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PMID: 15461793 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Variation in alternative splicing across human tissues.

Genome biology ·Vol. 5 ·No. 10 ·2004-00-00 ·Pages R74

Yeo G, Holste D, Kreiman G, Burge CB

Abstract

Alternative pre-mRNA splicing (AS) is widely used by higher eukaryotes to generate different protein isoforms in specific cell or tissue types. To compare AS events across human tissues, we analyzed the splicing patterns of genomically aligned expressed sequence tags (ESTs) derived from libraries of cDNAs from different tissues. Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most pronounced differences between tissues were seen for the frequencies of alternative 3' splice site and alternative 5' splice site usage, which were about 50 to 100% higher in the liver than in any other human tissue studied. Quantifying differences in splice junction usage, the brain, pancreas, liver and the peripheral nervous system had the most distinctive patterns of AS. Analysis of available microarray expression data showed that the liver had the most divergent pattern of expression of serine-arginine protein and heterogeneous ribonucleoprotein genes compared to the other human tissues studied, possibly contributing to the unusually high frequency of alternative splice site usage seen in liver. Sequence motifs enriched in alternative exons in genes expressed in the brain, testis and liver suggest specific splicing factors that may be important in AS regulation in these tissues. This study distinguishes the human brain, testis and liver as having unusually high levels of AS, highlights differences in the types of AS occurring commonly in different tissues, and identifies candidate cis-regulatory elements and trans-acting factors likely to have important roles in tissue-specific AS in human cells.

MeSH Terms
Alternative Splicing/genetics Brain/metabolism Exons/genetics Expressed Sequence Tags Gene Library Genetic Variation/genetics Humans Liver/metabolism Male Organ Specificity Protein Isoforms/genetics RNA Splice Sites/genetics RNA, Messenger/genetics,metabolism Regulatory Sequences, Nucleic Acid/genetics Testis/metabolism
Chemicals
Protein Isoforms RNA Splice Sites RNA, Messenger
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Yeo Gene
Department of Biology, Center for Biological and Computational Learning, Massachusetts Institute of Technology, Cambridge, MA 02319, USA. geneyeo@mit.edu
Holste Dirk
Kreiman Gabriel
Burge Christopher B
References (68)
68 references, click to expand
  1. hnRNP A/B proteins are required for inhibition of HIV-1 pre-mRNA splicing.
    EMBO J. 1999 Jul 15;18(14):4060-7 PMID: 10406810
  2. Alternative splicing in the murine and human FXR1 genes.
    Genomics. 1999 Jul 15;59(2):193-202 PMID: 10409431
  3. A sampling of the yeast proteome.
    Mol Cell Biol. 1999 Nov;19(11):7357-68 PMID: 10523624
  4. Frequent alternative splicing of human genes.
    Genome Res. 1999 Dec;9(12):1288-93 PMID: 10613851
  5. Expression profiles of active genes in human and mouse livers.
    Gene. 1996 Sep 26;174(1):151-8 PMID: 8863742
  6. A comparison of selected mRNA and protein abundances in human liver.
    Electrophoresis. 1997 Mar-Apr;18(3-4):533-7 PMID: 9150937
  7. G triplets located throughout a class of small vertebrate introns enforce intron borders and regulate splice site selection.
    Mol Cell Biol. 1997 Aug;17(8):4562-71 PMID: 9234714
  8. Single molecule profiling of alternative pre-mRNA splicing.
    Science. 2003 Aug 8;301(5634):836-8 PMID: 12907803
  9. Genetic evidence for a Nova regulator of alternative splicing in the brain.
    Neuron. 2000 Feb;25(2):254-6 PMID: 10719879
  10. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability.
    Neuron. 2000 Feb;25(2):359-71 PMID: 10719891
  11. EST comparison indicates 38% of human mRNAs contain possible alternative splice forms.
    FEBS Lett. 2000 May 26;474(1):83-6 PMID: 10828456
  12. Multisite RNA binding and release of polypyrimidine tract binding protein during the regulation of c-src neural-specific splicing.
    Mol Cell. 2000 Jun;5(6):949-57 PMID: 10911989
  13. Selection of alternative 5' splice sites: role of U1 snRNP and models for the antagonistic effects of SF2/ASF and hnRNP A1.
    Mol Cell Biol. 2000 Nov;20(22):8303-18 PMID: 11046128
  14. An alternative-exon database and its statistical analysis.
    DNA Cell Biol. 2000 Dec;19(12):739-56 PMID: 11177572
  15. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing.
    Mol Cell Biol. 2001 Feb;21(4):1285-96 PMID: 11158314
  16. Alternative splicing: increasing diversity in the proteomic world.
    Trends Genet. 2001 Feb;17(2):100-7 PMID: 11173120
  17. Computational analysis of candidate intron regulatory elements for tissue-specific alternative pre-mRNA splicing.
    Nucleic Acids Res. 2001 Jun 1;29(11):2338-48 PMID: 11376152
  18. Genome-wide detection of alternative splicing in expressed sequences of human genes.
    Nucleic Acids Res. 2001 Jul 1;29(13):2850-9 PMID: 11433032
  19. Predicting splice variant from DNA chip expression data.
    Genome Res. 2001 Jul;11(7):1237-45 PMID: 11435406
  20. Strong RNA splicing enhancers identified by a modified method of cycled selection interact with SR protein.
    J Biol Chem. 2001 Sep 7;276(36):33833-9 PMID: 11454855
  21. A computational analysis of sequence features involved in recognition of short introns.
    Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11193-8 PMID: 11572975
  22. Comparative genomic sequence analysis of the FXR gene family: FMR1, FXR1, and FXR2.
    Genomics. 2001 Dec;78(3):169-77 PMID: 11735223
  23. Alternative splicing and genome complexity.
    Nat Genet. 2002 Jan;30(1):29-30 PMID: 11743582
  24. A genomic view of alternative splicing.
    Nat Genet. 2002 Jan;30(1):13-9 PMID: 11753382
  25. SR proteins and hnRNP H regulate the splicing of the HIV-1 tev-specific exon 6D.
    EMBO J. 2002 Feb 15;21(4):845-55 PMID: 11847131
  26. Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human.
    Hum Mol Genet. 2002 Feb 15;11(4):451-64 PMID: 11854178
  27. Large-scale analysis of the human and mouse transcriptomes.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4465-70 PMID: 11904358
  28. Listening to silence and understanding nonsense: exonic mutations that affect splicing.
    Nat Rev Genet. 2002 Apr;3(4):285-98 PMID: 11967553
  29. Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays.
    Science. 2002 May 3;296(5569):907-10 PMID: 11988574
  30. Complementary profiling of gene expression at the transcriptome and proteome levels in Saccharomyces cerevisiae.
    Mol Cell Proteomics. 2002 Apr;1(4):323-33 PMID: 12096114
  31. Predictive identification of exonic splicing enhancers in human genes.
    Science. 2002 Aug 9;297(5583):1007-13 PMID: 12114529
  32. Large-scale proteomic analysis of the human spliceosome.
    Genome Res. 2002 Aug;12(8):1231-45 PMID: 12176931
  33. Genome-wide detection of tissue-specific alternative splicing in the human transcriptome.
    Nucleic Acids Res. 2002 Sep 1;30(17):3754-66 PMID: 12202761
  34. Comprehensive proteomic analysis of the human spliceosome.
    Nature. 2002 Sep 12;419(6903):182-5 PMID: 12226669
  35. Distribution and characterization of regulatory elements in the human genome.
    Genome Res. 2002 Dec;12(12):1827-36 PMID: 12466286
  36. Selecting for functional alternative splices in ESTs.
    Genome Res. 2002 Dec;12(12):1837-45 PMID: 12466287
  37. CD44 in cancer.
    Crit Rev Clin Lab Sci. 2002 Nov;39(6):527-79 PMID: 12484499
  38. Computational analysis and experimental validation of tumor-associated alternative RNA splicing in human cancer.
    Cancer Res. 2003 Feb 1;63(3):655-7 PMID: 12566310
  39. Pre-mRNA splicing and human disease.
    Genes Dev. 2003 Feb 15;17(4):419-37 PMID: 12600935
  40. Positional clustering of differentially expressed genes on human chromosomes 20, 21 and 22.
    Genome Biol. 2003;4(2):P1 PMID: 12620117
  41. Impact of alternative initiation, splicing, and termination on the diversity of the mRNA transcripts encoded by the mouse transcriptome.
    Genome Res. 2003 Jun;13(6B):1290-300 PMID: 12819126
  42. Intronic sequences flanking alternatively spliced exons are conserved between human and mouse.
    Genome Res. 2003 Jul;13(7):1631-7 PMID: 12840041
  43. Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes.
    Bioinformatics. 2003;19 Suppl 1:i118-21 PMID: 12855447
  44. Pre-mRNA splicing: awash in a sea of proteins.
    Mol Cell. 2003 Jul;12(1):5-14 PMID: 12887888
  45. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays.
    Science. 2003 Dec 19;302(5653):2141-4 PMID: 14684825
  46. Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay.
    Mol Cell. 2004 Jan 16;13(1):91-100 PMID: 14731397
  47. In NF1, CFTR, PER3, CARS and SYT7, alternatively included exons show higher conservation of surrounding intron sequences than constitutive exons.
    Eur J Hum Genet. 2004 Feb;12(2):139-49 PMID: 14560314
  48. An unappreciated role for RNA surveillance.
    Genome Biol. 2004;5(2):R8 PMID: 14759258
  49. Transcriptome and genome conservation of alternative splicing events in humans and mice.
    Pac Symp Biocomput. 2004;:66-77 PMID: 14992493
  50. Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment.
    Oncogene. 2004 Apr 15;23(17):3013-23 PMID: 15048092
  51. A gene atlas of the mouse and human protein-encoding transcriptomes.
    Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7 PMID: 15075390
  52. RNA binding specificity of hnRNP A1: significance of hnRNP A1 high-affinity binding sites in pre-mRNA splicing.
    EMBO J. 1994 Mar 1;13(5):1197-204 PMID: 7510636
  53. Exon recognition in vertebrate splicing.
    J Biol Chem. 1995 Feb 10;270(6):2411-4 PMID: 7852296
  54. An intronic (A/U)GGG repeat enhances the splicing of an alternative intron of the chicken beta-tropomyosin pre-mRNA.
    Nucleic Acids Res. 1995 Sep 11;23(17):3501-7 PMID: 7567462
  55. Cell type-specific expression of hnRNP proteins.
    Exp Cell Res. 1995 Nov;221(1):187-96 PMID: 7589244
  56. The developmental consequences of alternate splicing in sex determination and differentiation in Drosophila.
    Dev Biol. 1995 Dec;172(2):353-76 PMID: 8612957
  57. Mechanisms of alternative pre-messenger RNA splicing.
    Annu Rev Biochem. 2003;72:291-336 PMID: 12626338
  58. Alternative splicing in the nervous system: an emerging source of diversity and regulation.
    Biol Psychiatry. 2003 Oct 15;54(8):771-6 PMID: 14550676
  59. CLIP identifies Nova-regulated RNA networks in the brain.
    Science. 2003 Nov 14;302(5648):1212-5 PMID: 14615540
  60. The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream.
    Mol Cell Biol. 1997 Aug;17(8):4667-76 PMID: 9234723
  61. A complex intronic splicing enhancer from the c-src pre-mRNA activates inclusion of a heterologous exon.
    Mol Cell Biol. 1997 Nov;17(11):6537-45 PMID: 9343417
  62. Splicing regulation in neurons: tinkering with cell-specific control.
    Cell. 1998 Mar 20;92(6):709-12 PMID: 9529247
  63. Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors.
    RNA. 1998 Apr;4(4):430-44 PMID: 9630249
  64. Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins.
    Genes Dev. 1998 Jul 1;12(13):1998-2012 PMID: 9649504
  65. A computer program for aligning a cDNA sequence with a genomic DNA sequence.
    Genome Res. 1998 Sep;8(9):967-74 PMID: 9750195
  66. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation.
    Annu Rev Genet. 1998;32:279-305 PMID: 9928482
  67. Control of 3' splice site choice in vivo by ASF/SF2 and hnRNP A1.
    Nucleic Acids Res. 1999 Feb 15;27(4):1126-34 PMID: 9927747
  68. Selection and characterization of pre-mRNA splicing enhancers: identification of novel SR protein-specific enhancer sequences.
    Mol Cell Biol. 1999 Mar;19(3):1705-19 PMID: 10022858
Article Info
Journal
Genome biology
Abbr.
Genome Biol
ISSN
1474-760X
DOI
10.1186/gb-2004-5-10-r74
Email
geneyeo@mit.edu
Published
2004-00-00
Epub
2004-00-13
Pages
R74
Language
English
Region
England
NLM ID
100960660
PMCID
PMC545594
Subset
IM
External Links
PubMed source DOI: 10.1186/gb-2004-5-10-r74 PMC Full Text View journal details
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