Genomics & Informatics

Korea Genome Organization (한국유전체학회)
권호 표지
DOI QR코드

DOI QR Code

Introns: The Functional Benefits of Introns in Genomes

  • Jo, Bong-Seok (Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University) ;
  • Choi, Sun Shim (Department of Medical Biotechnology, College of Biomedical Science, and Institute of Bioscience & Biotechnology, Kangwon National University)
  • Received : 2015.10.30
  • Accepted : 2015.12.21
  • Published : 2015.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

The intron has been a big biological mystery since it was first discovered in several aspects. First, all of the completely sequenced eukaryotes harbor introns in the genomic structure, whereas no prokaryotes identified so far carry introns. Second, the amount of total introns varies in different species. Third, the length and number of introns vary in different genes, even within the same species genome. Fourth, all introns are copied into RNAs by transcription and DNAs by replication processes, but intron sequences do not participate in protein-coding sequences. The existence of introns in the genome should be a burden to some cells, because cells have to consume a great deal of energy to copy and excise them exactly at the correct positions with the help of complicated spliceosomal machineries. The existence throughout the long evolutionary history is explained, only if selective advantages of carrying introns are assumed to be given to cells to overcome the negative effect of introns. In that regard, we summarize previous research about the functional roles or benefits of introns. Additionally, several other studies strongly suggesting that introns should not be junk will be introduced.

Keywords

References

  1. Wahl MC, Will CL, Luhrmann R. The spliceosome: design principles of a dynamic RNP machine. Cell 2009;136:701-718. https://doi.org/10.1016/j.cell.2009.02.009
  2. Chorev M, Carmel L. The function of introns. Front Genet 2012;3:55.
  3. Koonin EV. The origin of introns and their role in eukaryogenesis: a compromise solution to the introns-early versus introns-late debate? Biol Direct 2006;1:22. https://doi.org/10.1186/1745-6150-1-22
  4. Martin W, Koonin EV. Introns and the origin of nucleus-cytosol compartmentalization. Nature 2006;440:41-45. https://doi.org/10.1038/nature04531
  5. Koonin EV. Intron-dominated genomes of early ancestors of eukaryotes. J Hered 2009;100:618-623. https://doi.org/10.1093/jhered/esp056
  6. Rogozin IB, Wolf YI, Sorokin AV, Mirkin BG, Koonin EV. Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution. Curr Biol 2003;13:1512-1517. https://doi.org/10.1016/S0960-9822(03)00558-X
  7. Sakharkar MK, Chow VT, Kangueane P. Distributions of exons and introns in the human genome. In Silico Biol 2004;4: 387-393.
  8. Lynch M. The Origins of Genome Architecture. Sunderland: Sinauer Associates, 2007.
  9. Lynch M. Intron evolution as a population-genetic process. Proc Natl Acad Sci U S A 2002;99:6118-6123. https://doi.org/10.1073/pnas.092595699
  10. Blake CC. Do genes-in-pieces imply proteins-in-pieces? Nature 1978;273:267. https://doi.org/10.1038/273267a0
  11. Blake C. Exons: present from the beginning? Nature 1983; 306:535-537. https://doi.org/10.1038/306535a0
  12. Blake CC. Exons and the evolution of proteins. Int Rev Cytol 1985;93:149-185. https://doi.org/10.1016/S0074-7696(08)61374-1
  13. Gilbert W. Why genes in pieces? Nature 1978;271:501. https://doi.org/10.1038/271501a0
  14. Gilbert W. Genes-in-pieces revisited. Science 1985;228:823-824. https://doi.org/10.1126/science.4001923
  15. Gruss P, Lai CJ, Dhar R, Khoury G. Splicing as a requirement for biogenesis of functional 16S mRNA of simian virus 40. Proc Natl Acad Sci U S A 1979;76:4317-4321. https://doi.org/10.1073/pnas.76.9.4317
  16. Cavaller-Smith T. The Evolution of Genome Size. Chichester: John Wiley & Sons Ltd., 1985.
  17. Doolittle RF. The genealogy of some recently evolved vertebrate proteins. Trends Biochem Sci 1985;10:233-237.
  18. Rogers J. Exon shuffling and intron insertion in serine protease genes. Nature 1985;315:458-459. https://doi.org/10.1038/315458a0
  19. Sudhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science 1985;228:815-822. https://doi.org/10.1126/science.2988123
  20. Cech TR, Bass BL. Biological catalysis by RNA. Annu Rev Biochem 1986;55:599-629. https://doi.org/10.1146/annurev.bi.55.070186.003123
  21. Li W, Graur D. Fundamentals of Molecular Evolution. Sunderland: Sinauer Associates, 1991.
  22. Wen-Hsiung L. Molecular Evolution. Sunderland: Sinauer Associates Inc., 1997.
  23. Jareborg N, Birney E, Durbin R. Comparative analysis of noncoding regions of 77 orthologous mouse and human gene pairs. Genome Res 1999;9:815-824. https://doi.org/10.1101/gr.9.9.815
  24. Shabalina SA, Kondrashov AS. Pattern of selective constraint in C. elegans and C. briggsae genomes. Genet Res 1999;74:23-30. https://doi.org/10.1017/S0016672399003821
  25. Bergman CM, Kreitman M. Analysis of conserved noncoding DNA in Drosophila reveals similar constraints in intergenic and intronic sequences. Genome Res 2001;11:1335-1345. https://doi.org/10.1101/gr.178701
  26. Sorek R, Ast G. Intronic sequences flanking alternatively spliced exons are conserved between human and mouse. Genome Res 2003;13:1631-1637. https://doi.org/10.1101/gr.1208803
  27. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008;40:1413-1415. https://doi.org/10.1038/ng.259
  28. Roy M, Kim N, Xing Y, Lee C. The effect of intron length on exon creation ratios during the evolution of mammalian genomes. RNA 2008;14:2261-2273. https://doi.org/10.1261/rna.1024908
  29. Callis J, Fromm M, Walbot V. Introns increase gene expression in cultured maize cells. Genes Dev 1987;1:1183-1200. https://doi.org/10.1101/gad.1.10.1183
  30. Beaulieu E, Green L, Elsby L, Alourfi Z, Morand EF, Ray DW, et al. Identification of a novel cell type-specific intronic enhancer of macrophage migration inhibitory factor (MIF) and its regulation by mithramycin. Clin Exp Immunol 2011;163: 178-188. https://doi.org/10.1111/j.1365-2249.2010.04289.x
  31. Valencia P, Dias AP, Reed R. Splicing promotes rapid and efficient mRNA export in mammalian cells. Proc Natl Acad Sci U S A 2008;105:3386-3391. https://doi.org/10.1073/pnas.0800250105
  32. Schwartz S, Meshorer E, Ast G. Chromatin organization marks exon-intron structure. Nat Struct Mol Biol 2009;16: 990-995. https://doi.org/10.1038/nsmb.1659
  33. Spies N, Nielsen CB, Padgett RA, Burge CB. Biased chromatin signatures around polyadenylation sites and exons. Mol Cell 2009;36:245-254. https://doi.org/10.1016/j.molcel.2009.10.008
  34. Lewis BP, Green RE, Brenner SE. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A 2003; 100:189-192. https://doi.org/10.1073/pnas.0136770100
  35. Hillman RT, Green RE, Brenner SE. An unappreciated role for RNA surveillance. Genome Biol 2004;5:R8. https://doi.org/10.1186/gb-2004-5-2-r8
  36. Kalyna M, Simpson CG, Syed NH, Lewandowska D, Marquez Y, Kusenda B, et al. Alternative splicing and nonsense-mediated decay modulate expression of important regulatory genes in Arabidopsis. Nucleic Acids Res 2012;40: 2454-2469. https://doi.org/10.1093/nar/gkr932
  37. Marais G, Nouvellet P, Keightley PD, Charlesworth B. Intron size and exon evolution in Drosophila. Genetics 2005;170: 481-485. https://doi.org/10.1534/genetics.104.037333
  38. Bradnam KR, Korf I. Longer first introns are a general property of eukaryotic gene structure. PLoS One 2008;3:e3093. https://doi.org/10.1371/journal.pone.0003093
  39. Park SG, Hannenhalli S, Choi SS. Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals. BMC Genomics 2014;15:526. https://doi.org/10.1186/1471-2164-15-526
  40. Otto SP, Barton NH. The evolution of recombination: removing the limits to natural selection. Genetics 1997;147:879-906.
  41. Comeron JM, Williford A, Kliman RM. The Hill-Robertson effect: evolutionary consequences of weak selection and linkage in finite populations. Heredity (Edinb) 2008;100:19-31. https://doi.org/10.1038/sj.hdy.6801059
  42. Carvunis AR, Rolland T, Wapinski I, Calderwood MA, Yildirim MA, Simonis N, et al. Proto-genes and de novo gene birth. Nature 2012;487:370-374. https://doi.org/10.1038/nature11184
  43. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 2014;42:D1001-D1006. https://doi.org/10.1093/nar/gkt1229
  44. Baskerville S, Bartel DP. Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 2005;11:241-247. https://doi.org/10.1261/rna.7240905
  45. Dieci G, Preti M, Montanini B. Eukaryotic snoRNAs: a paradigm for gene expression flexibility. Genomics 2009;94:83-88. https://doi.org/10.1016/j.ygeno.2009.05.002
  46. Rearick D, Prakash A, McSweeny A, Shepard SS, Fedorova L, Fedorov A. Critical association of ncRNA with introns. Nucleic Acids Res 2011;39:2357-2366. https://doi.org/10.1093/nar/gkq1080
  47. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57-74. https://doi.org/10.1038/nature11247
  48. Buchman AR, Berg P. Comparison of intron-dependent and intron- independent gene expression. Mol Cell Biol 1988;8:4395-4405. https://doi.org/10.1128/MCB.8.10.4395
  49. Clark AJ, Archibald AL, McClenaghan M, Simons JP, Wallace R, Whitelaw CB. Enhancing the efficiency of transgene expression. Philos Trans R Soc Lond B Biol Sci 1993;339:225-232. https://doi.org/10.1098/rstb.1993.0020
  50. Juneau K, Miranda M, Hillenmeyer ME, Nislow C, Davis RW. Introns regulate RNA and protein abundance in yeast. Genetics 2006;174:511-518. https://doi.org/10.1534/genetics.106.058560
  51. Shabalina SA, Ogurtsov AY, Spiridonov AN, Novichkov PS, Spiridonov NA, Koonin EV. Distinct patterns of expression and evolution of intronless and intron-containing mammalian genes. Mol Biol Evol 2010;27:1745-1749. https://doi.org/10.1093/molbev/msq086
  52. Oswald A, Oates AC. Control of endogenous gene expression timing by introns. Genome Biol 2011;12:107. https://doi.org/10.1186/gb-2011-12-3-107
  53. Parra G, Bradnam K, Rose AB, Korf I. Comparative and functional analysis of intron-mediated enhancement signals reveals conserved features among plants. Nucleic Acids Res 2011;39:5328-5337. https://doi.org/10.1093/nar/gkr043
  54. Tourmente S, Chapel S, Dreau D, Drake ME, Bruhat A, Couderc JL, et al. Enhancer and silencer elements within the first intron mediate the transcriptional regulation of the beta 3 tubulin gene by 20-hydroxyecdysone in Drosophila Kc cells. Insect Biochem Mol Biol 1993;23:137-143. https://doi.org/10.1016/0965-1748(93)90092-7
  55. Green RE, Lewis BP, Hillman RT, Blanchette M, Lareau LF, Garnett AT, et al. Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes. Bioinformatics 2003;19 Suppl 1:i118-i121. https://doi.org/10.1093/bioinformatics/btg1015
  56. Ryu WS, Mertz JE. Simian virus 40 late transcripts lacking excisable intervening sequences are defective in both stability in the nucleus and transport to the cytoplasm. J Virol 1989; 63:4386-4394.
  57. Luo MJ, Reed R. Splicing is required for rapid and efficient mRNA export in metazoans. Proc Natl Acad Sci U S A 1999; 96:14937-14942. https://doi.org/10.1073/pnas.96.26.14937
  58. Rodrigues JP, Rode M, Gatfield D, Blencowe BJ, Carmo-Fonseca M, Izaurralde E. REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus. Proc Natl Acad Sci U S A 2001;98:1030-1035. https://doi.org/10.1073/pnas.98.3.1030
  59. Nott A, Meislin SH, Moore MJ. A quantitative analysis of intron effects on mammalian gene expression. RNA 2003;9: 607-617. https://doi.org/10.1261/rna.5250403
  60. Palazzo AF, Springer M, Shibata Y, Lee CS, Dias AP, Rapoport TA. The signal sequence coding region promotes nuclear export of mRNA. PLoS Biol 2007;5:e322. https://doi.org/10.1371/journal.pbio.0050322
  61. Majewski J, Ott J. Distribution and characterization of regulatory elements in the human genome. Genome Res 2002;12: 1827-1836. https://doi.org/10.1101/gr.606402
  62. Hong X, Scofield DG, Lynch M. Intron size, abundance, and distribution within untranslated regions of genes. Mol Biol Evol 2006;23:2392-2404. https://doi.org/10.1093/molbev/msl111
  63. Haddrill PR, Charlesworth B, Halligan DL, Andolfatto P. Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content. Genome Biol 2005;6:R67. https://doi.org/10.1186/gb-2005-6-8-r67
  64. Antoniou M, Geraghty F, Hurst J, Grosveld F. Efficient 3'-end formation of human beta-globin mRNA in vivo requires sequences within the last intron but occurs independently of the splicing reaction. Nucleic Acids Res 1998;26:721-729. https://doi.org/10.1093/nar/26.3.721
  65. Hachet O, Ephrussi A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 2004;428:959-963. https://doi.org/10.1038/nature02521
  66. Matsumoto K, Wassarman KM, Wolffe AP. Nuclear history of a pre-mRNA determines the translational activity of cytoplasmic mRNA. EMBO J 1998;17:2107-2121. https://doi.org/10.1093/emboj/17.7.2107
  67. Furger A, O'Sullivan JM, Binnie A, Lee BA, Proudfoot NJ. Promoter proximal splice sites enhance transcription. Genes Dev 2002;16:2792-2799. https://doi.org/10.1101/gad.983602
  68. Li MJ, Wang P, Liu X, Lim EL, Wang Z, Yeager M, et al. GWASdb: a database for human genetic variants identified by genome-wide association studies. Nucleic Acids Res 2012;40: D1047-D1054. https://doi.org/10.1093/nar/gkr1182
  69. Hawkins JD. A survey on intron and exon lengths. Nucleic Acids Res 1988;16:9893-9908. https://doi.org/10.1093/nar/16.21.9893
  70. Deutsch M, Long M. Intron-exon structures of eukaryotic model organisms. Nucleic Acids Res 1999;27:3219-3228. https://doi.org/10.1093/nar/27.15.3219
  71. Simpson AG, MacQuarrie EK, Roger AJ. Eukaryotic evolution: early origin of canonical introns. Nature 2002;419:270. https://doi.org/10.1038/419270a
  72. Mourier T, Jeffares DC. Eukaryotic intron loss. Science 2003;300:1393. https://doi.org/10.1126/science.1080559
  73. Jeffares DC, Mourier T, Penny D. The biology of intron gain and loss. Trends Genet 2006;22:16-22. https://doi.org/10.1016/j.tig.2005.10.006

Cited by

  1. The peptidylglycine-α-amidating monooxygenase (PAM) gene rs13175330 A>G polymorphism is associated with hypertension in a Korean population vol.11, pp.1, 2017, https://doi.org/10.1186/s40246-017-0125-3
  2. Klf5 Mediates Odontoblastic Differentiation through Regulating Dentin-Specific Extracellular Matrix Gene Expression during Mouse Tooth Development vol.7, pp.2045-2322, 2017, https://doi.org/10.1038/srep46746
  3. The sociobiology of genes: the gene’s eye view as a unifying behavioural-ecological framework for biological evolution vol.40, pp.1, 2018, https://doi.org/10.1007/s40656-017-0174-x
  4. Alternative mRNA Splicing in the Pathogenesis of Obesity vol.19, pp.2, 2018, https://doi.org/10.3390/ijms19020632
  5. Polymorphisms and Precancerous Cervical Lesions vol.22, pp.9, 2018, https://doi.org/10.1089/gtmb.2018.0097
  6. ) pp.10656995, 2019, https://doi.org/10.1002/cbin.11001
  7. A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid pp.1476-3524, 2018, https://doi.org/10.1007/s12640-018-9922-2
  8. Associations between hypertension and the peroxisome proliferator-activated receptor-δ (PPARD) gene rs7770619 C>T polymorphism in a Korean population vol.12, pp.1, 2018, https://doi.org/10.1186/s40246-018-0162-6
  9. A genome-wide association study reveals novel genomic regions and positional candidate genes for fat deposition in broiler chickens vol.19, pp.1, 2018, https://doi.org/10.1186/s12864-018-4779-6
  10. Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset vol.25, pp.4, 2018, https://doi.org/10.1080/13506129.2018.1534731
  11. Insights into the Evolution of the Suppressors of Cytokine Signaling (SOCS) Gene Family in Vertebrates vol.36, pp.2, 2018, https://doi.org/10.1093/molbev/msy230
  12. Features of a novel protein, rusticalin, from the ascidian Styela rustica reveal ancestral horizontal gene transfer event vol.10, pp.1, 2019, https://doi.org/10.1186/s13100-019-0146-7
  13. Introns are mediators of cell response to starvation vol.565, pp.7741, 2019, https://doi.org/10.1038/s41586-018-0859-7
  14. Intronic CNVs and gene expression variation in human populations vol.15, pp.1, 2019, https://doi.org/10.1371/journal.pgen.1007902