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  • Print publication year: 2016
  • Online publication date: December 2015

10 - Finding SNPs that affect microRNA regulation in disease-associated genomic regions

from Part III - Single nucleotide polymorphisms, copy number variants, haplotypes and eQTLs

Summary

Introduction

MicroRNAs (miRNAs) are small, single-stranded RNAs of about 22 nucleotides involved in gene regulation by binding to 3′ untranslated regions (UTRs) of messenger RNAs (mRNAs) (Bartel, 2004). By bringing the RNA-induced silencing complex (RISC) to the mRNAs, they enable gene expression inhibition (gene silencing), either by affecting protein translation or by destabilizing mRNAs through deadenylation or decapping (Fabian et al., 2010). Target mRNAs are recognized by miRNAs through Watson–Crick matching between the nucleotides two to seven of the 5′ end of miRNAs (seed sequences), and complementary sequences called seed sites in the 3′ UTR of mRNAs (Bartel, 2009). Gene silencing by miRNAs is an important mechanism in physiological processes, and its deregulation can lead to complex diseases such as cancer (Garzon et al., 2006).

Complex diseases that are heritable are commonly analysed by studying genomic DNA variants, such as single nucleotide polymorphisms (SNPs), which are a change of one nucleotide that occurs in more than 1% in a population (Frazer et al., 2009). A SNP can take several forms called alleles. Because recombination events between closely located SNPs are less likely than recombination between SNPs that are located far apart on a chromosome, alleles at close SNPs often co-occur, or correlate, in which case the SNPs are said to be in linkage disequilibrium (LD; Reich et al., 2001; Clague et al., 2010).

SNPs in the coding sequence of mRNAs have been well studied for their role in changing the amino-acid chain, as it may result in protein isoforms with affected function, leading to phenotypic differences and also disease. Nevertheless, SNPs can also occur in non-coding regions of the genome such as the 3′ UTR of mRNAs, which harbors many functional sequence elements involved in gene regulation. One type of functional element that can be disrupted by SNPs is the miRNA target site. SNPs in miRNA target sites (miRSNPs) can change the affinity between the miRNA seed sequence and its target mRNA, resulting in deregulation of gene expression (Figure 10.1), and possibly in phenotype differences and diseases (Sethupathy and Collins, 2008).

One classic example that a miRSNP determines phenotype is the single nucleotide change in the myostatin gene (GDF8) of Texel sheep (Clop et al., 2006).

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Genome-Wide Association Studies
  • Online ISBN: 9781107337459
  • Book DOI: https://doi.org/10.1017/CBO9781107337459
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Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.
Bartel, D.P. (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136, 215–233.
Chen, K. and Rajewsky, N. (2006). Natural selection on human microRNA binding sites inferred from SNP data. Nature Genet., 38, 1452–1456.
Clague, J., Lippman, S.M., Yang, H., et al. (2010). Genetic variation in microRNA genes and risk of oral premalignant lesions. Molec. Carcinog., 49, 183–189.
Clop, A., Marcq, F., Takeda, H., et al. (2006). A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nature Genet., 38, 813–818.
Colgan, D.F. and Manley, J.L. (1997). Mechanism and regulation of mRNA polyadenylation. Genes Develop., 11, 2755–2766.
Danckwardt, S., Hentze, M.W. and Kulozik, A.E. (2008). 3′ end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J., 27, 482–498.
Di Giammartino, D.C., Nishida, K. and Manley, J.L. (2011). Mechanisms and consequences of alternative polyadenylation. Molec. Cell., 43, 853–866.
Fabian, M.R., Sonenberg, N. and Filipowicz, W. (2010). Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem., 79, 351–379.
Frazer, K.A., Ballinger, D.G., Cox, D.R., et al. (2007). A second generation human haplotype map of over 3.1 million SNPs. Nature, 449, 851–861.
Frazer, K.A., Murray, S.S., Schork, N.J. and Topol, E.J. (2009). Human genetic variation and its contribution to complex traits. Nature Rev. Genet., 10, 241–251.
Garzon, R., Fabbri, M., Cimmino, A., Calin, G.A. and Croce, C.M. (2006). MicroRNA expression and function in cancer. Trends Molec. Med., 12, 580–587.
Griffiths-Jones, S., Grocock, R.J., van Dongen, S., Bateman, A. and Enright, A.J. (2006). miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res., 34, D140–144.
Heath, A.C., Whitfield, J.B., Martin, N.G., et al. (2011). A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biol. Psych., 70, 513–518.
Hindorff, L.A., Sethupathy, P., Junkins, H.A., et al. (2009). Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA, 106, 9362–9367.
Hollingworth, P., Harold, D., Sims, R., et al. (2011). Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet., 43, 429–435.
Illig, T., Gieger, C., Zhai, G., et al. (2010). A genome-wide perspective of genetic variation in human metabolism. Nature Genet., 42, 137–141.
Kim, J. and Bartel, D.P. (2009). Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression. Nature Biotechnol., 27, 472–477.
Kraja, A.T., Vaidya, D., Pankow, J.S., et al. (2011). A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium. Diabetes, 60, 1329–1339.
Lewis, B.P., Burge, C.B. and Bartel, D.P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120, 15–20.
Lutz, C.S. (2008). Alternative polyadenylation: a twist on mRNA 3′ end formation. ACS Chem. Biol., 3, 609–617.
Mu, X.J., Lu, Z.J., Kong, Y., Lam, H.Y. and Gerstein, M.B. (2011). Analysis of genomic variation in non-coding elements using population-scale sequencing data from the 1000 Genomes Project. Nucleic Acids Res., 39, 7058–7076.
Pankratz, N., Beecham, G.W., DeStefano, A.L., et al. (2012). Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann. Neurol., 71, 370–384.
Papaemmanuil, E., Hosking, F.J., Vijayakrishnan, J., et al. (2009). Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nature Genet., 41, 1006–1010.
Rehmsmeier, M., Steffen, P., Hochsmann, M. and Giegerich, R. (2004). Fast and effective prediction of microRNA/target duplexes. RNA, 10, 1507–1517.
Reich, D.E., Cargill, M., Bolk, S., et al. (2001). Linkage disequilibrium in the human genome. Nature, 411, 199–204.
Saetrom, P., Heale, B.S., Snove, O. Jr., et al. (2007). Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res., 35, 2333–2342.
Saetrom, P., Biesinger, J., Li, S.M., et al. (2009). A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Res., 69, 7459–7465.
Saito, T. and Saetrom, P. (2010). A two-step site and mRNA-level model for predicting microRNA targets. BMC Bioinform., 11, 612.
Saunders, M.A., Liang, H. and Li, W.H. (2007). Human polymorphism at microRNAs and microRNA target sites. Proc. Natl Acad. Sci. USA, 104, 3300–3305.
Sethupathy, P. and Collins, F.S. (2008). MicroRNA target site polymorphisms and human disease. Trends Genet, 24, 489–497.
Suhre, K., Shin, S.Y., Petersen, A.K., et al. (2011). Human metabolic individuality in biomedical and pharmaceutical research. Nature, 477, 54–60.
Thomas, L.F. and Saetrom, P. (2012). Single nucleotide polymorphisms can create alternative polyadenylation signals and affect gene expression through loss of microRNA-regulation. PLoS Comput. Biol., 8, e1002621.
Thomas, L.F., Saito, T. and Saetrom, P. (2011). Inferring causative variants in microRNA target sites. Nucleic Acids Res., 39, e109.
Tian, B., Hu, J., Zhang, H. and Lutz, C.S. (2005). A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res., 33, 201–212.
Uitte de Willige, S., Rietveld, I.M., De Visser, M.C., Vos, H.L. and Bertina, R.M. (2007). Polymorphism 10034C>T is located in a region regulating polyadenylation of FGG transcripts and influences the fibrinogen gamma′/gammaA mRNA ratio. J. Thromb. Haemost., 5, 1243–1249.
Wang, E.T., Sandberg, R., Luo, S., et al. (2008). Alternative isoform regulation in human tissue transcriptomes. Nature, 456, 470–476.
Yang, Q., Kathiresan, S., Lin, J.P., Tofler, G.H. and O'Donnell, C.J. (2007). Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Med. Genet., 8(Suppl 1), S12