Alternative splicing

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Alternative splicing is the process that occurs in eukaryotes in which the splicing process of a pre-mRNA transcribed from one gene can lead to different mature mRNA molecules and therefore to different proteins. Also viruses have adapted to this biochemical process when using the protein biosynthesis apparatus.

When the pre-mRNA has been transcribed from the DNA, it includes several introns and exons. In nematodes, the mean is 4-5 exons and introns; in the fruit fly Drosophila there can be more than 100 introns and exons in one transcribed pre-mRNA. But introns and exons are not yet determined at this stage. This decision is made during the splicing process. The regulation and selection of splice sites is done by Serine/Arginine-residue proteins, or SR proteins. The use of alternative splicing factors leads to a modification of the definition of a "gene". Some have proposed that a gene should be considered as a twofold information structure:

  • A DNA sequence coding for the pre-mRNA
  • An additional DNA code or other regulating process, which regulates the alternative splicing.

There are four known modes of alternative splicing:

  • Alternative selection of promoters: this is the only method of splicing which can produce an alternative N-terminus domain in proteins. In this case, different sets of promoters can be spliced with certain sets of other exons.
  • Alternative selection of cleavage/polyadenylation sites: this is the only method of splicing which can produce an alternative C-terminus domain in proteins. In this case, different sets of polyadenylation sites can be spliced with the other exons.
  • Intron retaining mode: in this case, instead of splicing out an intron, the intron is retained in the mRNA transcript. However, the intron must be properly encoding for amino acids. The intron's code must be properly expressible, otherwise a stop codon or a shift in the reading frame will cause the protein to be non-functional.
  • Exon cassette mode: in this case, certain exons are spliced out to alter the sequence of amino acids in the expressed protein.
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Importance in molecular genetics

Alternative splicing is of great importance to genetics - it invalidates the old theory of one DNA sequence coding for one polypeptide (the "one-gene-one-protein" hypothesis). External information is needed in order to decide which polypeptide is produced, given a DNA sequence and pre-mRNA. (This does not necessarily negate the central dogma of molecular biology which is about the flow of information from genes to proteins). Since the methods of regulation are inherited, the interpretation of a mutation may be changed.

It has been proposed that for eukaryotes it was a very important step towards higher efficiency, because information can be stored much more economically. Several proteins can be encoded in a DNA sequence whose length would only be enough for two proteins in the prokaryote way of coding. Others have noted that it is unnecessary to change the DNA of a gene for the evolution of a new protein. Instead, a new way of regulation could lead to the same effect, but leaving the code for the established proteins unharmed.

Another speculation is that new proteins could be allowed to evolve much faster than in prokaryotes. Furthermore, they are based on hitherto functional amino acid subchains. This may allow for a higher probability for a functional new protein. Therefore the adaptation to new environments can be much faster - with fewer generations - than in prokaryotes. This might have been one very important step for multicellular organisms with a longer life cycle.

A common myth is that alternative splicing is responsible for humans supposedly being the most complex animals, saying that humans perform more alternative splicing than the other animals. However, this is not the case. A study conducted on the subject found that "the amount of alternative splicing is comparable, with no large differences between humans and other animals."[1] The "record-holder" for alternative splicing is actually a Drosophila gene with 38 000 splice variants called Dscam.

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References

  1. ^ http://www.nature.com/ng/journal/v30/n1/abs/ng803.html;jsessionid=BF0AED8347574D063F5E347EC693AE83
  2.    Hastings ML, Krainer AR: Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001, 13(3):302-309.
  3.  Sharp PA: Split genes and RNA splicing. Cell 1994, 77(6):805-815.
     
  4.  Brett D, Hanke J, Lehmann G, Haase S, Delbruck S, Krueger S, Reich J, Bork P: EST comparison indicates 38% of human mRNAs contain possible alternative splice forms. FEBS Lett 2000, 474(1):83-86.
     
  5. 4.         Clark F, Thanaraj TA: Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human. Hum Mol Genet 2002, 11(4):451-464.
     
  6. 5.         Kan Z, Rouchka EC, Gish WR, States DJ: Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res 2001, 11(5):889-900.
     
  7. 6.         Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W et al: Initial sequencing and analysis of the human genome. Nature 2001, 409(6822):860-921.
     
  8. 7.         Mironov AA, Fickett JW, Gelfand MS: Frequent alternative splicing of human genes. Genome Res 1999, 9(12):1288-1293.
    8.         Modrek B, Resch A, Grasso C, Lee C: Genome-wide detection of alternative splicing in expressed sequences of human genes.
  9. Nucleic Acids Res 2001, 29(13):2850-2859.
     
  10. 9.         Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM, Armour CD, Santos R, Schadt EE, Stoughton R, Shoemaker DD: Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 2003, 302(5653):2141-2144.
    10.        Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D, Thanaraj TA, Soreq H: Function of alternative splicing. Gene 2005, 344:1-20.
    11.        Garcia-Blanco MA, Baraniak AP, Lasda EL: Alternative splicing in disease and therapy. Nat Biotechnol 2004, 22(5):535-546.
    12.        Xu Q, Lee C: Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res 2003, 31(19):5635-5643.
    13.        Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, Nikaido I, Osato N, Saito R, Suzuki H et al: Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 2002, 420(6915):563-573.
    14.        Zavolan M, Kondo S, Schonbach C, Adachi J, Hume DA, Hayashizaki Y, Gaasterland T: Impact of alternative initiation, splicing, and termination on the diversity of the mRNA transcripts encoded by the mouse transcriptome. Genome Res 2003, 13(6B):1290-1300.
    15.        Ast G: How did alternative splicing evolve? Nat Rev Genet 2004, 5(10):773-782.
    16.        Goodison S, Yoshida K, Churchman M, Tarin D: Multiple intron retention occurs in tumor cell CD44 mRNA processing. Am J Pathol 1998, 153(4):1221-1228.
    17.        Mansilla A, Lopez-Sanchez C, de la Rosa EJ, Garcia-Martinez V, Martinez-Salas E, de Pablo F, Hernandez-Sanchez C: Developmental regulation of a proinsulin messenger RNA generated by intron retention. EMBO Rep 2005, 6(12):1182-1187.
    18.        Galante PA, Sakabe NJ, Kirschbaum-Slager N, de Souza SJ: Detection and evaluation of intron retention events in the human transcriptome. Rna 2004, 10(5):757-765.
    19.        Hiller M, Huse K, Platzer M, Backofen R: Non-EST based prediction of exon skipping and intron retention events using Pfam information. Nucleic Acids Res 2005, 33(17):5611-5621.
    20.        Liu S, Altman RB: Large scale study of protein domain distribution in the context of alternative splicing. Nucleic Acids Res 2003, 31(16):4828-4835.
    21.        Kriventseva EV, Koch I, Apweiler R, Vingron M, Bork P, Gelfand MS, Sunyaev S: Increase of functional diversity by alternative splicing. Trends Genet 2003, 19(3):124-128.
    22.        Venables JP: Aberrant and alternative splicing in cancer. Cancer Res 2004, 64(21):7647-7654.
    23.        Stamm S, Zhu J, Nakai K, Stoilov P, Stoss O, Zhang MQ: An alternative-exon database and its statistical analysis. DNA Cell Biol 2000, 19(12):739-756.
    24.        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(1):189-192.
    25.        He F, Peltz SW, Donahue JL, Rosbash M, Jacobson A: Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1- mutant. Proc Natl Acad Sci U S A 1993, 90(15):7034-7038.
    26.        Li Z, Paulovich AG, Woolford JL, Jr.: Feedback inhibition of the yeast ribosomal protein gene CRY2 is mediated by the nucleotide sequence and secondary structure of CRY2 pre-mRNA. Mol Cell Biol 1995, 15(11):6454-6464.
    27.        Morrison M, Harris KS, Roth MB: smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1997, 94(18):9782-9785.
    28.        Mitrovich QM, Anderson P: Unproductively spliced ribosomal protein mRNAs are natural targets of mRNA surveillance in C. elegans. Genes Dev 2000, 14(17):2173-2184.
    29.        Cuccurese M, Russo G, Russo A, Pietropaolo C: Alternative splicing and nonsense-mediated mRNA decay regulate mammalian ribosomal gene expression. Nucleic Acids Res 2005, 33(18):5965-5977.
    30.        Skandalis A, Uribe E: A survey of splice variants of the human hypoxanthine phosphoribosyl transferase and DNA polymerase beta genes: products of alternative or aberrant splicing? Nucleic Acids Res 2004, 32(22):6557-6564.
    31.        Lejeune F, Maquat LE: Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 2005, 17(3):309-315.
    32.        Kim N, Shin S, Lee S: ECgene: genome-based EST clustering and gene modeling for alternative splicing. Genome Res 2005, 15(4):566-576.
    33.        Kim P, Kim N, Lee Y, Kim B, Shin Y, Lee S: ECgene: genome annotation for alternative splicing. Nucleic Acids Res 2005, 33(Database issue):D75-79.
    34.        Bateman A, Coin L, Durbin R, Finn RD, Hollich V, Griffiths-Jones S, Khanna A, Marshall M, Moxon S, Sonnhammer EL et al: The Pfam protein families database. Nucleic Acids Res 2004, 32(Database issue):D138-141.
    35.        Droin N, Beauchemin M, Solary E, Bertrand R: Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade. Cancer Res 2000, 60(24):7039-7047.
    36.        Horiuchi T, Himeji D, Tsukamoto H, Harashima S, Hashimura C, Hayashi K: Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes. Biochem Biophys Res Commun 2000, 272(3):877-881.
    37.        Waltereit R, Weller M: The role of caspases 9 and 9-short (9S) in death ligand- and drug-induced apoptosis in human astrocytoma cells. Brain Res Mol Brain Res 2002, 106(1-2):42-49.
    38.        Sharov AA, Dudekula DB, Ko MS: Genome-wide assembly and analysis of alternative transcripts in mouse. Genome Res 2005, 15(5):748-754.
    39.        Le Hir H, Charlet-Berguerand N, de Franciscis V, Thermes C: 5'-End RET splicing: absence of variants in normal tissues and intron retention in pheochromocytomas. Oncology 2002, 63(1):84-91.
    40.        Sampson ND, Hewitt JE: SF4 and SFRS14, two related putative splicing factors on human chromosome 19p13.11. Gene 2003, 305(1):91-100.
    41.        Jiang ZH, Wu JY: Alternative splicing and programmed cell death. Proc Soc Exp Biol Med 1999, 220(2):64-72.
    42.        Wu JY, Tang H, Havlioglu N: Alternative pre-mRNA splicing and regulation of programmed cell death. Prog Mol Subcell Biol 2003, 31:153-185.
    43.        Lopez AJ: Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu Rev Genet 1998, 32:279-305.
    44.        Hui L, Zhang X, Wu X, Lin Z, Wang Q, Li Y, Hu G: Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment. Oncogene 2004, 23(17):3013-3023.
    45.        Koslowski M, Tureci O, Bell C, Krause P, Lehr HA, Brunner J, Seitz G, Nestle FO, Huber C, Sahin U: Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res 2002, 62(22):6750-6755.
    46.        Nagy E, Maquat LE: A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci 1998, 23(6):198-199.
    47.       Wagner E, Lykke-Andersen J: mRNA surveillance: the perfect persist. J Cell Sci 2002, 115(Pt 15):3033-3038.
    48.        Conti E, Izaurralde E: Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 2005, 17(3):316-325.
    49.        Baker KE, Parker R: Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol 2004, 16(3):293-299.
    50.        He F, Li X, Spatrick P, Casillo R, Dong S, Jacobson A: Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5' to 3' mRNA decay pathways in yeast. Mol Cell 2003, 12(6):1439-1452.
    51.        Lelivelt MJ, Culbertson MR: Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome. Mol Cell Biol 1999, 19(10):6710-6719.
    52.        Hillman RT, Green RE, Brenner SE: An unappreciated role for RNA surveillance. Genome Biol 2004, 5(2):R8.
    53.        Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC: Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 2004, 36(10):1073-1078.
    1.        Hastings ML, Krainer AR: Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001, 13(3):302-309.
    2.         Sharp PA: Split genes and RNA splicing. Cell 1994, 77(6):805-815.
    3.         Brett D, Hanke J, Lehmann G, Haase S, Delbruck S, Krueger S, Reich J, Bork P: EST comparison indicates 38% of human mRNAs contain possible alternative splice forms. FEBS Lett 2000, 474(1):83-86.
    4.         Clark F, Thanaraj TA: Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human. Hum Mol Genet 2002, 11(4):451-464.
    5.         Kan Z, Rouchka EC, Gish WR, States DJ: Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. Genome Res 2001, 11(5):889-900.
    6.         Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W et al: Initial sequencing and analysis of the human genome. Nature 2001, 409(6822):860-921.
    7.         Mironov AA, Fickett JW, Gelfand MS: Frequent alternative splicing of human genes. Genome Res 1999, 9(12):1288-1293.
    8.         Modrek B, Resch A, Grasso C, Lee C: Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res 2001, 29(13):2850-2859.
    9.         Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM, Armour CD, Santos R, Schadt EE, Stoughton R, Shoemaker DD: Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 2003, 302(5653):2141-2144.
    10.        Stamm S, Ben-Ari S, Rafalska I, Tang Y, Zhang Z, Toiber D, Thanaraj TA, Soreq H: Function of alternative splicing. Gene 2005, 344:1-20.
    11.        Garcia-Blanco MA, Baraniak AP, Lasda EL: Alternative splicing in disease and therapy. Nat Biotechnol 2004, 22(5):535-546.
    12.        Xu Q, Lee C: Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences. Nucleic Acids Res 2003, 31(19):5635-5643.
    13.        Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, Nikaido I, Osato N, Saito R, Suzuki H et al: Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 2002, 420(6915):563-573.
    14.        Zavolan M, Kondo S, Schonbach C, Adachi J, Hume DA, Hayashizaki Y, Gaasterland T: Impact of alternative initiation, splicing, and termination on the diversity of the mRNA transcripts encoded by the mouse transcriptome. Genome Res 2003, 13(6B):1290-1300.
    15.        Ast G: How did alternative splicing evolve? Nat Rev Genet 2004, 5(10):773-782.
    16.        Goodison S, Yoshida K, Churchman M, Tarin D: Multiple intron retention occurs in tumor cell CD44 mRNA processing. Am J Pathol 1998, 153(4):1221-1228.
    17.        Mansilla A, Lopez-Sanchez C, de la Rosa EJ, Garcia-Martinez V, Martinez-Salas E, de Pablo F, Hernandez-Sanchez C: Developmental regulation of a proinsulin messenger RNA generated by intron retention. EMBO Rep 2005, 6(12):1182-1187.
    18.        Galante PA, Sakabe NJ, Kirschbaum-Slager N, de Souza SJ: Detection and evaluation of intron retention events in the human transcriptome. Rna 2004, 10(5):757-765.
    19.        Hiller M, Huse K, Platzer M, Backofen R: Non-EST based prediction of exon skipping and intron retention events using Pfam information. Nucleic Acids Res 2005, 33(17):5611-5621.
    20.        Liu S, Altman RB: Large scale study of protein domain distribution in the context of alternative splicing. Nucleic Acids Res 2003, 31(16):4828-4835.
    21.        Kriventseva EV, Koch I, Apweiler R, Vingron M, Bork P, Gelfand MS, Sunyaev S: Increase of functional diversity by alternative splicing. Trends Genet 2003, 19(3):124-128.
    22.        Venables JP: Aberrant and alternative splicing in cancer. Cancer Res 2004, 64(21):7647-7654.
    23.        Stamm S, Zhu J, Nakai K, Stoilov P, Stoss O, Zhang MQ: An alternative-exon database and its statistical analysis. DNA Cell Biol 2000, 19(12):739-756.
    24.        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(1):189-192.
    25.        He F, Peltz SW, Donahue JL, Rosbash M, Jacobson A: Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1- mutant. Proc Natl Acad Sci U S A 1993, 90(15):7034-7038.
    26.        Li Z, Paulovich AG, Woolford JL, Jr.: Feedback inhibition of the yeast ribosomal protein gene CRY2 is mediated by the nucleotide sequence and secondary structure of CRY2 pre-mRNA. Mol Cell Biol 1995, 15(11):6454-6464.
    27.        Morrison M, Harris KS, Roth MB: smg mutants affect the expression of alternatively spliced SR protein mRNAs in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1997, 94(18):9782-9785.
    28.        Mitrovich QM, Anderson P: Unproductively spliced ribosomal protein mRNAs are natural targets of mRNA surveillance in C. elegans. Genes Dev 2000, 14(17):2173-2184.
    29.        Cuccurese M, Russo G, Russo A, Pietropaolo C: Alternative splicing and nonsense-mediated mRNA decay regulate mammalian ribosomal gene expression. Nucleic Acids Res 2005, 33(18):5965-5977.
    30.        Skandalis A, Uribe E: A survey of splice variants of the human hypoxanthine phosphoribosyl transferase and DNA polymerase beta genes: products of alternative or aberrant splicing? Nucleic Acids Res 2004, 32(22):6557-6564.
    31.        Lejeune F, Maquat LE: Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol 2005, 17(3):309-315.
    32.        Kim N, Shin S, Lee S: ECgene: genome-based EST clustering and gene modeling for alternative splicing. Genome Res 2005, 15(4):566-576.
    33.        Kim P, Kim N, Lee Y, Kim B, Shin Y, Lee S: ECgene: genome annotation for alternative splicing. Nucleic Acids Res 2005, 33(Database issue):D75-79.
    34.        Bateman A, Coin L, Durbin R, Finn RD, Hollich V, Griffiths-Jones S, Khanna A, Marshall M, Moxon S, Sonnhammer EL et al: The Pfam protein families database. Nucleic Acids Res 2004, 32(Database issue):D138-141.
    35.        Droin N, Beauchemin M, Solary E, Bertrand R: Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade. Cancer Res 2000, 60(24):7039-7047.
    36.        Horiuchi T, Himeji D, Tsukamoto H, Harashima S, Hashimura C, Hayashi K: Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes. Biochem Biophys Res Commun 2000, 272(3):877-881.
    37.        Waltereit R, Weller M: The role of caspases 9 and 9-short (9S) in death ligand- and drug-induced apoptosis in human astrocytoma cells. Brain Res Mol Brain Res 2002, 106(1-2):42-49.
    38.        Sharov AA, Dudekula DB, Ko MS: Genome-wide assembly and analysis of alternative transcripts in mouse. Genome Res 2005, 15(5):748-754.
    39.        Le Hir H, Charlet-Berguerand N, de Franciscis V, Thermes C: 5'-End RET splicing: absence of variants in normal tissues and intron retention in pheochromocytomas. Oncology 2002, 63(1):84-91.
    40.        Sampson ND, Hewitt JE: SF4 and SFRS14, two related putative splicing factors on human chromosome 19p13.11. Gene 2003, 305(1):91-100.
    41.        Jiang ZH, Wu JY: Alternative splicing and programmed cell death. Proc Soc Exp Biol Med 1999, 220(2):64-72.
    42.        Wu JY, Tang H, Havlioglu N: Alternative pre-mRNA splicing and regulation of programmed cell death. Prog Mol Subcell Biol 2003, 31:153-185.
    43.        Lopez AJ: Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu Rev Genet 1998, 32:279-305.
    44.        Hui L, Zhang X, Wu X, Lin Z, Wang Q, Li Y, Hu G: Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment. Oncogene 2004, 23(17):3013-3023.
    45.        Koslowski M, Tureci O, Bell C, Krause P, Lehr HA, Brunner J, Seitz G, Nestle FO, Huber C, Sahin U: Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res 2002, 62(22):6750-6755.
    46.        Nagy E, Maquat LE: A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci 1998, 23(6):198-199.
    47.       Wagner E, Lykke-Andersen J: mRNA surveillance: the perfect persist. J Cell Sci 2002, 115(Pt 15):3033-3038.
    48.        Conti E, Izaurralde E: Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 2005, 17(3):316-325.
    49.        Baker KE, Parker R: Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol 2004, 16(3):293-299.
    50.        He F, Li X, Spatrick P, Casillo R, Dong S, Jacobson A: Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5' to 3' mRNA decay pathways in yeast. Mol Cell 2003, 12(6):1439-1452.
    51.        Lelivelt MJ, Culbertson MR: Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome. Mol Cell Biol 1999, 19(10):6710-6719.
    52.        Hillman RT, Green RE, Brenner SE: An unappreciated role for RNA surveillance. Genome Biol 2004, 5(2):R8.
    53.        Mendell JT, Sharifi NA, Meyers JL, Martinez-Murillo F, Dietz HC: Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nat Genet 2004, 36(10):1073-1078.

[edit]

 

External links

  • HHMI article on alternative splicing
  • Study on alternative splicing and complexity
  • Stamms-lab.net: Research Group dealing with alternative Splicing issues and mis-splicing in human diseases
  • Alternative Splicing of ion channels in the brain, connected to mental and neurological diseases
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