991) A C→G mutation at nt position 6 3′ to the terminating codon may be the cause of a silent beta-thalassemia. Int J Hematol 54:289–293
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS (2004) Human microRNA targets. PLoS Biol 2:e363
Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 5:142–149
Kim VN, Nam JW (2006) Genomics of microRNA. Trends Genet 22:165–173
Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z, Hatzigeorgiou A (2004) A combined computational-experimental approach predicts human microRNA targets. Genes Dev 18:1165–1178
Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500
Krutzfeldt J, Poy MN, Stoffel M (2006) Strategies to determine the biological function of microRNAs. Nat Genet 38(Suppl 1):S14–S19
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115:787–798
Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773
Maragoudaki E, Vrettou C, Kanavakis E, Traeger-Synodinos J, Metaxotou-Mavrommati A, Kattamis C (1998) Molecular, haematological and clinical studies of a silent beta-gene C→G mutation at 6 bp 3′ to the termination codon (+1480 C→G) in twelve Greek families. Br J Haematol 103:45–51
Nakata K, Ujike H, Sakai A, Takaki M, Imamura T, Tanaka Y, Kuroda S (2003) The human dihydropyrimidinase-related protein 2 gene on chromosome 8p21 is associated with paranoid-type schizophrenia. Biol Psychiatry 53:571–576
Pillai RS (2005) MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11:1753–1761
Rajewsky N (2006) microRNA target predictions in animals. Nat Genet 38(Suppl 1):S8–S13
Rajewsky N, Socci ND (2004) Computational identification of microRNA targets. Dev Biol 267:529–535
Robins H, Press WH (2005) Human microRNAs target a functionally distinct population of genes with AT-rich 3′ UTRs. Proc Natl Acad Sci USA 102:15557–15562
Robins H, Li Y, Padgett RW (2005) Incorporating structure to predict microRNA targets. Proc Natl Acad Sci USA 102:4006–4009
Sgourou A, Papachatzopoulou A, Psiouri L, Antoniou M, Zoumbos N, Gibbs R, Athanassiadou A (2002) The beta-globin C→G mutation at 6 bp 3′ to the termination codon causes beta-thalassaemia by decreasing the mRNA level. Br J Haematol 118:671–676
Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524
Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES, Kellis M (2005) Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434:338–345
Yang M, Li Y, Padgett RW (2005) MicroRNAs: small regulators with a big impact. Cytokine Growth Factor Rev 16:387–393
Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O’brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G (2006) MicroRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 103:9136–9141
Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220
Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31:3406–3415
Acknowledgements
This work was performed during early 2006 while JMC was a visiting Professor of Genetics supported by the Ministère de la Jeunesse, de l’Éducation Nationale et de la Recherche, France. This work was supported by the INSERM (Institut National de la SantÉ et de la Recherche MÉdicale), France.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Chuzhanova, N., Cooper, D.N., Férec, C. et al. Searching for potential microRNA-binding site mutations amongst known disease-associated 3′ UTR variants. HUGO J 1, 29–33 (2007). https://doi.org/10.1007/s11568-006-9000-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11568-006-9000-3