Human Genetics

, Volume 133, Issue 6, pp 679–687 | Cite as

Genomics of alternative splicing: evolution, development and pathophysiology

Review Paper

Abstract

Alternative splicing is a major cellular mechanism in metazoans for generating proteomic diversity. A large proportion of protein-coding genes in multicellular organisms undergo alternative splicing, and in humans, it has been estimated that nearly 90 % of protein-coding genes—much larger than expected—are subject to alternative splicing. Genomic analyses of alternative splicing have illuminated its universal role in shaping the evolution of genomes, in the control of developmental processes, and in the dynamic regulation of the transcriptome to influence phenotype. Disruption of the splicing machinery has been found to drive pathophysiology, and indeed reprogramming of aberrant splicing can provide novel approaches to the development of molecular therapy. This review focuses on the recent progress in our understanding of alternative splicing brought about by the unprecedented explosive growth of genomic data and highlights the relevance of human splicing variation on disease and therapy.

References

  1. Aaronson Y, Meshorer E (2013) Stem cells: regulation by alternative splicing. Nature 498:176–177PubMedCrossRefGoogle Scholar
  2. Aartsma-Rus A, van Ommen GJ (2009) Less is more: therapeutic exon skipping for Duchenne muscular dystrophy. Lancet Neurol 8:873–875PubMedCrossRefGoogle Scholar
  3. Aberg K, Saetre P, Jareborg N, Jazin E (2006) Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci USA 103:7482–7487PubMedCentralPubMedCrossRefGoogle Scholar
  4. Alekseyenko AV, Kim N, Lee CJ (2007) Global analysis of exon creation versus loss and the role of alternative splicing in 17 vertebrate genomes. RNA 13:661–670PubMedCentralPubMedCrossRefGoogle Scholar
  5. Anders S, McCarthy DJ, Chen Y, Okoniewski M, Smyth GK et al (2013) Count-based differential expression analysis of RNA sequencing data using R and Bioconductor. Nat Protoc 8:1765–1786PubMedCrossRefGoogle Scholar
  6. Asmann YW, Necela BM, Kalari KR, Hossain A, Baker TR et al (2012) Detection of redundant fusion transcripts as biomarkers or disease-specific therapeutic targets in breast cancer. Cancer Res 72:1921–1928PubMedCrossRefGoogle Scholar
  7. Baranauskas G, Tkatch T, Nagata K, Yeh JZ, Surmeier DJ (2003) Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nat Neurosci 6:258–266PubMedCrossRefGoogle Scholar
  8. Barbosa-Morais NL, Carmo-Fonseca M, Aparicio S (2006) Systematic genome-wide annotation of spliceosomal proteins reveals differential gene family expansion. Genome Res 16:66–77PubMedCentralPubMedCrossRefGoogle Scholar
  9. Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–1593PubMedCrossRefGoogle Scholar
  10. Barry G, Briggs JA, Vanichkina DP, Poth EM, Beveridge NJ et al (2013) The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing. Mol Psychiatry. doi:  10.1038/mp.2013.45
  11. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816PubMedCrossRefGoogle Scholar
  12. Brandenberger R, Wei H, Zhang S, Lei S, Murage J et al (2004) Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nat Biotechnol 22:707–716PubMedCrossRefGoogle Scholar
  13. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571PubMedCentralPubMedCrossRefGoogle Scholar
  14. Cavalier-Smith T (1991) Intron phylogeny: a new hypothesis. Trends Genet 7:145–148PubMedCrossRefGoogle Scholar
  15. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J et al (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 99:13926–13931PubMedCentralPubMedCrossRefGoogle Scholar
  16. Cloonan N, Forrest AR, Kolle G, Gardiner BB, Faulkner GJ et al (2008) Stem cell transcriptome profiling via massive-scale mRNA sequencing. Nat Methods 5:613–619PubMedCrossRefGoogle Scholar
  17. Coulombe-Huntington J, Lam KC, Dias C, Majewski J (2009) Fine-scale variation and genetic determinants of alternative splicing across individuals. PLoS Genet 5:e1000766PubMedCentralPubMedCrossRefGoogle Scholar
  18. Crick F (1979) Split genes and RNA splicing. Science 204:264–271PubMedCrossRefGoogle Scholar
  19. Cusack BP, Wolfe KH (2005) Changes in alternative splicing of human and mouse genes are accompanied by faster evolution of constitutive exons. Mol Biol Evol 22:2198–2208PubMedCrossRefGoogle Scholar
  20. Davuluri RV, Suzuki Y, Sugano S, Plass C, Huang TH (2008) The functional consequences of alternative promoter use in mammalian genomes. Trends Genet 24:167–177PubMedCrossRefGoogle Scholar
  21. DeLuca DS, Levin JZ, Sivachenko A, Fennell T, Nazaire MD et al (2012) RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics 28:1530–1532PubMedCentralPubMedCrossRefGoogle Scholar
  22. Dibb NJ (1991) Proto-splice site model of intron origin. J Theor Biol 151:405–416PubMedCrossRefGoogle Scholar
  23. Dillman AA, Hauser DN, Gibbs JR, Nalls MA, McCoy MK et al (2013) mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex. Nat Neurosci 16:499–506PubMedCentralPubMedCrossRefGoogle Scholar
  24. Dominski Z, Kole R (1993) Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci USA 90:8673–8677PubMedCentralPubMedCrossRefGoogle Scholar
  25. Doolittle RF (1991) Counting and discounting the universe of exons. Science 253:677–680PubMedCrossRefGoogle Scholar
  26. Duan S, Huang RS, Zhang W, Mi S, Bleibel WK et al (2009) Expression and alternative splicing of folate pathway genes in HapMap lymphoblastoid cell lines. Pharmacogenomics 10:549–563PubMedCentralPubMedCrossRefGoogle Scholar
  27. ENCODE Project Consortium (2004) The ENCODE (ENCyclopedia Of DNA Elements) project. Science 306:636–640CrossRefGoogle Scholar
  28. ENCODE Project Consortium (2011) A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 9:e1001046CrossRefGoogle Scholar
  29. Ergun A, Doran G, Costello JC, Paik HH, Collins JJ et al (2013) Differential splicing across immune system lineages. Proc Natl Acad Sci USA 110:14324–14329PubMedCentralPubMedCrossRefGoogle Scholar
  30. Fairbrother WG, Yeh RF, Sharp PA, Burge CB (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297:1007–1013PubMedCrossRefGoogle Scholar
  31. Foissac S, Sammeth M (2007) ASTALAVISTA: dynamic and flexible analysis of alternative splicing events in custom gene datasets. Nucleic Acids Res 35:W297–W299PubMedCentralPubMedCrossRefGoogle Scholar
  32. Frankish A, Mudge JM, Thomas M, Harrow J (2012) The importance of identifying alternative splicing in vertebrate genome annotation. Database (Oxford) 2012:bas014CrossRefGoogle Scholar
  33. Gamazon ER, Duan S, Zhang W, Huang RS, Kistner EO et al (2010) PACdb: a database for cell-based pharmacogenomics. Pharmacogenet Genomics 20:269–273PubMedCentralPubMedGoogle Scholar
  34. Garcia-Blanco MA (2006) Alternative splicing: therapeutic target and tool. Prog Mol Subcell Biol 44:47–64PubMedCrossRefGoogle Scholar
  35. Gilbert W (1978) Why genes in pieces? Nature 271:501PubMedCrossRefGoogle Scholar
  36. GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580–585CrossRefGoogle Scholar
  37. Han H, Irimia M, Ross PJ, Sung HK, Alipanahi B et al (2013) MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498:241–245PubMedCentralPubMedCrossRefGoogle Scholar
  38. Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M et al (2012) GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 22:1760–1774PubMedCentralPubMedCrossRefGoogle Scholar
  39. Hermiston ML, Xu Z, Majeti R, Weiss A (2002) Reciprocal regulation of lymphocyte activation by tyrosine kinases and phosphatases. J Clin Invest 109:9–14PubMedCentralPubMedCrossRefGoogle Scholar
  40. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP et al (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367PubMedCentralPubMedCrossRefGoogle Scholar
  41. Hogg M, Paro S, Keegan LP, O’Connell MA (2011) RNA editing by mammalian ADARs. Adv Genet 73:87–120PubMedCrossRefGoogle Scholar
  42. Hubbard T, Barker D, Birney E, Cameron G, Chen Y et al (2002) The Ensembl genome database project. Nucleic Acids Res 30:38–41PubMedCentralPubMedCrossRefGoogle Scholar
  43. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA et al (2002) A stem cell molecular signature. Science 298:601–604PubMedCrossRefGoogle Scholar
  44. Jacobsen M, Hoffmann S, Cepok S, Stei S, Ziegler A et al (2002) A novel mutation in PTPRC interferes with splicing and alters the structure of the human CD45 molecule. Immunogenetics 54:158–163PubMedCrossRefGoogle Scholar
  45. Jia G, Fu Y, He C (2013) Reversible RNA adenosine methylation in biological regulation. Trends Genet 29:108–115PubMedCentralPubMedCrossRefGoogle Scholar
  46. Kalsotra A, Xiao X, Ward AJ, Castle JC, Johnson JM et al (2008) A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc Natl Acad Sci USA 105:20333–20338PubMedCentralPubMedCrossRefGoogle Scholar
  47. Katz Y, Wang ET, Airoldi EM, Burge CB (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7:1009–1015PubMedCentralPubMedCrossRefGoogle Scholar
  48. Kim P, Kim N, Lee Y, Kim B, Shin Y et al (2005) ECgene: genome annotation for alternative splicing. Nucleic Acids Res 33:D75–D79PubMedCentralPubMedCrossRefGoogle Scholar
  49. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D et al (2009) Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol 8:918–928PubMedCentralPubMedCrossRefGoogle Scholar
  50. Koo T, Wood MJ (2013) Clinical trials using antisense oligonucleotides in duchenne muscular dystrophy. Hum Gene Ther 24:479–488PubMedCrossRefGoogle Scholar
  51. Kwan T, Benovoy D, Dias C, Gurd S, Serre D et al (2007) Heritability of alternative splicing in the human genome. Genome Res 17:1210–1218PubMedCentralPubMedCrossRefGoogle Scholar
  52. Kwan T, Benovoy D, Dias C, Gurd S, Provencher C et al (2008) Genome-wide analysis of transcript isoform variation in humans. Nat Genet 40:225–231PubMedCrossRefGoogle Scholar
  53. Lee Y, Gamazon ER, Rebman E, Lee S, Dolan ME et al (2012) Variants affecting exon skipping contribute to complex traits. PLoS Genet 8:e1002998PubMedCentralPubMedCrossRefGoogle Scholar
  54. Li Q, Lee JA, Black DL (2007) Neuronal regulation of alternative pre-mRNA splicing. Nat Rev Neurosci 8:819–831PubMedCrossRefGoogle Scholar
  55. Licatalosi DD, Darnell RB (2010) RNA processing and its regulation: global insights into biological networks. Nat Rev Genet 11:75–87PubMedCentralPubMedCrossRefGoogle Scholar
  56. Lutz CS (2008) Alternative polyadenylation: a twist on mRNA 3′ end formation. ACS Chem Biol 3:609–617PubMedCrossRefGoogle Scholar
  57. Martinez NM, Pan Q, Cole BS, Yarosh CA, Babcock GA et al (2012) Alternative splicing networks regulated by signaling in human T cells. RNA 18:1029–1040PubMedCentralPubMedCrossRefGoogle Scholar
  58. Merkin J, Russell C, Chen P, Burge CB (2012) Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338:1593–1599PubMedCentralPubMedCrossRefGoogle Scholar
  59. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS et al (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9:1415–1423PubMedCrossRefGoogle Scholar
  60. Modrek B, Lee CJ (2003) Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nat Genet 34:177–180PubMedCrossRefGoogle Scholar
  61. Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C et al (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464:773–777PubMedCrossRefGoogle Scholar
  62. Moroy T, Heyd F (2007) The impact of alternative splicing in vivo: mouse models show the way. RNA 13:1155–1171PubMedCentralPubMedCrossRefGoogle Scholar
  63. Nakata K, Lipska BK, Hyde TM, Ye T, Newburn EN et al (2009) DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci USA 106:15873–15878PubMedCentralPubMedCrossRefGoogle Scholar
  64. Pagani F, Buratti E, Stuani C, Romano M, Zuccato E et al (2000) Splicing factors induce cystic fibrosis transmembrane regulator exon 9 skipping through a nonevolutionary conserved intronic element. J Biol Chem 275:21041–21047PubMedCrossRefGoogle Scholar
  65. Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P et al (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 365:1384–1395PubMedCentralPubMedCrossRefGoogle Scholar
  66. Papasaikas P, Valcarcel J (2012) Evolution. Splicing in 4D. Science 338:1547–1548PubMedCrossRefGoogle Scholar
  67. Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE et al (2010a) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464:768–772PubMedCentralPubMedCrossRefGoogle Scholar
  68. Pickrell JK, Pai AA, Gilad Y, Pritchard JK (2010b) Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet 6:e1001236PubMedCentralPubMedCrossRefGoogle Scholar
  69. Planet E, Attolini CS, Reina O, Flores O, Rossell D (2012) htSeqTools: high-throughput sequencing quality control, processing and visualization in R. Bioinformatics 28:589–590PubMedCrossRefGoogle Scholar
  70. Pritsker M, Doniger TT, Kramer LC, Westcot SE, Lemischka IR (2005) Diversification of stem cell molecular repertoire by alternative splicing. Proc Natl Acad Sci USA 102:14290–14295PubMedCentralPubMedCrossRefGoogle Scholar
  71. Pruitt KD, Maglott DR (2001) RefSeq and LocusLink: NCBI gene-centered resources. Nucleic Acids Res 29:137–140PubMedCentralPubMedCrossRefGoogle Scholar
  72. Qiu WG, Schisler N, Stoltzfus A (2004) The evolutionary gain of spliceosomal introns: sequence and phase preferences. Mol Biol Evol 21:1252–1263PubMedCrossRefGoogle Scholar
  73. Roberts JM, Ennajdaoui H, Edmondson C, Wirth B, Sanford J et al (2013) Splicing factor TRA2B is required for neural progenitor survival. J Comp Neurol 522(2):372–392CrossRefGoogle Scholar
  74. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES et al (2011) Integrative genomics viewer. Nat Biotechnol 29:24–26PubMedCentralPubMedCrossRefGoogle Scholar
  75. Schwartz SH, Silva J, Burstein D, Pupko T, Eyras E et al (2008) Large-scale comparative analysis of splicing signals and their corresponding splicing factors in eukaryotes. Genome Res 18:88–103PubMedCentralPubMedCrossRefGoogle Scholar
  76. Schwartz S, Meshorer E, Ast G (2009) Chromatin organization marks exon–intron structure. Nat Struct Mol Biol 16:990–995PubMedCrossRefGoogle Scholar
  77. Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33:787–791PubMedCrossRefGoogle Scholar
  78. St Clair D, Blackwood D, Muir W, Carothers A, Walker M et al (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336:13–16PubMedCrossRefGoogle Scholar
  79. Stranger BE, Forrest MS, Clark AG, Minichiello MJ, Deutsch S et al (2005) Genome-wide associations of gene expression variation in humans. PLoS Genet 1:e78PubMedCentralPubMedCrossRefGoogle Scholar
  80. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP et al (2007) Population genomics of human gene expression. Nat Genet 39:1217–1224PubMedCentralPubMedCrossRefGoogle Scholar
  81. Sugnet CW, Kent WJ, Ares M Jr, Haussler D (2004) Transcriptome and genome conservation of alternative splicing events in humans and mice. Pac Symp Biocomput 2004:66–77Google Scholar
  82. Thorn CF, Klein TE, Altman RB (2005) PharmGKB: the pharmacogenetics and pharmacogenomics knowledge base. Methods Mol Biol 311:179–191PubMedGoogle Scholar
  83. Tilgner H, Nikolaou C, Althammer S, Sammeth M, Beato M et al (2009) Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol 16:996–1001PubMedCrossRefGoogle Scholar
  84. Trapnell C, Roberts A, Goff L, Pertea G, Kim D et al (2012) Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 7:562–578PubMedCentralPubMedCrossRefGoogle Scholar
  85. Vandiedonck C, Taylor MS, Lockstone HE, Plant K, Taylor JM et al (2011) Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex. Genome Res 21:1042–1054PubMedCentralPubMedCrossRefGoogle Scholar
  86. Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14:802–813PubMedCentralPubMedCrossRefGoogle Scholar
  87. Wang Z, Rolish ME, Yeo G, Tung V, Mawson M et al (2004) Systematic identification and analysis of exonic splicing silencers. Cell 119:831–845PubMedCrossRefGoogle Scholar
  88. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476PubMedCentralPubMedCrossRefGoogle Scholar
  89. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63PubMedCentralPubMedCrossRefGoogle Scholar
  90. Wang Y, Ma M, Xiao X, Wang Z (2012) Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules. Nat Struct Mol Biol 19:1044–1052PubMedCentralPubMedCrossRefGoogle Scholar
  91. Wong MS, Chen L, Foster C, Kainthla R, Shay JW et al (2013) Regulation of telomerase alternative splicing: a target for chemotherapy. Cell Rep 3:1028–1035PubMedCentralPubMedCrossRefGoogle Scholar
  92. Xing Y, Lee C (2005) Evidence of functional selection pressure for alternative splicing events that accelerate evolution of protein subsequences. Proc Natl Acad Sci USA 102:13526–13531PubMedCentralPubMedCrossRefGoogle Scholar
  93. Xu X, Yang D, Ding JH, Wang W, Chu PH et al (2005) ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation–contraction coupling in cardiac muscle. Cell 120:59–72PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Section of Genetic Medicine, Department of MedicineThe University of ChicagoChicagoUSA
  2. 2.Institute of Genomics and Systems BiologyThe University of ChicagoChicagoUSA

Personalised recommendations