Abstract
Alternative pre-mRNA splicing is an integral part of gene regulation in eukaryotes. Here we provide a basic overview of the various types of alternative splicing, as well as the functional role, highlighting how alternative splicing varies across phylogeny. Regulated alternative splicing can affect protein function and ultimately impact biological outcomes. We examine the possibility that portions of alternatively spliced transcripts are the result of stochastic processes rather than regulated. We discuss the implications of misregulated alternative splicing and explore of the role of alternative splicing in human disease.
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References
McGuire AM, Pearson MD, Neafsey DE et al (2008) Cross-kingdom patterns of alternative splicing and splice recognition. Genome Biol 9:R50
Wang B, Guo G, Wang C et al (2010) Survey of the transcriptome of Aspergillus oryzae via massively parallel mRNA sequencing. Nucleic Acids Res 38:5075–5087
Filichkin SA, Priest HD, Givan SA et al (2010) Genome-wide mapping of alternative splicing in Arabidopsis thaliana. Genome Res 20:45–58
Wang B-B, Brendel V (2006) Genomewide comparative analysis of alternative splicing in plants. Proc Natl Acad Sci U S A 103:7175–7180
Kalyna M, Simpson CG, Syed NH et al (2012) Alternative splicing and nonsense-mediated decay modulate expression of important regulatory genes in Arabidopsis. Nucleic Acids Res 40:2454–2469
Gan X, Stegle O, Behr J et al (2011) Multiple reference genomes and transcriptomes for Arabidopsis thaliana. Nature 477:419–423
Ramani AK, Calarco JA, Pan Q et al (2011) Genome-wide analysis of alternative splicing in Caenorhabditis elegans. Genome Res 21:342–348
Yook K, Harris TW, Bieri T et al (2012) WormBase 2012: more genomes, more data, new website. Nucleic Acids Res 40:735–741
Gerstein MB, Lu ZJ, Van Nostrand EL et al (2010) Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330:1775–1787
Graveley BR, Brooks AN, Carlson JW et al (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471:473–479
Venables JP, Tazi J, Juge F (2012) Regulated functional alternative splicing in Drosophila. Nucleic Acids Res 40:1–10
Salz HK (2011) Sex determination in insects: a binary decision based on alternative splicing. Curr Opin Genet Dev 21:395–400
Katz Y, Wang ET, Airoldi EM et al (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7:1009–1015
Frankish A, Mudge JM, Thomas M et al (2012) The importance of identifying alternative splicing in vertebrate genome annotation. Database 2012:bas014. doi:10.1093/database/bas014
Pan Q, Shai O, Lee JL et al (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40:1413–1415
Wang ET, Sandberg R, Luo S et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476
Yeo G, Holste D, Kreiman G et al (2004) Variation in alternative splicing across human tissues. Genome Biol 5:R74
Djebali S, Davis CA, Merkel A et al (2012) Landscape of transcription in human cells. Nature 489:101–108
Pickrell JK, Pai AA, Gilad Y et al (2010) Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet 6:e1001236
Sugnet CW, Kent WJ, Ares M Jr et al (2004) Transcriptome and genome conservation of alternative splicing events in humans and mice. Pac Symp Biocomput 9:66–77
Sorek R, Shamir R, Ast G (2004) How prevalent is functional alternative splicing in the human genome? Trends Genet 20:68–71
Merkin J, Russell C, Chen P et al (2012) Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338:1593–1599
Barbosa-Morais NL, Irimia M, Pan Q et al (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–1593
Tress ML, Martelli PL, Frankish A et al (2007) The implications of alternative splicing in the ENCODE protein complement. Proc Natl Acad Sci U S A 104:5495–5500
Tress ML, Bodenmiller B, Aebersold R et al (2008) Proteomics studies confirm the presence of alternative protein isoforms on a large scale. Genome Biol 9:R162
Kelemen O, Convertini P, Zhang Z et al (2012) Function of alternative splicing. Gene 514:1–30
Gabut M, Samavarchi-Tehrani P, Wang X et al (2011) An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell 147:132–146
Salomonis N, Schlieve CR, Pereira L et al (2010) Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation. Proc Natl Acad Sci U S A 107:10514–10519
Sunmonu NA, Li K, Li JYH (2011) Numerous isoforms of Fgf8 reflect its multiple roles in the developing brain. J Cell Physiol 226:1722–1726
Fletcher RB, Baker JC, Harland RM (2006) FGF8 spliceforms mediate early mesoderm and posterior neural tissue formation in Xenopus. Development 133:1703–1714
Guo Q, Li JYH (2007) Distinct functions of the major Fgf8 spliceform, Fgf8b, before and during mouse gastrulation. Development 134:2251–2260
Itoh N (2007) The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biol Pharm Bull 30:1819–1825
Lewis BP, Green RE, Brenner SE (2002) Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proc Natl Acad Sci U S A 100:189–192
Pan Q, Saltzman AL, Kim YK et al (2006) Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression. Genes Dev 20:153–158
Baek D, Green P (2005) Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing. Proc Natl Acad Sci U S A 102:12813–12818
Lareau LF, Brooks AN, Soergel D et al (2007) The coupling of alternative splicing and nonsense mediated mRNA decay. In: Blencowe B, Graveley B (eds) Alternative splicing in the postgenomic era. Landes Biosciences, Austin, TX, pp 190–211
Hyvönen MT, Uimari A, Keinänen TA et al (2006) Polyamine-regulated unproductive splicing and translation of spermidine/spermine N1-acetyltransferase. RNA 12:1569–1582
Wang G-S, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761
Venables JP (2004) Aberrant and alternative splicing in cancer. Cancer Res 64:7647–7654
Biamonti G, Bonomi S, Gallo S et al (2012) Making alternative splicing decisions during epithelial-to-mesenchymal transition (EMT). Cell Mol Life Sci 69:2515–2526
Singh RK, Cooper TA (2012) Pre-mRNA splicing in disease and therapeutics. Trends Mol Med 18:472–482
Mills JD, Janitz M (2012) Alternative splicing of mRNA in the molecular pathology of neurodegenerative diseases. Neurobiol Aging 33:11–24
Poulos MG, Batra R, Charizanis K (2011) Developments in RNA splicing and disease. Cold Spring Harb Perspect Biol 3:a000778
Klamt B, Koziell A, Poulat F et al (1998) Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet 7:709–714
Hammes A, Guo JK, Lutsch G et al (2001) Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106:319–329
Lee SB, Huang K, Palmer R et al (1999) The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 98:663–673
Reynolds PA, Smolen GA, Palmer RE et al (2003) Identification of a DNA-binding site and transcriptional target for the EWS-WT1(+KTS) oncoprotein. Genes Dev 17:2094–2107
Morrison AA, Viney RL, Ladomery MR (2008) The post-transcriptional roles of WT1, a multifunctional zinc-finger protein. Biochim Biophys Acta 1785:55–62
Huff V (2011) Wilms’ tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer 11:111–121
Chau Y-Y, Hastie ND (2012) The role of Wt1 in regulating mesenchyme in cancer, development, and tissue homeostasis. Trends Genet 28:515–524
Shin C, Manley JL (2004) Cell signalling and the control of pre-mRNA splicing. Nat Rev Mol Cell Biol 5:727–738
Day JW, Ranum LPW (2005) RNA pathogenesis of the myotonic dystrophies. Neuromuscul Disord 15:5–16
Osborne RJ, Thornton CA (2006) RNA-dominant diseases. Hum Mol Genet 15:162–169
Ranum LPW, Day JW (2004) Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet 74:793–804
Cooper TA, Wan L, Dreyfuss G (2009) RNA and disease. Cell 136:777–793
Mahadevan MS (2011) Myotonic muscular dystrophy, RNA toxicity, and the brain: trouble making the connection? Cell Stem Cell 8:349–350
Wang G-S, Kearney DL, De Biasi M et al (2007) Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J Clin Invest 117:2802–2811
Du H, Cline MS, Osborne RJ et al (2010) Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol 17:187–193
Wang ET, Cody NAL, Jog S et al (2012) Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150:710–724
Paul S, Dansithong W, Kim D et al (2006) Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing. EMBO J 25:4271–4283
Koshelev M, Sarma S, Price RE et al (2010) Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum Mol Genet 19:1066–1075
Kino Y, Washizu C, Oma Y et al (2009) MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1. Nucleic Acids Res 37:6477–6490
Mankodi A, Takahashi MP, Jiang H et al (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10:35–44
Darnell RB, Posner JB (2003) Paraneoplastic syndromes involving the nervous system. N Engl J Med 349:1543–1554
Ruggiu M, Herbst R, Kim N et al (2009) Rescuing Z+ agrin splicing in Nova null mice restores synapse formation and unmasks a physiologic defect in motor neuron firing. Proc Natl Acad Sci U S A 106:3513–3518
Ule J, Stefani G, Mele A et al (2006) An RNA map predicting Nova-dependent splicing regulation. Nature 444:580–586
Licatalosi DD, Mele A, Fak JJ et al (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456:464–469
Acknowledgment
Research in the Berglund laboratory is supported by NIH (AR059833) and the Myotonic Dystrophy Foundation.
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Wagner, S.D., Berglund, J.A. (2014). Alternative Pre-mRNA Splicing. In: Hertel, K. (eds) Spliceosomal Pre-mRNA Splicing. Methods in Molecular Biology, vol 1126. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-980-2_4
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DOI: https://doi.org/10.1007/978-1-62703-980-2_4
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