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Functional genetic variation of human miRNAs and phenotypic consequences

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Abstract

A large number of human protein-coding genes are finely regulated by one or more microRNAs. Members of this small noncoding RNA family have emerged as important post-transcriptional regulators of gene expression and are involved in a number of disease phenotypes. Variability in the human genome is extensive and includes the common and rare single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). The functional significance of the genome’s variability is under intense investigation. In this article we review the emerging literature on how human genomic variation influences the outcome of microRNA targeting and the associated phenotypic effects. Illustrative examples are discussed that demonstrate the biological importance of functional polymorphisms affecting miRNA-mediated gene regulation.

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References

  • Abelson JF, Kwan KY, O’Roak BJ, Baek DY, Stillman AA et al (2005) Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science 310:317–320

    CAS  PubMed  Google Scholar 

  • Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    CAS  PubMed  Google Scholar 

  • Bao L, Zhou M, Wu L, Lu L, Goldowitz D et al (2007) PolymiRTS Database: linking polymorphisms in microRNA target sites with complex traits. Nucleic Acids Res 35:D51–D54

    CAS  PubMed  Google Scholar 

  • Bar M, Wyman SK, Fritz BR, Qi J, Garg KS et al (2008) MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries. Stem Cells

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    CAS  PubMed  Google Scholar 

  • Beckmann JS, Estivill X, Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 8:639–646

    CAS  PubMed  Google Scholar 

  • Berezikov E, Chung WJ, Willis J, Cuppen E, Lai EC (2007) Mammalian mirtron genes. Mol Cell 28:328–336

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brennecke J, Stark A, Russell RB, Cohen SM (2005) Principles of microRNA-target recognition. PLoS Biol 3:e85

    PubMed  PubMed Central  Google Scholar 

  • Burnier M, Brunner HR (2000) Angiotensin II receptor antagonists. Lancet 355:637–645

    CAS  PubMed  Google Scholar 

  • Bushati N, Cohen SM (2007) microRNA functions. Annu Rev Cell Dev Biol 23:175–205

    CAS  PubMed  Google Scholar 

  • Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M et al (2005) A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801

    CAS  PubMed  Google Scholar 

  • Carrington JC, Ambros V (2003) Role of microRNAs in plant and animal development. Science 301:336–338

    CAS  PubMed  Google Scholar 

  • Chang S, Johnston RJ Jr, Frokjaer-Jensen C, Lockery S, Hobert O (2004) MicroRNAs act sequentially and asymmetrically to control chemosensory laterality in the nematode. Nature 430:785–789

    CAS  PubMed  Google Scholar 

  • Chen K, Rajewsky N (2006) Natural selection on human microRNA binding sites inferred from SNP data. Nat Genet 38:1452–1456

    CAS  PubMed  Google Scholar 

  • Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X et al (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38:813–818

    CAS  PubMed  Google Scholar 

  • Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA Jr et al (2006) The colorectal microRNAome. Proc Natl Acad Sci USA 103:3687–3692

    CAS  PubMed  PubMed Central  Google Scholar 

  • Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432:231–235

    CAS  PubMed  Google Scholar 

  • Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18:504–511

    CAS  PubMed  PubMed Central  Google Scholar 

  • Draheim CC, McCubbin JA, Williams DP (2002) Differences in cardiovascular disease risk between nondiabetic adults with mental retardation with and without Down syndrome. Am J Ment Retard 107:201–211

    PubMed  Google Scholar 

  • Duan R, Pak C, Jin P (2007) Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16:1124–1131

    CAS  PubMed  Google Scholar 

  • Duggirala R, Blangero J, Almasy L, Arya R, Dyer TD et al (2001) A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 68:1149–1164

    CAS  PubMed  PubMed Central  Google Scholar 

  • Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK et al (2005) The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310:1817–1821

    CAS  PubMed  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    CAS  PubMed  Google Scholar 

  • Franco-Zorrilla JM, Valli A, Todesco M, Mateos I, Puga MI et al (2007) Target mimicry provides a new mechanism for regulation of microRNA activity. Nat Genet 39:1033–1037

    CAS  PubMed  Google Scholar 

  • Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    CAS  PubMed  Google Scholar 

  • Georges M, Coppieters W, Charlier C (2007) Polymorphic miRNA-mediated gene regulation: contribution to phenotypic variation and disease. Curr Opin Genet Dev 17:166–176

    CAS  PubMed  Google Scholar 

  • Glazov EA, Cottee PA, Barris WC, Moore RJ, Dalrymple BP et al (2008) A microRNA catalog of the developing chicken embryo identified by a deep sequencing approach. Genome Res 18:957–964

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goossens M, Dozy AM, Embury SH, Zachariades Z, Hadjiminas MG et al (1980) Triplicated alpha-globin loci in humans. Proc Natl Acad Sci USA 77:518–521

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B et al (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240

    CAS  PubMed  Google Scholar 

  • Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW (2006) Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442:82–85

    CAS  PubMed  Google Scholar 

  • Han J, Lee Y, Yeom KH, Kim YK, Jin H et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027

    CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, Lee Y, Yeom KH, Nam JW, Heo I et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125:887–901

    CAS  PubMed  Google Scholar 

  • Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E et al (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079

    CAS  PubMed  Google Scholar 

  • Hwang HW, Wentzel EA, Mendell JT (2007) A hexanucleotide element directs microRNA nuclear import. Science 315:97–100

    CAS  PubMed  Google Scholar 

  • Iwai N, Naraba H (2005) Polymorphisms in human pre-miRNAs. Biochem Biophys Res Commun 331:1439–1444

    CAS  PubMed  Google Scholar 

  • Jackson RJ, Standart N (2007) How do microRNAs regulate gene expression? Sci STKE 2007:re1

    PubMed  Google Scholar 

  • Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR et al (2008) Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci USA 105:7269–7274

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnston RJ, Hobert O (2003) A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426:845–849

    CAS  PubMed  Google Scholar 

  • Johnston RJ Jr, Chang S, Etchberger JF, Ortiz CO, Hobert O (2005) MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc Natl Acad Sci USA 102:12449–12454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kan YW, Dozy AM (1978) Polymorphism of DNA sequence adjacent to human beta-globin structural gene: relationship to sickle mutation. Proc Natl Acad Sci USA 75:5631–5635

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kan YW, Holland JP, Dozy AM, Charache S, Kazazian HH (1975) Deletion of the beta-globin structure gene in hereditary persistence of foetal haemoglobin. Nature 258:162–163

    CAS  PubMed  Google Scholar 

  • Khvorova A, Reynolds A, Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115:209–216

    CAS  PubMed  Google Scholar 

  • Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C et al (2004) A combined computational-experimental approach predicts human microRNA targets. Genes Dev 18:1165–1178

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W et al (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739

    CAS  PubMed  Google Scholar 

  • Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  • Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14:2162–2167

    CAS  PubMed  Google Scholar 

  • Lee Y, Ahn C, Han J, Choi H, Kim J et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419

    CAS  PubMed  Google Scholar 

  • Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115:787–798

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773

    CAS  PubMed  Google Scholar 

  • Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98

    CAS  PubMed  Google Scholar 

  • Lv K, Guo Y, Zhang Y, Wang K, Jia Y et al (2008) Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes. Biochem Biophys Res Commun 374:101–105

    CAS  PubMed  Google Scholar 

  • Lytle JR, Yario TA, Steitz JA (2007) Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci USA 104:9667–9672

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin MM, Lee EJ, Buckenberger JA, Schmittgen TD, Elton TS (2006) MicroRNA-155 regulates human angiotensin II type 1 receptor expression in fibroblasts. J Biol Chem 281:18277–18284

    CAS  PubMed  Google Scholar 

  • Mishra PJ, Humeniuk R, Mishra PJ, Longo-Sorbello GS, Banerjee D et al (2007) A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci USA 104:13513–13518

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morin RD, O’Connor MD, Griffith M, Kuchenbauer F, Delaney A et al (2008) Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res 18:610–621

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morrison RA, McGrath A, Davidson G, Brown JJ, Murray GD et al (1996) Low blood pressure in Down’s syndrome, A link with Alzheimer’s disease? Hypertension 28:569–575

    CAS  PubMed  Google Scholar 

  • Nielsen CB, Shomron N, Sandberg R, Hornstein E, Kitzman J et al (2007) Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13:1894–1910

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nilsen TW (2007) Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet 23:243–249

    CAS  PubMed  Google Scholar 

  • Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130:89–100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH et al (2006) Global variation in copy number in the human genome. Nature 444:444–454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ruby JG, Jan C, Player C, Axtell MJ, Lee W et al (2006) Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127:1193–1207

    CAS  PubMed  Google Scholar 

  • Ruby JG, Jan CH, Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448:83–86

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saunders MA, Liang H, Li WH (2007) Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A 104:3300–3305

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME et al (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289

    CAS  PubMed  Google Scholar 

  • Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N et al (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115:199–208

    CAS  PubMed  Google Scholar 

  • Sethupathy P, Borel C, Gagnebin M, Grant GR, Deutsch S et al (2007) Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet 81:405–413

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song JC, White CM (2002) Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet 41:207–224

    CAS  PubMed  Google Scholar 

  • Stark A, Brennecke J, Bushati N, Russell RB, Cohen SM (2005) Animal microRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123:1133–1146

    CAS  PubMed  Google Scholar 

  • Sunkar R, Zhou X, Zheng Y, Zhang W, Zhu JK (2008) Identification of novel and candidate miRNAs in rice by high throughput sequencing. BMC Plant Biol 8:25

    PubMed  PubMed Central  Google Scholar 

  • Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R et al (2007) Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet 81:829–834

    CAS  PubMed  PubMed Central  Google Scholar 

  • The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796

    Google Scholar 

  • Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    CAS  PubMed  Google Scholar 

  • Van Geel PP, Pinto YM, Voors AA, Buikema H, Oosterga M et al (2000) Angiotensin II type 1 receptor A1166C gene polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 35:717–721

    PubMed  Google Scholar 

  • Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934

    CAS  PubMed  Google Scholar 

  • Villuendas G, Botella-Carretero JI, Lopez-Bermejo A, Gubern C, Ricart W et al (2006) The ACAA-insertion/deletion polymorphism at the 3′ UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance. Eur J Endocrinol 155:331–336

    CAS  PubMed  Google Scholar 

  • Wang G, van der Walt JM, Mayhew G, Li YJ, Zuchner S et al (2008) Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 82:283–289

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872–876

    CAS  PubMed  Google Scholar 

  • Wong KK, de Leeuw RJ, Dosanjh NS, Kimm LR, Cheng Z et al (2007) A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80:91–104

    CAS  PubMed  Google Scholar 

  • Wu H, Neilson JR, Kumar P, Manocha M, Shankar P et al (2007) miRNA profiling of naive, effector and memory CD8 T cells. PLoS ONE 2:e1020

    PubMed  PubMed Central  Google Scholar 

  • Zeng Y, Cullen BR (2003) Sequence requirements for microRNA processing and function in human cells. RNA 9:112–123

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng Y, Cullen BR (2005) Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J Biol Chem 280:27595–27603

    CAS  PubMed  Google Scholar 

  • Zeng Y, Yi R, Cullen BR (2005) Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J 24:138–148

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors’ lab is supported by the Swiss National Science Foundation, the NCCR Frontiers in Genetics, The European Union, the NIH, and the Lejeune and ChildCare Foundations. We thank our laboratory colleagues for discussions, critical reading, and numerous suggestions.

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Correspondence to Stylianos E. Antonarakis.

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Borel, C., Antonarakis, S.E. Functional genetic variation of human miRNAs and phenotypic consequences. Mamm Genome 19, 503–509 (2008). https://doi.org/10.1007/s00335-008-9137-6

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