Systems genomics evaluation of the SH-SY5Y neuroblastoma cell line as a model for Parkinson’s disease

BMC Genomics

Patrick May⁵  Rudi Balling¹  David J Galas²  Reinhard Schneider¹  Andreas Tholey³  Leroy Hood⁵  Kai Wang⁵  David Huang²  Dennis Linke³  Bart HJ van den Berg³  Olga Boyd¹  Sandra Köglsberger¹  Gustavo Glusman⁵  Merja Heinäniemi⁴  Jake Lin¹  Rene Hussong¹  Paul MA Antony¹  Christophe Trefois¹  Maria Biryukov¹  Abhimanyu Krishna¹ 

[1] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Campus Belval, 7, avenue des Hauts-Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg;Pacific Northwest Diabetes Research, Seattle, Washington, USA;Systematic Proteomics, Institute for Experimental Medicine, University Kiel, Kiel, Germany;Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland;Institute for Systems Biology, Seattle, Washington, USA

关键词: Parkinson’s disease;    Cell line suitability evaluation;    Proteomics;    RNA-seq;    Whole genome sequencing;    Cell line;    SH-SY5Y;   

Others  :  1122592
DOI  :  10.1186/1471-2164-15-1154

 received in 2014-04-03, accepted in 2014-12-12,  发布年份 2014

【 摘 要 】

Background

The human neuroblastoma cell line, SH-SY5Y, is a commonly used cell line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this cell line is often used as a cellular model for Parkinson’s disease, the relevance of this cellular model in the context of Parkinson’s disease (PD) and other neurodegenerative diseases has not yet been systematically evaluated.

Results

We have used a systems genomics approach to characterize the SH-SY5Y cell line using whole-genome sequencing to determine the genetic content of the cell line and used transcriptomics and proteomics data to determine molecular correlations. Further, we integrated genomic variants using a network analysis approach to evaluate the suitability of the SH-SY5Y cell line for perturbation experiments in the context of neurodegenerative diseases, including PD.

Conclusions

The systems genomics approach showed consistency across different biological levels (DNA, RNA and protein concentrations). Most of the genes belonging to the major Parkinson’s disease pathways and modules were intact in the SH-SY5Y genome. Specifically, each analysed gene related to PD has at least one intact copy in SH-SY5Y. The disease-specific network analysis approach ranked the genetic integrity of SH-SY5Y as higher for PD than for Alzheimer’s disease but lower than for Huntington’s disease and Amyotrophic Lateral Sclerosis for loss of function perturbation experiments.

【 授权许可】

   
2014 Krishna et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Goncalves J, Warnick S: System Theoretic Approaches to Network Reconstruction. In Control Theory and Systems Biology. 1st edition. Edited by Iglesias PA, Ingalis BP. Cambridge: MIT Press; 2009.
• [2]Biedler JL, Roffler-tarlov S, Schachner M, Freedman LS: Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res 1978, 38:3751-3757.
• [3]Biedler JL, Helson L, Spengler BA: Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res 1973, 33:2643-2652.
• [4]Xie HR, Hu LS, Li GY: SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J (Engl) 2010, 123(8):1086-1092.
• [5]Gilany K, Van Elzen R, Mous K, Coen E, Van Dongen W, Vandamme S, Gevaert K, Timmerman E, Vandekerckhove J, Dewilde S, Van Ostade X, Moens L: The proteome of the human neuroblastoma cell line SH-SY5Y: an enlarged proteome. Biochim Biophys Acta 2008, 1784(7–8):983-985.
• [6]Schapira AH: Mitochondrial dysfunction in neurodegenerative diseases. Neurochem Res 2008, 33(12):2502-2509.
• [7]Pahlman S, Ruusala AI, Abrahamsson L, Mattsson ME, Esscher T: Retinoic acid-induced differentiation of cultured human neuroblastoma cells: a comparison with phorbolester-induced differentiation. Cell Differ 1984, 14(2):135-144.
• [8]Kovalevich J, Langford D: Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol 2013, 1078:9-21.
• [9]Lam HY, Clark MJ, Chen R, Chen R, Natsoulis G, O’Huallachain M, Dewey FE, Habegger L, Ashley EA, Gerstein MB, Butte AJ, Ji HP, Snyder M: Performance comparison of whole-genome sequencing platforms. Nat Biotechnol 2012, 30(1):78-82.
• [10]Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G, Dahl F, Fernandez A, Staker B, Pant KP, Baccash J, Borcherding AP, Brownley A, Cedeno R, Chen L, Chernikoff D, Cheung A, Chirita R, Curson B, Ebert JC, Hacker CR, Hartlage R, Hauser B, Huang S, Jiang Y, Karpinchyk V, et al.: Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science (New York, NY) 2010, 327(5961):78-81.
• [11]Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, Boutell JM, Bryant J, Carter RJ, Keira Cheetham R, Cox AJ, Ellis DJ, Flatbush MR, Gormley NA, Humphray SJ, Irving LJ, Karbelashvili MS, Kirk SM, Li H, Liu X, Maisinger KS, Murray LJ, Obradovic B, Ost T, Parkinson ML, Pratt MR, et al.: Accurate whole human genome sequencing using reversible terminator chemistry. Nature 2008, 456(7218):53-59.
• [12]Reumers J, De Rijk P, Zhao H, Liekens A, Smeets D, Cleary J, Van Loo P, Van Den Bossche M, Catthoor K, Sabbe B, Despierre E, Vergote I, Hilbush B, Lambrechts D, Del-Favero J: Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing. Nat Biotechnol 2012, 30(1):61-68.
• [13]Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K: dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001, 29(1):308-311.
• [14]Khurana E, Fu Y, Colonna V, Mu XJ, Kang HM, Lappalainen T, Sboner A, Lochovsky L, Chen J, Harmanci A, Das J, Abyzov A, Balasubramanian S, Beal K, Chakravarty D, Challis D, Chen Y, Clarke D, Clarke L, Cunningham F, Evani US, Flicek P, Fragoza R, Garrison E, Gibbs R, Gümüs ZH, Herrero J, Kitabayashi N, Kong Y, Lage K, et al.: Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 2013, 342(6154):1235587.
• [15]Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, Gibbs RA, Hurles ME, McVean GA: A map of human genome variation from population-scale sequencing. Nature 2010, 467(7319):1061-1073.
• [16]Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA: COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2010, 39(suppl 1):D945-D950.
• [17]Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, Martin BK, Qiu R, Lee C, Shendure J: The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature 2013, 500(7461):207-211.
• [18]Meyer M, Kircher M, Gansauge MT, Li H, Racimo F, Mallick S, Schraiber JG, Jay F, Prufer K, de Filippo C, Sudmant PH, Alkan C, Fu Q, Do R, Rohland N, Tandon A, Siebauer M, Green RE, Bryc K, Briggs AW, Stenzel U, Dabney J, Shendure J, Kitzman J, Hammer MF, Shunkov MV, Derevianko AP, Patterson N, Andrés AM, Eichler EE, et al.: A high-coverage genome sequence from an archaic Denisovan individual. Science 2012, 338(6104):222-226.
• [19]Exome Variant Server [http://evs.gs.washington.edu/EVS/ webcite]
• [20]Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, Dermitzakis E, Schaffner SF, Yu F, Peltonen L, Dermitzakis E, Bonnen PE, Altshuler DM, Gibbs RA, de Bakker PI, Deloukas P, Gabriel SB, Gwilliam R, Hunt S, Inouye M, Jia X, Palotie A, Parkin M, Whittaker P, Yu F, Chang K, Hawes A, Lewis LR, Ren Y, Wheeler D, et al.: Integrating common and rare genetic variation in diverse human populations. Nature 2010, 467(7311):52-58.
• [21]Wang K, Li M, Hakonarson H: ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010, 38:e164.
• [22]Pruitt KD, Tatusova T, Klimke W, Maglott DR: NCBI reference sequences: current status, policy and new initiatives. Nucleic Acids Res 2009, 37(Database issue):D32-D36.
• [23]Fujita P, Rhead B, Zweig AS, Hinrichs AS, Karolchik D, Cline MS, Goldman M, Barber GP, Clawson H, Coelho A, Diekhans M, Dreszer TR, Giardine BM, Harte RA, Hillman-Jackson J, Hsu F, Kirkup V, Kuhn RM, Learned K, Li CH, Meyer LR, Pohl A, Raney BJ, Rosenbloom KR, Smith KE, Haussler D, Kent WJ: The UCSC genome browser database: update 2011. Nucleic Acids Res 2011, 39(Database issue):D876-D882.
• [24]Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S, Fitzgerald S, Gil L, García-Girón C, Gordon L, Hourlier T, Hunt S, Juettemann T, Kähäri AK, Keenan S, Komorowska M, Kulesha E, Longden I, Maurel T, McLaren WM, Muffato M, Nag R, Overduin B, Pignatelli M, Pritchard B, Pritchard E, et al.: Ensembl 2013. Nucleic Acids Res 2013, 41(Database issue):D48-D55.
• [25]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(9):1760-1774.
• [26]Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R: Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 2012, 483(7391):589-593.
• [27]Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC: SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012, 40(Web Server issue):W452-W457.
• [28]Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, Shefler E, Sivachenko A, Sougnez C, Stewart C, Ally A, Birol I, Chiu R, Corbett RD, Hirst M, Jackman SD, Kamoh B, Khodabakshi AH, Krzywinski M, Lo A, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 2013, 45(3):279-284.
• [29]Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, Heguy A, Pappo AS, Federico S, Dalton J, Cheung IY, Ding L, Fulton R, Wang J, Chen X, Becksfort J, Wu J, Billups CA, Ellison D, Mardis ER, Wilson RK, Downing JR, Dyer MA: Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 2012, 307(10):1062-1071.
• [30]Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, et al.: Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011, 144(1):27-40.
• [31]Grady DL, Ratliff RL, Robinson DL, McCanlies EC, Meyne J, Moyzis RK: Highly conserved repetitive DNA sequences are present at human centromeres. Proc Natl Acad Sci U S A 1992, 89(5):1695-1699.
• [32]Complete Genomics Baseline Genome Set [ftp2.completegenomics.com/Baseline_Genome_Set/CNVBaseline/]
• [33]Chu EC, Tarnawski AS: PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 2004, 10(10):RA235-RA241.
• [34]Complete Genomics Data File Formats [http://media.completegenomics.com/documents/DataFileFormats_Standard_Pipeline_2.5.pdf webcite]
• [35]Yusuf M, Leung K, Morris KJ, Volpi EV: Comprehensive cytogenomic profile of the in vitro neuronal model SH-SY5Y. Neurogenetics 2013, 14(1):63-70.
• [36]Do JH, Kim IS, Park T-k, Choi D-k: Molecules and genome-wide examination of chromosomal aberrations in neuroblastoma SH-SY5Y cells by array-based comparative genomic hybridization. Mol Cells 2007, 24(1):105-112.
• [37]Leinonen R, Akhtar R, Birney E, Bower L, Cerdeno-Tarraga 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 issue):D28-D31.
• [38]Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R: The sequence alignment/Map format and SAMtools. Bioinformatics (Oxford, England) 2009, 25(16):2078-2079.
• [39]DePristo MA, Banks E, Poplin RE, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ: A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat ldots 2011, 43(5):491-498.
• [40]O’Rawe J, Guangqing S, Wang W, Hu J, Bodily P, Tian L, Hakonarson H, Johnson E, Wei Z, Jiang T, Wei Z, Wang K, Lyon GJ: Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing. Genome Med 2013, 5(3):28. BioMed Central Full Text
• [41]Piskol R, Ramaswami G, Li JB: Reliable identification of genomic variants from RNA-seq data. Am J Hum Genet 2013, 93(4):641-651.
• [42]Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A: NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 2013, 41(Database issue):D991-D995.
• [43]Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M: Global quantification of mammalian gene expression control. Nature 2011, 473(7347):337-342.
• [44]Biryukov M, Antony PM, Krishna A, Trefois C, May P: Evaluation for Cell Line Suitability for Disease Specific Perturbation Experiments. In Data Science, Learning by Latent Structures, and Knowledge: 2014. Luxembourg: Springer; 2014.
• [45]Domcke S, Sinha R, Levine DA, Sander C, Schultz N: Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun 2013, 4:2126.
• [46]Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P: Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 2002, 277(41):38884-38894.
• [47]Freeman LC: Centrality in social networks conceptual clarification. Social Networks 1978–1979, 1(3):215-239.
• [48]Fujita KA, Ostaszewski M, Matsuoka Y, Ghosh S, Glaab E, Trefois C, Crespo I, Perumal TM, Jurkowski W, Antony PM, Diederich N, Buttini M, Kodama A, Satagopam VP, Eifes S, Del Sol A, Schneider R, Kitano H, Balling R: Integrating pathways of Parkinson’s disease in a molecular interaction Map. Mol Neurobiol 2013, 49(1):88-102.
• [49]Antony PM, Diederich NJ, Kruger R, Balling R: The hallmarks of Parkinson’s disease. FEBS J 2013, 280(23):5981-5993.
• [50]Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004, 4(11):891-899.
• [51]Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324(5930):1029-1033.
• [52]Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009, 4(7):1073-1081.
• [53]Nash JE, Appleby VJ, Correa SA, Wu H, Fitzjohn SM, Garner CC, Collingridge GL, Molnar E: Disruption of the interaction between myosin VI and SAP97 is associated with a reduction in the number of AMPARs at hippocampal synapses. J Neurochem 2010, 112(3):677-690.
• [54]Thomas DA, Scorrano L, Putcha GV, Korsmeyer SJ, Ley TJ: Granzyme B can cause mitochondrial depolarization and cell death in the absence of BID, BAX, and BAK. Proc Natl Acad Sci U S A 2001, 98(26):14985-14990.
• [55]Murray J, Taylor SW, Zhang B, Ghosh SS, Capaldi RA: Oxidative damage to mitochondrial complex I due to peroxynitrite: identification of reactive tyrosines by mass spectrometry. J Biol Chem 2003, 278(39):37223-37230.
• [56]Bertolin G, Ferrando-Miguel R, Jacoupy M, Traver S, Grenier K, Greene AW, Dauphin A, Waharte F, Bayot A, Salamero J, Lombès A, Bulteau AL, Fon EA, Brice A, Corti O: The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance. Autophagy 2013, 9(11):1801-1817.
• [57]Maglott D, Ostell J, Pruitt KD, Tatusova T: Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res 2011, 39(Database issue):D52-D57.
• [58]Hiroi T, Imaoka S, Funae Y: Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun 1998, 249(3):838-843.
• [59]Bromek E, Haduch A, Golembiowska K, Daniel WA: Cytochrome P450 mediates dopamine formation in the brain in vivo. J Neurochem 2011, 118(5):806-815.
• [60]Meiser J, Weindl D, Hiller K: Complexity of dopamine metabolism. Cell Commun Signal 2013, 11(1):34. BioMed Central Full Text
• [61]Romero P, Wagg J, Green ML, Kaiser D, Krummenacker M, Karp PD: Computational prediction of human metabolic pathways from the complete human genome. Genome Biol 2005, 6(1):R2.
• [62]Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, Furey TS, Harte RA, Hsu F, Hillman-Jackson J, Kuhn RM, Pedersen JS, Pohl A, Raney BJ, Rosenbloom KR, Siepel A, Smith KE, Sugnet CW, Sultan-Qurraie A, Thomas DJ, Trumbower H, Weber RJ, Weirauch M, Zweig AS, Haussler D, Kent WJ: The UCSC genome browser database: update 2006. Nucleic Acids Res 2006, 34(Database issue):D590-D598.
• [63]Trapnell C, Pachter L, Salzberg SL: TopHat: discovering splice junctions with RNA-Seq. Bioinformatics (Oxford, England) 2009, 25(9):1105-1111.
• [64]Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, Pimentel H, Salzberg SL, Rinn JL, Pachter L: Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012, 7:562-578.
• [65]Langmead B, Salzberg SL: Fast gapped-read alignment with Bowtie 2. Nat Methods 2012, 9(4):357-359.
• [66]Quinlan AR, Hall IM: BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics (Oxford, England) 2010, 26(6):841-842.
• [67]Cox J, Mann M: MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 2008, 26(12):1367-1372.
• [68]Cohen KB, Johnson HL, Verspoor K, Roeder C, Hunter LE: The structural and content aspects of abstracts versus bodies of full text journal articles are different. BMC Bioinformatics 2010, 11(1):492. BioMed Central Full Text
• [69]McDonald D, Chen H: Using Sentence-Selection Heuristics to Rank Text Segments in TXTRACTOR. Management Information Systems 2002, 28-35.
• [70]Biopython [http://biopython.org/wiki/Main_Page webcite]
• [71]The lxml.etree Tutorial [http://lxml.de/tutorial.html webcite]
• [72]Pafilis E, O’Donoghue SI, Jensen LJ, Horn H, Kuhn M, Brown NP, Schneider R: Reflect: augmented browsing for the life scientist. Nat Biotechnol 2009, 27(6):508-510.
• [73]Zhu X, Gerstein M, Snyder M: Getting connected: analysis and principles of biological networks. Genes Dev 2007, 21(9):1010-1024.
• [74]del Sol A, Balling R, Hood L, Galas D: Diseases as network perturbations. Curr Opin Biotechnol 2010, 21(4):566-571.
• [75]McKusick VA: Mendelian inheritance in Man and its online version, OMIM. Am J Hum Genet 2007, 80(4):588-604.
• [76]Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C, Jensen LJ: STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013, 41(Database issue):D808-D815.
• [77]Wasserman S, Faust K: Social Network Analysis: Methods and Applications. Cambridge, UK: Cambrudge University Press; 1994.
• [78]Newman MEJ: A measure of betweenness centrality based on random walks. Social Networks 2005, 27(1):39-54.
• [79]Bonacich P: Power and centrality: a family of measures. Am J Sociol 1987, 92(5):1170-1182.
• [80]Brandes U, Fleischer D: Centrality Measures Based on Current Flow. STACS 2005, Lecture Notes in Computer Science 2005, 3404:533-544.
• [81]Missiuro PV, Liu K, Zou L, Ross BC, Zhao G, Liu JS, Ge H: Information flow analysis of interactome networks. PLoS Comput Biol 2009, 5(4):e1000350.
• [82]bioCompendium [http://biocompendium.embl.de/ webcite]