期刊论文详细信息
Genome Biology
Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene
Alvis Brazma2  Jennifer Harrow1  Johan Rung2  Adam Frankish1  Mar Gonzàlez-Porta2 
[1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom;European Molecular Biology Laboratory - European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
关键词: RNA-seq;    gene expression;    transcriptome;    splicing;   
Others  :  864155
DOI  :  10.1186/gb-2013-14-7-r70
 received in 2013-01-17, accepted in 2013-07-01,  发布年份 2013
PDF
【 摘 要 】

Background

RNA sequencing has opened new avenues for the study of transcriptome composition. Significant evidence has accumulated showing that the human transcriptome contains in excess of a hundred thousand different transcripts. However, it is still not clear to what extent this diversity prevails when considering the relative abundances of different transcripts from the same gene.

Results

Here we show that, in a given condition, most protein coding genes have one major transcript expressed at significantly higher level than others, that in human tissues the major transcripts contribute almost 85 percent to the total mRNA from protein coding loci, and that often the same major transcript is expressed in many tissues. We detect a high degree of overlap between the set of major transcripts and a recently published set of alternatively spliced transcripts that are predicted to be translated utilizing proteomic data. Thus, we hypothesize that although some minor transcripts may play a functional role, the major ones are likely to be the main contributors to the proteome. However, we still detect a non-negligible fraction of protein coding genes for which the major transcript does not code a protein.

Conclusions

Overall, our findings suggest that the transcriptome from protein coding loci is dominated by one transcript per gene and that not all the transcripts that contribute to transcriptome diversity are equally likely to contribute to protein diversity. This observation can help to prioritize candidate targets in proteomics research and to predict the functional impact of the detected changes in variation studies.

【 授权许可】

   
2013 Gonzàlez-Porta et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20140725083211515.pdf 749KB PDF download
41KB Image download
37KB Image download
18KB Image download
57KB Image download
39KB Image download
【 图 表 】

【 参考文献 】
  • [1]Flicek P, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, Gordon L, Hendrix M, Hourlier T, Johnson N, Kahari AK, Keefe D, Keenan S, Kinsella R, Komorowska M, Koscielny G, Kulesha E, Larsson P, Longden I, McLaren W, Muffato M, Overduin B, Pignatelli M, Pritchard B, Riat HS, et al.: Ensembl 2012. Nucleic Acids Res 2011, 40:D84-D90.
  • [2]Wang Z, Gerstein M, Snyder M: RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009, 10:57-63.
  • [3]Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008, 5:621-628.
  • [4]Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, Baren MJ van, Salzberg SL, Wold BJ, Pachter L: Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010, 28:511-515.
  • [5]Turro E, Su SY, Gonçalves Â, Coin LJM, Richardson S, Lewin A: Haplotype and isoform specific expression estimation using multi-mapping RNA-seq reads. Genome Biol 2011, 12:R13. BioMed Central Full Text
  • [6]Katz Y, Wang ET, Airoldi EM, Burge CB: Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 2010, 7:1009-1015.
  • [7]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.
  • [8]Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB: Alternative isoform regulation in human tissue transcriptomes. Nature 2008, 456:470-476.
  • [9]Tang F, Barbacioru C, Wang Y, Nordman E, Lee C, Xu N, Wang X, Bodeau J, Tuch BB, Siddiqui A, Lao K, Surani MA: mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 2009, 6:377-382.
  • [10]Bland CS, Wang ET, Vu A, David MP, Castle JC, Johnson JM, Burge CB, Cooper TA: Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res 2010, 38:7651-7664.
  • [11]Waks Z, Klein AM, Silver PA: Cell-to-cell variability of alternative RNA splicing. Mol Syst Biol 2011, 7:506.
  • [12]Taneri B, Snyder B, Gaasterland T: Distribution of alternatively spliced transcript isoforms within human and mouse transcriptomes. J OMICS Res 2011, 1:1-5.
  • [13]Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, et al.: Landscape of transcription in human cells. Nature 2012, 489:101-108.
  • [14]Lukk M, Kapushesky M, Nikkilä J, Parkinson H, Goncalves A, Huber W, Ukkonen E, Brazma A: A global map of human gene expression. Nat Biotechnol 2010, 28:322-324.
  • [15]Padhi BK, Pelletier G: Perturbation of myelin basic protein (Mbp) splice variant expression in developing rat cerebellum following perinatal exposure to methylmercury. Toxicol Lett 2012, 213:374-380.
  • [16]Griebel T, Zacher B, Ribeca P, Raineri E, Lacroix V, Guigó R, Sammeth M: Modelling and simulating generic RNA-Seq experiments with the flux simulator. Nucleic Acids Res 2012, 40:10073-10083.
  • [17]Lundberg E, Fagerberg L, Klevebring D, Matic I, Geiger T, Cox J, Algenäs C, Lundeberg J, Mann M, Uhlen M: Defining the transcriptome and proteome in three functionally different human cell lines. Mol Syst Biol 2010, 6:450.
  • [18]Zhao Q, Caballero OL, Davis ID, Jonasch E, Tamboli P, Yung WKA, Weinstein JN, Strausberg RL, Yao J, Shaw K: Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas. Clin Cancer Res 2013, 19:2460-2472.
  • [19]Ezkurdia I, del Pozo A, Frankish A, Rodriguez JM, Harrow J, Ashman K, Valencia A, Tress ML: Comparative proteomics reveals a significant bias toward alternative protein isoforms with conserved structure and function. Mol Biol Evol 2012, 29:2265-2283.
  • [20]Lareau LF, Brooks AN, Soergel DAW, Meng Q, Brenner SE: The coupling of alternative splicing and nonsense-mediated mRNA decay. Adv Exp Med Biol 2007, 623:190-211.
  • [21]Vogel C, Marcotte EM: Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012, 13:227-232.
  • [22]Hebenstreit D, Fang M, Gu M, Charoensawan V, van Oudenaarden A, Teichmann SA: RNA sequencing reveals two major classes of gene expression levels in metazoan cells. Mol Syst Biol 2011, 7:497.
  • [23]Fagerberg L, Oksvold P, Skogs M, Algenäs C, Lundberg E, Pontén F, Sivertsson A, Odeberg J, Klevebring D, Kampf C, Asplund A, Sjöstedt E, Al-Khalili Szigyarto C, Edqvist P-H, Olsson I, Rydberg U, Hudson P, Ottosson Takanen J, Berling H, Björling L, Tegel H, Rockberg J, Nilsson P, Navani S, Jirström K, Mulder J, Schwenk JM, Zwahlen M, Hober S, Forsberg M, et al.: Contribution of antibody-based protein profiling to the human Chromosome-centric Proteome Project (C-HPP). J Proteome Res 2013, 12:2439-2448.
  • [24]Licatalosi DD, Darnell RB: RNA processing and its regulation: global insights into biological networks. Nat Rev Genet 2010, 11:75-87.
  • [25]Buljan M, Chalancon G, Eustermann S, Wagner GP, Fuxreiter M, Bateman A, Babu MM: Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol Cell 2012, 46:871-883.
  • [26]Ellis JD, Barrios-Rodiles M, Colak R, Irimia M, Kim T, Calarco JA, Wang X, Pan Q, O'Hanlon D, Kim PM, Wrana JL, Blencowe BJ: Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell 2012, 46:884-892.
  • [27]The UniProt Consortium: Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 2011, 40:D71-D75.
  • [28]Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, Aken BL, Barrell D, Zadissa A, Searle S, Barnes I, Bignell A, Boychenko V, Hunt T, Kay M, Mukherjee G, Rajan J, Despacio-Reyes G, Saunders G, Steward C, Harte R, Lin M, Howald C, Tanzer A, Derrien T, Chrast J, Walters N, Balasubramanian S, Pei B, Tress M, et al.: GENCODE: The reference human genome annotation for The ENCODE Project. Genome Res 2012, 22:1760-1774.
  • [29]Sommer P, Nehrbass U: Quality control of messenger ribonucleoprotein particles in the nucleus and at the pore. Curr Opin Cell Biol 2005, 17:294-301.
  • [30]Egecioglu DE, Chanfreau G: Proofreading and spellchecking: a two-tier strategy for pre-mRNA splicing quality control. RNA 2011, 17:383-389.
  • [31]Kurmangaliyev YZ, Gelfand MS: Computational analysis of splicing errors and mutations in human transcripts. BMC Genomics 2008, 9:13. BioMed Central Full Text
  • [32]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 USA 2003, 100:189-192.
  • [33]Hillman RT, Green RE, Brenner SE: An unappreciated role for RNA surveillance. Genome Biol 2004, 5:R8. BioMed Central Full Text
  • [34]Buckley PT, Lee MT, Sul J-Y, Miyashiro KY, Bell TJ, Fisher SA, Kim J, Eberwine J: Cytoplasmic intron sequence-retaining transcripts can be dendritically targeted via ID element retrotransposons. Neuron 2011, 69:877-884.
  • [35]Bell TJ, Miyashiro KY, Sul J-Y, McCullough R, Buckley PT, Jochems J, Meaney DF, Haydon P, Cantor C, Parsons TD, Eberwine J: Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons. Proc Natl Acad Sci USA 2008, 105:1901-1906.
  • [36]Li Y, Bor Y-C, Misawa Y, Xue Y, Rekosh D, Hammarskjöld M-L: An intron with a constitutive transport element is retained in a Tap messenger RNA. Nature 2006, 443:234-237.
  • [37]Yap K, Lim ZQ, Khandelia P, Friedman B, Makeyev EV: Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev 2012, 26:1209-1223.
  • [38]Averbeck N, Sunder S, Sample N, Wise JA, Leatherwood J: Negative control contributes to an extensive program of meiotic splicing in fission yeast. Mol Cell 2005, 18:491-498.
  • [39]Mansilla A, López-Sánchez C, de la Rosa EJ, García-Martínez V, Martínez-Salas E, de Pablo F, Hernández-Sánchez C: Developmental regulation of a proinsulin messenger RNA generated by intron retention. EMBO Rep 2005, 6:1182-1187.
  • [40]Parenteau J, Durand M, Morin G, Gagnon J, Lucier J-F, Wellinger RJ, Chabot B, Elela SA: Introns within ribosomal protein genes regulate the production and function of yeast ribosomes. Cell 2011, 147:320-331.
  • [41]Foss EJ, Radulovic D, Shaffer SA, Ruderfer DM, Bedalov A, Goodlett DR, Kruglyak L: Genetic basis of proteome variation in yeast. Nat Genet 2007, 39:1369-1375.
  • [42]Fu X, Fu N, Guo S, Yan Z, Xu Y, Hu H, Menzel C, Chen W, Li Y, Zeng R, Khaitovich P: Estimating accuracy of RNA-Seq and microarrays with proteomics. BMC Genomics 2009, 10:161. BioMed Central Full Text
  • [43]Rodriguez JM, Maietta P, Ezkurdia I, Pietrelli A, Wesselink J-J, Lopez G, Valencia A, Tress ML: APPRIS: annotation of principal and alternative splice isoforms. Nucleic Acids Res 2013, 41:D110-D117.
  • [44]Tress ML, Martelli PL, Frankish A, Reeves GA, Wesselink JJ, Yeats C, Olason PI, Albrecht M, Hegyi H, Giorgetti A, Raimondo D, Lagarde J, Laskowski RA, López G, Sadowski MI, Watson JD, Fariselli P, Rossi I, Nagy A, Kai W, Størling Z, Orsini M, Assenov Y, Blankenburg H, Huthmacher C, Ramírez F, Schlicker A, Denoeud F, Jones P, Kerrien S, et al.: The implications of alternative splicing in the ENCODE protein complement. Proc Natl Acad Sci USA 2007, 104:5495-5500.
  • [45]Nilsen TW, Graveley BR: Expansion of the eukaryotic proteome by alternative splicing. Nature 2010, 463:457-463.
  • [46]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.
  • [47]Skandalis A, Frampton M, Seger J, Richards MH: The adaptive significance of unproductive alternative splicing in primates. RNA 2010, 16:2014-2022.
  • [48]Pickrell JK, Pai AA, Gilad Y, Pritchard JK: Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet 2010, 6:e1001236.
  • [49]ENCODE Project Consortium: An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489:57-74.
  • [50]Leinonen R, Akhtar R, Birney E, Bower L, Cerdeno-Tárraga A, Cheng Y, Cleland I, Faruque N, Goodgame N, Gibson R, Hoad G, Jang M, Pakseresht N, Plaister S, Radhakrishnan R, Reddy K, Sobhany S, Ten Hoopen P, Vaughan R, Zalunin V, Cochrane G: The European Nucleotide Archive. Nucleic Acids Res 2011, 39(Database):D28-31.
  • [51]Trapnell C, Pachter L, Salzberg SL: TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 2009, 25:1105-1111.
  • [52]Langmead B, Trapnell C, Pop M, Salzberg SL: Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 2009, 10:R25. BioMed Central Full Text
  • [53]Anders S, Reyes A, Huber W: Detecting differential usage of exons from RNA-seq data. Genome Res 2012, 22:2008-2017.
  • [54]Ramsköld D, Wang ET, Burge CB, Sandberg R: An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput Biol 2009, 5:e1000598.
  • [55]Huang DW, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009, 37:1-13.
  • [56]Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009, 4:44-57.
  • [57]Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995, 57:289-300.
  • [58]Gonzàlez-Porta M, Calvo M, Sammeth M, Guigó R: Estimation of alternative splicing variability in human populations. Genome Res 2012, 22:528-538.
  • [59]Down TA, Hubbard TJP: Computational detection and location of transcription start sites in mammalian genomic DNA. Genome Res 2002, 12:458-461.
  • [60]Derti A, Garrett-Engele P, Macisaac KD, Stevens RC, Sriram S, Chen R, Rohl CA, Johnson JM, Babak T: A quantitative atlas of polyadenylation in five mammals. Genome Res 2012, 22:1173-1183.
  文献评价指标  
  下载次数:6次 浏览次数:10次