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Evolution of microRNA diversity and regulation in animals

Nature Reviews Genetics volume 12, pages 846–860 (2011)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) have ancient origins and were present as gene regulators early on in the evolution of animals.

  • The number of miRNA genes correlates with organismal complexity. Several waves of miRNA innovation have occurred: at the base of bilaterian lineage (the bilaterian expansion), at the base of the vertebrate lineage and in placental mammals.

  • miRNA genes evolve relatively easily, compared to protein-coding genes, from various genomic sources, including gene duplications, introns, pseudogenes, transposable elements, antisense transcripts and intergenic regions (de novo emergence).

  • Diversification of miRNA genes can take place by various mechanisms, including direct nucleotide changes in the seed region, seed shifting, arm switching and hairpin shifting.

  • miRNA targets can be easily acquired and lost.

  • The expression patterns of conserved miRNAs are overall conserved over large evolutionary distances. However, orthologous miRNAs in closely related species can vary in their spatio-temporal expression patterns.

  • miRNAs confer robustness to gene networks and provide reduction in variability of traits (canalization). The canalization of traits is an important mechanism in the evolution of increasing morphological complexity.

Abstract

In the past decade, microRNAs (miRNAs) have been uncovered as key regulators of gene expression at the post-transcriptional level. The ancient origin of miRNAs, their dramatic expansion in bilaterian animals and their function in providing robustness to transcriptional programmes suggest that miRNAs are instrumental in the evolution of organismal complexity. Advances in understanding miRNA biology, combined with the increasing availability of diverse sequenced genomes, have begun to reveal the molecular mechanisms that underlie the evolution of miRNAs and their targets. Insights are also emerging into how the evolution of miRNA-containing regulatory networks has contributed to organismal complexity.

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Figure 1: RNA gene structure and biogenesis.
Figure 2: Genomic sources of novel miRNA genes.
Figure 3: Mechanisms of miRNA sequence diversification.
Figure 4: Principles of miRNA targeting.

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References

  1. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

    CAS  PubMed  Google Scholar 

  2. Wightman, B., Ha, I. & Ruvkun, G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75, 855–862 (1993).

    CAS  PubMed  Google Scholar 

  3. Pasquinelli, A. E. et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408, 86–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ambros, V. The evolution of our thinking about microRNAs. Nature Med. 14, 1036–1040 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Axtell, M. J., Westholm, J. O. & Lai, E. C. Vive la différence: biogenesis and evolution of microRNAs in plants and animals. Genome Biol. 12, 221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cuperus, J. T., Fahlgren, N. & Carrington, J. C. Evolution and functional diversification of miRNA genes. Plant Cell 23, 431–442 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nature Rev. Genet. 11, 597–610 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Czech, B. & Hannon, G. J. Small RNA sorting: matchmaking for Argonautes. Nature Rev. Genet. 12, 19–31 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Reinhart, B. J. et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901–906 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 858–862 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, R. C. & Ambros, V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294, 862–864 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Grimson, A. et al. Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals. Nature 455, 1193–1197 (2008). This work demonstrates that miRNAs as class of gene regulators were present early on in the evolution of animals.

    Article  CAS  PubMed  Google Scholar 

  14. Christodoulou, F. et al. Ancient animal microRNAs and the evolution of tissue identity. Nature 463, 1084–1088 (2010). The authors of this paper show conservation of miRNA expression patterns over large evolutionary distances and reconstruct the minimal set of miRNAs that were present in the bilaterian ancestor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hertel, J. et al. The expansion of the metazoan microRNA repertoire. BMC Genomics 7, 25 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peterson, K. J., Dietrich, M. R. & McPeek, M. A. MicroRNAs and metazoan macroevolution: insights into canalization, complexity, and the Cambrian explosion. Bioessays 31, 736–747 (2009). References 16, 23 and 144 explore the concept of the role of miRNAs in canalization, in which they function to decrease the variability of traits.

    Article  CAS  PubMed  Google Scholar 

  17. Heimberg, A. M., Sempere, L. F., Moy, V. N., Donoghue, P. C. & Peterson, K. J. MicroRNAs and the advent of vertebrate morphological complexity. Proc. Natl Acad. Sci. USA 105, 2946–2950 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wheeler, B. M. et al. The deep evolution of metazoan microRNAs. Evol. Dev. 11, 50–68 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Heimberg, A. M., Cowper-Sal-lari, R., Semon, M., Donoghue, P. C. & Peterson, K. J. microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. Proc. Natl Acad. Sci. USA 107, 19379–19383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Campo-Paysaa, F., Semon, M., Cameron, R. A., Peterson, K. J. & Schubert, M. microRNA complements in deuterostomes: origin and evolution of microRNAs. Evol. Dev. 13, 15–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Berezikov, E. et al. Evolutionary flux of canonical microRNAs and mirtrons in Drosophila. Nature Genet. 42, 6–9 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Berezikov, E. et al. Diversity of microRNAs in human and chimpanzee brain. Nature Genet. 38, 1375–1377 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Hornstein, E. & Shomron, N. Canalization of development by microRNAs. Nature Genet. 38, S20–S24 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Sempere, L. F., Cole, C. N., McPeek, M. A. & Peterson, K. J. The phylogenetic distribution of metazoan microRNAs: insights into evolutionary complexity and constraint. J. Exp. Zool. B 306, 575–588 (2006).

    Article  CAS  Google Scholar 

  25. Lee, C. T., Risom, T. & Strauss, W. M. Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny. DNA Cell Biol. 26, 209–218 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Prochnik, S. E., Rokhsar, D. S. & Aboobaker, A. A. Evidence for a microRNA expansion in the bilaterian ancestor. Dev. Genes Evol. 217, 73–77 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nature Rev. Genet. 8, 93–103 (2007). This excellent Review formulates a hypothesis for the mode of emergence of novel miRNAs through initial restriction of miRNA expression levels.

    Article  CAS  PubMed  Google Scholar 

  28. Ambros, V. et al. A uniform system for microRNA annotation. RNA 9, 277–279 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Gu, X., Su, Z. & Huang, Y. Simultaneous expansions of microRNAs and protein-coding genes by gene/genome duplications in early vertebrates. J. Exp. Zool. B 312B, 164–170 (2009).

    Article  CAS  Google Scholar 

  31. Ruby, J. G. et al. Evolution, biogenesis, expression, and target predictions of a substantially expanded set of Drosophila microRNAs. Genome Res. 17, 1850–1864 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rodriguez, A., Griffiths-Jones, S., Ashurst, J. L. & Bradley, A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 14, 1902–1910 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Isik, M., Korswagen, H. C. & Berezikov, E. Expression patterns of intronic microRNAs in Caenorhabditis elegans. Silence 1, 5 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martinez, N. J. et al. Genome-scale spatiotemporal analysis of Caenorhabditis elegans microRNA promoter activity. Genome Res. 18, 2005–2015 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ozsolak, F. et al. Chromatin structure analyses identify miRNA promoters. Genes Dev. 22, 3172–3183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu, J. et al. The birth and death of microRNA genes in Drosophila. Nature Genet. 40, 351–355 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Berezikov, E. et al. Deep annotation of Drosophila melanogaster microRNAs yields insights into their processing, modification, and emergence. Genome Res. 21, 203–215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Devor, E. J. Primate microRNAs miR-220 and miR-492 lie within processed pseudogenes. J. Hered. 97, 186–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Ender, C. et al. A human snoRNA with microRNA-like functions. Mol. Cell 32, 519–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Scott, M. S., Avolio, F., Ono, M., Lamond, A. I. & Barton, G. J. Human miRNA precursors with box H/ACA snoRNA features. PLoS Comp. Biol. 5 e1000507 (2009).

    Article  CAS  Google Scholar 

  41. Pederson, T. Regulatory RNAs derived from transfer RNA? RNA 16, 1865–1869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brameier, M., Herwig, A., Reinhardt, R., Walter, L. & Gruber, J. Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Res. 39, 675–686 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Ono, M. et al. Identification of human miRNA precursors that resemble box C/D snoRNAs. Nucleic Acids Res. 39, 3879–3891 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burroughs, A. M. et al. Deep-sequencing of human Argonaute-associated small RNAs provides insight into miRNA sorting and reveals Argonaute association with RNA fragments of diverse origin. RNA Biol. 8, 158–177 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sinzelle, L., Izsvak, Z. & Ivics, Z. Molecular domestication of transposable elements: from detrimental parasites to useful host genes. Cell. Mol. Life Sci. 66, 1073–1093 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nature Rev. Genet. 10, 691–703 (2009).

    Article  CAS  PubMed  Google Scholar 

  47. Smalheiser, N. R. & Torvik, V. I. Mammalian microRNAs derived from genomic repeats. Trends Genet. 21, 322–326 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Piriyapongsa, J. & Jordan, I. K. A family of human microRNA genes from miniature inverted-repeat transposable elements. PLoS ONE 2, e203 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Piriyapongsa, J., Marino-Ramirez, L. & Jordan, I. K. Origin and evolution of human microRNAs from transposable elements. Genetics 176, 1323–1337 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Devor, E. J., Peek, A. S., Lanier, W. & Samollow, P. B. Marsupial-specific microRNAs evolved from marsupial-specific transposable elements. Gene 448, 187–191 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yuan, Z. et al. Origin and evolution of a placental-specific microRNA family in the human genome. BMC Evol. Biol. 10, 346 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yuan, Z., Sun, X., Liu, H. & Xie, J. MicroRNA genes derived from repetitive elements and expanded by segmental duplication events in mammalian genomes. PLoS ONE 6, e17666 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedlander, M. R., Mackowiak, S. D., Li, N., Chen, W. & Rajewsky, N. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic Acids Res. 12 Sep 2011 (doi:10.1093/nar/gkr688).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ketting, R. F. The many faces of RNAi. Dev. Cell 20, 148–161 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Bender, W. MicroRNAs in the Drosophila bithorax complex. Genes Dev. 22, 14–19 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stark, A. et al. A single Hox locus in Drosophila produces functional microRNAs from opposite DNA strands. Genes Dev. 22, 8–13 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tyler, D. M. et al. Functionally distinct regulatory RNAs generated by bidirectional transcription and processing of microRNA loci. Genes Dev. 22, 26–36 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bentwich, I. et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genet. 37, 766–770 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Birney, E. et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447, 799–816 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Liu, N. et al. The evolution and functional diversification of animal microRNA genes. Cell Res. 18, 985–996 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Lu, J. et al. Adaptive evolution of newly emerged micro-RNA genes in Drosophila. Mol. Biol. Evol. 25, 929–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tang, T. et al. Adverse interactions between micro-RNAs and target genes from different species. Proc. Natl Acad. Sci. USA 107, 12935–12940 (2010). The study demonstrates experimentally the adverse effect of high-level expression of foreign miRNAs. The findings support the hypothesis of coevolution of miRNAs and their targets and the emergence of novel miRNAs from transcripts that are expressed at low levels, as formulated in reference 27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu, H. et al. miRNA profiling of naive, effector and memory CD8 T cells. PLoS ONE 2, e1020 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Azuma-Mukai, A. et al. Characterization of endogenous human Argonautes and their miRNA partners in RNA silencing. Proc. Natl Acad. Sci. USA 105, 7964–7969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Seitz, H., Ghildiyal, M. & Zamore, P. D. Argonaute loading improves the 5′ precision of both microRNAs and their miRNA* strands in flies. Curr. Biol. 18, 147–151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Morin, R. D. et al. Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res. 18, 610–621 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ruby, J. G. et al. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127, 1193–1207 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Burroughs, A. M. et al. A comprehensive survey of 3′ animal miRNA modification events and a possible role for 3′ adenylation in modulating miRNA targeting effectiveness. Genome Res. 20, 1398–1410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fernandez-Valverde, S. L., Taft, R. J. & Mattick, J. S. Dynamic isomiR regulation in Drosophila development. RNA 16, 1881–1888 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lim, L. P. et al. The microRNAs of Caenorhabditis elegans. Genes Dev. 17, 991–1008 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009). This is an excellent review of miRNA targeting principles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Marco, A., Hui, J. H., Ronshaugen, M. & Griffiths-Jones, S. Functional shifts in insect microRNA evolution. Genome Biol. Evol. 2, 686–696 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Okamura, K. et al. The regulatory activity of microRNA* species has substantial influence on microRNA and 3′ UTR evolution. Nature Struct. Mol. Biol. 15, 354–363 (2008).

    Article  CAS  Google Scholar 

  77. Kuchenbauer, F. et al. Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells. Blood 31 May 2011 (doi:10.1182/blood-2010-10-312454).

    Article  CAS  PubMed  Google Scholar 

  78. de Wit, E., Linsen, S. E., Cuppen, E. & Berezikov, E. Repertoire and evolution of miRNA genes in four divergent nematode species. Genome Res. 19, 2064–2074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Griffiths-Jones, S., Hui, J. H., Marco, A. & Ronshaugen, M. MicroRNA evolution by arm switching. EMBO Rep. 12, 172–177 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Khvorova, A., Reynolds, A. & Jayasena, S. D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 209–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Schwarz, D. S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Ro, S., Park, C., Young, D., Sanders, K. M. & Yan, W. Tissue-dependent paired expression of miRNAs. Nucleic Acids Res. 35, 5944–5953 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nishikura, K. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nature Rev. Mol. Cell. Biol. 7, 919–931 (2006).

    Article  CAS  Google Scholar 

  84. Luciano, D. J., Mirsky, H., Vendetti, N. J. & Maas, S. RNA editing of a miRNA precursor. RNA 10, 1174–1177 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Blow, M. J. et al. RNA editing of human microRNAs. Genome Biol. 7 (2006).

  86. Kawahara, Y., Zinshteyn, B., Chendrimada, T. P., Shiekhattar, R. & Nishikura, K. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer–TRBP complex. EMBO Rep. 8, 763–769 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nature Struct. Mol. Biol. 13, 13–21 (2006).

    Article  CAS  Google Scholar 

  89. Heale, B. S., Keegan, L. P. & O'Connell, M. A. The effect of RNA editing and ADARs on miRNA biogenesis and function. Adv. Exp. Med. Biol. 700, 76–84 (2011).

    Article  PubMed  Google Scholar 

  90. De Mulder, K. & Berezikov, E. Tracing the evolution of tissue identity with microRNAs. Genome Biol. 11, 111 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ason, B. et al. Differences in vertebrate microRNA expression. Proc. Natl Acad. Sci. USA 103, 14385–14389 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Aboobaker, A. A., Tomancak, P., Patel, N., Rubin, G. M. & Lai, E. C. Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proc. Natl Acad. Sci. USA 102, 18017–18022 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nature Struct. Mol. Biol. 17, 1169–1174 (2010).

    Article  CAS  Google Scholar 

  94. Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Brennecke, J., Stark, A., Russell, R. B. & Cohen, S. M. Principles of microRNA-target recognition. PLoS Biol. 3, e85 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Friedman, R. C., Farh, K. K., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shin, C. et al. Expanding the microRNA targeting code: functional sites with centered pairing. Mol. Cell 38, 789–802 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Easow, G., Teleman, A. A. & Cohen, S. M. Isolation of microRNA targets by miRNP immunopurification. RNA 13, 1198–1204 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lytle, J. R., Yario, T. A. & Steitz, J. A. 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 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Duursma, A. M., Kedde, M., Schrier, M., le Sage, C. & Agami, R. miR-148 targets human DNMT3b protein coding region. RNA 14, 872–877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Forman, J. J., Legesse-Miller, A. & Coller, H. A. A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc. Natl Acad. Sci. USA 105, 14879–14884 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Orom, U. A., Nielsen, F. C. & Lund, A. H. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 30, 460–471 (2008).

    PubMed  Google Scholar 

  106. Shen, W. F., Hu, Y. L., Uttarwar, L., Passegue, E. & Largman, C. MicroRNA-126 regulates HOXA9 by binding to the homeobox. Mol.Cell. Biol. 28, 4609–4619 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tay, Y., Zhang, J., Thomson, A. M., Lim, B. & Rigoutsos, I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455, 1124–1128 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Elcheva, I., Goswami, S., Noubissi, F. K. & Spiegelman, V. S. CRD-BP protects the coding region of βTrCP1 mRNA from miR-183-mediated degradation. Mol. Cell 35, 240–246 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schnall-Levin, M., Zhao, Y., Perrimon, N. & Berger, B. Conserved microRNA targeting in Drosophila is as widespread in coding regions as in 3′UTRs. Proc. Natl Acad. Sci. USA 107, 15751–15756 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Huang, S. et al. MicroRNA-181a modulates gene expression of zinc finger family members by directly targeting their coding regions. Nucleic Acids Res. 38, 7211–7218 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Schnall-Levin, M. et al. Unusually effective microRNA targeting within repeat-rich coding regions of mammalian mRNAs. Genome Res. 21, 1395–1403 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fang, Z. & Rajewsky, N. The impact of miRNA target sites in coding sequences and in 3′UTRs. PLoS ONE 6, e18067 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Farh, K. K. et al. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005). References 113 and 118 explore the relationships between expression patterns of miRNAs and their targets and introduce the concept of selective target avoidance.

    Article  CAS  PubMed  Google Scholar 

  114. Giraldez, A. J. et al. Zebrafish miR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75–79 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Doench, J. G. & Sharp, P. A. Specificity of microRNA target selection in translational repression. Genes Dev. 18, 504–511 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Nielsen, C. B. et al. Determinants of targeting by endogenous and exogenous microRNAs and siRNAs. RNA 13, 1894–1910 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Saetrom, P. et al. Distance constraints between microRNA target sites dictate efficacy and cooperativity. Nucleic Acids Res. 35, 2333–2342 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Stark, A., Brennecke, J., Bushati, N., Russell, R. B. & Cohen, S. M. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123, 1133–1146 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Sood, P., Krek, A., Zavolan, M., Macino, G. & Rajewsky, N. Cell-type-specific signatures of microRNAs on target mRNA expression. Proc. Natl Acad. Sci. USA 103, 2746–2751 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bartel, D. P. & Chen, C. Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nature Rev. Genet. 5, 396–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ji, Z., Lee, J. Y., Pan, Z., Jiang, B. & Tian, B. Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc. Natl Acad. Sci. USA 106, 7028–7033 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Clop, A. et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nature Genet. 38, 813–818 (2006). This is an impressive example of the phenotypic consequences of creating a novel miRNA target site.

    Article  CAS  PubMed  Google Scholar 

  126. Kim, J. & Bartel, D. P. Allelic imbalance sequencing reveals that single-nucleotide polymorphisms frequently alter microRNA-directed repression. Nature Biotech. 27, 472–477 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  128. Saunders, M. A., Liang, H. & Li, W. H. Human polymorphism at microRNAs and microRNA target sites. Proc. Natl Acad. Sci. USA 104, 3300–3305 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Song, F. et al. An miR-502-binding site single-nucleotide polymorphism in the 3′-untranslated region of the SET8 gene is associated with early age of breast cancer onset. Clin. Cancer Res. 15, 6292–6300 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Chin, L. J. et al. A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res. 68, 8535–8540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ratner, E. et al. A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk. Cancer Res. 70, 6509–6515 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, L. et al. Functional SNP in the microRNA-367 binding site in the 3′UTR of the calcium channel ryanodine receptor gene 3 (RYR3) affects breast cancer risk and calcification. Proc. Natl Acad. Sci. USA 108, 13653–13658 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kocher, T. D. Adaptive evolution and explosive speciation: the cichlid fish model. Nature Rev. Genet. 5, 288–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Loh, Y. H., Yi, S. V. & Streelman, J. T. Evolution of microRNAs and the diversification of species. Genome Biol. Evol. 3, 55–65 (2011). The authors demonstrate the accelerated divergence of miRNA target sites in cichlids, suggesting that the selective divergence of miRNA regulation has a role in the diversification of cichlid species.

    Article  CAS  PubMed  Google Scholar 

  135. Herranz, H. & Cohen, S. M. MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev. 24, 1339–1344 (2010). This is an outstanding review of how miRNAs function in gene-regulatory networks.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Flynt, A. S. & Lai, E. C. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nature Rev. Genet. 9, 831–842 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Nakahara, K. et al. Targets. of microRNA regulation in the Drosophila oocyte proteome. Proc. Natl Acad. Sci. USA 102, 12023–12028 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Mukherji, S. et al. MicroRNAs can generate thresholds in target gene expression. Nature Genet. 43, 854–859 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Tsang, J., Zhu, J. & van Oudenaarden, A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 26, 753–767 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wu, C. I., Shen, Y. & Tang, T. Evolution under canalization and the dual roles of microRNAs: a hypothesis. Genome Res. 19, 734–743 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li, Y., Wang, F., Lee, J. A. & Gao, F. B. MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila. Genes Dev. 20, 2793–2805 (2006). References 145 and 146 provide good examples of the roles of miRNAs in ensuring the robustness of developmental programs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Li, X., Cassidy, J. J., Reinke, C. A., Fischboeck, S. & Carthew, R. W. A microRNA imparts robustness against environmental fluctuation during development. Cell 137, 273–282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Gibson, G. & Wagner, G. Canalization in evolutionary genetics: a stabilizing theory? Bioessays 22, 372–380 (2000).

    Article  CAS  PubMed  Google Scholar 

  148. Miska, E. A. et al. Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet. 3, e215 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Alvarez-Saavedra, E. & Horvitz, H. R. Many families of C. elegans microRNAs are not essential for development or viability. Curr. Biol. 20, 367–373 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Brenner, J. L., Jasiewicz, K. L., Fahley, A. F., Kemp, B. J. & Abbott, A. L. Loss of individual microRNAs causes mutant phenotypes in sensitized genetic backgrounds in C. elegans. Curr. Biol. 20, 1321–1325 (2010). This work shows that functions of miRNAs can be often revealed in sensitized genetic backgrounds, supporting the hypothesis that miRNAs confer robustness to gene networks.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ambros, V. MicroRNAs: genetically sensitized worms reveal new secrets. Curr. Biol. 20, R598–600 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Taft, R. J., Pheasant, M. & Mattick, J. S. The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29, 288–299 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Chen, K. & Rajewsky, N. Deep conservation of microRNA-target relationships and 3′UTR motifs in vertebrates, flies, and nematodes. Cold Spring Harb. Symp. Quant. Biol. 71, 149–156 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Berezikov, E., Cuppen, E. & Plasterk, R. H. Approaches to microRNA discovery. Nature Genet. 38, S2–S7 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Friedlander, M. R. et al. Discovering microRNAs from deep sequencing data using miRDeep. Nature Biotech. 26, 407–415 (2008). The use of signatures of processing by Drosha and Dicer for prediction of novel miRNA genes from deep sequencing data was formalized for the first time in this study.

    Article  CAS  Google Scholar 

  156. Srivastava, M. et al. The Trichoplax genome and the nature of placozoans. Nature 454, 955–960 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Cai, X., Hagedorn, C. H. & Cullen, B. R. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10, 1957–1966 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kim, Y. K. & Kim, V. N. Processing of intronic microRNAs. EMBO J. 26, 775–783 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the Microprocessor complex. Nature 432, 231–235 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Han, J. et al. Molecular basis for the recognition of primary microRNAs by the Drosha–DGCR8 complex. Cell 125, 887–901 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Berezikov, E., Chung, W. J., Willis, J., Cuppen, E. & Lai, E. C. Mammalian mirtron genes. Mol. Cell 28, 328–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Okamura, K., Hagen, J. W., Duan, H., Tyler, D. M. & Lai, E. C. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130, 89–100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ruby, J. G., Jan, C. H. & Bartel, D. P. Intronic microRNA precursors that bypass Drosha processing. Nature 448, 83–86 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Flynt, A. S., Greimann, J. C., Chung, W. J., Lima, C. D. & Lai, E. C. MicroRNA biogenesis via splicing and exosome-mediated trimming in Drosophila. Mol. Cell 38, 900–907 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Grishok, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Hutvagner, G. et al. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654–2659 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to thank K. J. Peterson and the anonymous referees for their insightful comments on the manuscript and members of his laboratory for stimulating discussions. The author is a European Molecular Biology Organisation (EMBO) Young Investigator. This work is supported by a VIDI grant from The Netherlands Organisation for Scientific Research (NWO).

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  1. Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands

    Eugene Berezikov

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Eugene Berezikov is a co-founder of InetRNA Technologies B.V. and a InteRNA Genomics B.V.

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miRBase

Glossary

Paralogous

The homology between two genomic segments in the same organism that arose from a duplication event.

Subfunctionalization

The division of the ancestral function of a gene following gene duplication, in which different copies of the duplicated gene retain different aspects of the original function.

Neofunctionalization

The acquisition of a novel function by one of the copies of a duplicated gene, which comes about through mutational changes.

DNA transposons

Transposable elements that rely on a transposase enzyme to excise themselves from one region of the genome and insert themselves into a different region without increasing in copy number.

Retrotransposon

Transposable element that replicates via an RNA intermediate, which is converted by reverse transcriptase to cDNA. The cDNA can be inserted into genomic DNA, increasing the number of copies of the retrotransposon in the genome.

PIWI-interacting RNAs

(piRNAs). Single-stranded RNAs in the range of 25–35 nucleotides that form complexes with the PIWI protein. piRNAs are involved in transposon silencing.

miRNA*

One of the strands in the imperfect double-stranded intermediate RNA duplex that is generated after processing of the primary miRNA precursor RNA by Drosha and Dicer. The other strand — mature miRNA — is predominantly loaded into the miRNA-induced silencing complex (miRISC), whereas miRNA* is degraded.

Drift

Random fluctuations in allele frequencies as genes are transmitted from one generation to the next.

Coherent feedforward loop

A gene network motif in which a regulator gene controls a target gene directly, as well as indirectly, through another regulator, and both regulation paths act in the same direction on the target.

Incoherent feedforward loop

A gene network motif where a regulator gene controls the target gene directly as well as indirectly through another regulator, and the two regulation paths act in opposite directions on the target.

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Berezikov, E. Evolution of microRNA diversity and regulation in animals. Nat Rev Genet 12, 846–860 (2011). https://doi.org/10.1038/nrg3079

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