Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis

PLoS Computational Biology

Volumn 12, Issue 9, 2016, Pages

  Cheng, Feixiong ^a,b,f,h   Murray, James L ^c,g   Zhao, Junfei ^d   Sheng, Jinsong ^b   Zhao, Zhongming ^b,d   Rubin, Donald H ^b,e  

^a SICHUAN UNIVERSITY   (China)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Zirus   (United States)

^d UNIVERSITY OF TEXAS   (United States)

^e Tennessee Valley Healthcare System   (United States)

^f HARVARD MEDICAL SCHOOL   (United States)

^g GeneTAG Technology Inc ^*  (United States)

^h NORTHEASTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BACTERIA; CYTOLOGY; DISEASES; GENES; INTEGRATION TESTING; MAMMALS; MUTAGENESIS;

ANTI-VIRAL DRUGS; ANTIVIRALS; CELLULAR GENES; CELLULARS; DRUG TARGETS; HOST CELLS; INSERTIONAL MUTAGENESIS; INTERACTOME; SYSTEMS BIOLOGY; VIRAL REPLICATION;

VIRUSES;

CYCLIN DEPENDENT KINASE INHIBITOR 1B; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; TRANSCRIPTION FACTOR CTCF; ANTIVIRUS AGENT;

ARTICLE; CDKN1B GENE; CONTROLLED STUDY; CTCF GENE; DOWN REGULATION; GENE; GENE IDENTIFICATION; GENE SEQUENCE; GENE TRAP INSERTIONAL MUTAGENESIS; MUTAGENESIS; NONHUMAN; ONCOGENE MYC; PURIFYING SELECTION; RHOA GENE; RNA INTERFERENCE; RNA REPLICATION; RNA TRANSCRIPTION; SIGNAL TRANSDUCTION; SOMATIC MUTATION; TAF4 GENE; UPREGULATION; VIRUS CELL INTERACTION; VIRUS REPLICATION; ANIMAL; CELL CYCLE; CELL LINE; DOG; DRUG DELIVERY SYSTEM; DRUG DEVELOPMENT; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; HEP-G2 CELL LINE; HOST PATHOGEN INTERACTION; HUMAN; MDCK CELL LINE; PROCEDURES; PROTEIN PROTEIN INTERACTION; SYSTEMS BIOLOGY;

ANIMALS; ANTIVIRAL AGENTS; CELL CYCLE; CELL LINE; DOGS; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; HEP G2 CELLS; HOST-PATHOGEN INTERACTIONS; HUMANS; MADIN DARBY CANINE KIDNEY CELLS; MUTAGENESIS, INSERTIONAL; PROTEIN INTERACTION MAPS; SYSTEMS BIOLOGY; VIRUS REPLICATION;

EID: 84989355048     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1005074     Document Type: Article

References (94)

1. Khabbaz RF, Moseley RR, Steiner RJ, Levitt AM, Bell BP, (2014) Challenges of infectious diseases in the USA. Lancet384: 53–63. doi: 10.1016/S0140-6736(14)60890-424996590.
2. 2013 Report on the Global AIDS Epidemic. Website: http://www.unaids.org/en/resources/campaigns/globalreport2013/factsheet/.
3. 2014 Ebola Outbreak in West Africa-Reported Cases. Website: http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/cumulative-cases-graphs.html.
4. Strauss S, (2014) Biotech drugs too little, too late for Ebola outbreak. Nat Biotechnol32: 849–850. doi: 10.1038/nbt0914-849a
5. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, et al. (2011) Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature477: 340–343. doi: 10.1038/nature10348
6. Qiu X, Wong G, Audet J, Bello A, Fernando L, et al. (2014) Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature514: 47–53. doi: 10.1038/nature13777
7. Kwong AD, Rao BG, Jeang KT, (2005) Viral and cellular RNA helicases as antiviral targets. Nat Rev Drug Discov4: 845–853. doi: 10.1038/nrd1853
8. Tan SL, Ganji G, Paeper B, Proll S, Katze MG, (2007) Systems biology and the host response to viral infection. Nat Biotechnol25: 1383–1389. doi: 10.1038/nbt1207-1383
9. Taylor CM, Martin J, Rao RU, Powell K, Abubucker S, et al. (2013) Using existing drugs as leads for broad spectrum anthelmintics targeting protein kinases. PLoS Pathog9: e1003149. doi: 10.1371/journal.ppat.1003149
10. Cheng F, Liu C, Jiang J, Lu W, Li W, et al. (2012) Prediction of drug-target interactions and drug repositioning via network-based inference. PLoS Comput Biol8: e1002503. doi: 10.1371/journal.pcbi.1002503
11. Cheng F, Hong H, Yang S, Wei Y, (2016) Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era. Brief Bioinform, published online June12, doi: 10.1093/bib/bbw051
12. Chasman D, Gancarz B, Hao L, Ferris M, Ahlquist P, et al. (2014) Inferring host gene subnetworks involved in viral replication. PLoS Comput Biol10: e1003626. doi: 10.1371/journal.pcbi.1003626
13. Weekes MP, Tomasec P, Huttlin EL, Fielding CA, Nusinow D, et al. (2014) Quantitative temporal viromics: an approach to investigate host-pathogen interaction. Cell157: 1460–1472. doi: 10.1016/j.cell.2014.04.028
14. Pichlmair A, Kandasamy K, Alvisi G, Mulhern O, Sacco R, et al. (2012) Viral immune modulators perturb the human molecular network by common and unique strategies. Nature487: 486–490. doi: 10.1038/nature11289
15. Jager S, Cimermancic P, Gulbahce N, Johnson JR, McGovern KE, et al. (2012) Global landscape of HIV-human protein complexes. Nature481: 365–370. doi: 10.1038/nature10719
16. Peng X, Chan EY, Li Y, Diamond DL, Korth MJ, et al. (2009) Virus-host interactions: from systems biology to translational research. Curr Opin Microbiol12: 432–438. doi: 10.1016/j.mib.2009.06.003
17. Sivasubbu S, Balciunas D, Amsterdam A, Ekker SC, (2007) Insertional mutagenesis strategies in zebrafish. Genome Biol8Suppl 1: S9. doi: 10.1186/gb-2007-8-s1-s9
18. Murray JL, Mavrakis M, McDonald NJ, Yilla M, Sheng J, et al. (2005) Rab9 GTPase is required for replication of human immunodeficiency virus type 1, filoviruses, and measles virus. J Virol79: 11742–11751. doi: 10.1128/JVI.79.18.11742-11751.2005
19. von Melchner H, Ruley HE, (1989) Identification of cellular promoters by using a retrovirus promoter trap. J Virol63: 3227–3233
20. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science313: 1929–1935. doi: 10.1126/science.1132939
21. Rastogi S, Rost B, (2011) LocDB: experimental annotations of localization for Homo sapiens and Arabidopsis thaliana. Nucleic Acids Res39: D230–234. doi: 10.1093/nar/gkq927
22. LaFrance ME, Farrow MA, Chandrasekaran R, Sheng J, Rubin DH, et al. (2015) Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc Natl Acad Sci U S A112: 7073–7078. doi: 10.1073/pnas.1500791112
23. Watanabe T, Kawakami E, Shoemaker JE, Lopes TJ, Matsuoka Y, et al. (2014) Influenza virus-host interactome screen as a platform for antiviral drug development. Cell Host Microbe16: 795–805. doi: 10.1016/j.chom.2014.11.002
24. Chen WH, Minguez P, Lercher MJ, Bork P, (2012) OGEE: an online gene essentiality database. Nucleic Acids Res40: D901–906. doi: 10.1093/nar/gkr986
25. Cheng F, Jia P, Wang Q, Lin CC, Li WH, et al. (2014) Studying tumorigenesis through network evolution and somatic mutational perturbations in the cancer interactome. Mol Biol Evol31: 2156–2169. doi: 10.1093/molbev/msu167
26. Cheng F, Jia P, Wang Q, Zhao Z, (2014) Quantitative network mapping of the human kinome interactome reveals new clues for rational kinase inhibitor discovery and individualized cancer therapy. Oncotarget5: 3697–3710.
27. Breuer K, Foroushani AK, Laird MR, Chen C, Sribnaia A, et al. (2013) InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation. Nucleic Acids Res41: D1228–1233. doi: 10.1093/nar/gks1147
28. Pechenick Jowers T, Featherstone RJ, Reynolds DK, Brown HK, James J, et al. (2015) RAB1A promotes Vaccinia virus replication by facilitating the production of intracellular enveloped virions. Virology475: 66–73. doi: 10.1016/j.virol.2014.11.007
29. Zhou X, You F, Chen H, Jiang Z, (2012) Poly(C)-binding protein 1 (PCBP1) mediates housekeeping degradation of mitochondrial antiviral signaling (MAVS). Cell Res22: 717–727. doi: 10.1038/cr.2011.184
30. You F, Sun H, Zhou X, Sun W, Liang S, et al. (2009) PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat Immunol10: 1300–1308. doi: 10.1038/ni.1815
31. Marchant D, Sall A, Si X, Abraham T, Wu W, et al. (2009) ERK MAP kinase-activated Arf6 trafficking directs coxsackievirus type B3 into an unproductive compartment during virus host-cell entry. J Gen Virol90: 854–862. doi: 10.1099/vir.0.005868-0
32. Yenugu S, Hamil KG, Radhakrishnan Y, French FS, Hall SH, (2004) The androgen-regulated epididymal sperm-binding protein, human beta-defensin 118 (DEFB118) (formerly ESC42), is an antimicrobial beta-defensin. Endocrinology145: 3165–3173. doi: 10.1210/en.2003-1698
33. Dyer MD, Murali TM, Sobral BW, (2008) The landscape of human proteins interacting with viruses and other pathogens. PLoS Pathog4: e32. doi: 10.1371/journal.ppat.0040032
34. Taterka J, Sutcliffe M, Rubin DH, (1994) Selective reovirus infection of murine hepatocarcinoma cells during cell division. A model of viral liver infection. J Clin Invest94: 353–360. doi: 10.1172/JCI117329
35. Kittler R, Pelletier L, Heninger AK, Slabicki M, Theis M, et al. (2007) Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat Cell Biol9: 1401–1412. doi: 10.1038/ncb1659
36. Wang J, Du J, Jin Q, (2014) Class I ADP-ribosylation factors are involved in enterovirus 71 replication. PLoS One9: e99768. doi: 10.1371/journal.pone.0099768
37. Reiling JH, Olive AJ, Sanyal S, Carette JE, Brummelkamp TR, et al. (2013) A CREB3-ARF4 signalling pathway mediates the response to Golgi stress and susceptibility to pathogens. Nat Cell Biol15: 1473–1485. doi: 10.1038/ncb2865
38. Kudelko M, Brault JB, Kwok K, Li MY, Pardigon N, et al. (2012) Class II ADP-ribosylation factors are required for efficient secretion of dengue viruses. J Biol Chem287: 767–777. doi: 10.1074/jbc.M111.270579
39. Quadt I, Gunther AK, Voss D, Schelhaas M, Knebel-Morsdorf D, (2006) TATA-binding protein and TBP-associated factors during herpes simplex virus type 1 infection: localization at viral DNA replication sites. Virus Res115: 207–213. doi: 10.1016/j.virusres.2005.09.010
40. Yang YC, Chang LK, (2013) Role of TAF4 in transcriptional activation by Rta of Epstein-Barr Virus. PLoS One8: e54075. doi: 10.1371/journal.pone.0054075
41. Santos A, Wernersson R, Jensen LJ, (2015) Cyclebase 3.0: a multi-organism database on cell-cycle regulation and phenotypes. Nucleic Acids Res43: D1140–1144. doi: 10.1093/nar/gku1092
42. Lacy J, Summers WP, Watson M, Glazer PM, Summers WC, (1987) Amplification and deregulation of MYC following Epstein-Barr virus infection of a human B-cell line. Proc Natl Acad Sci U S A84: 5838–5842.
43. Fanidi A, Hancock DC, Littlewood TD, (1998) Suppression of c-Myc-induced apoptosis by the Epstein-Barr virus gene product BHRF1. J Virol72: 8392–8395.
44. Walsh D, Mathews MB, Mohr I, (2013) Tinkering with translation: protein synthesis in virus-infected cells. Cold Spring Harb Perspect Biol5: a012351. doi: 10.1101/cshperspect.a012351
45. Rozenblatt-Rosen O, Deo RC, Padi M, Adelmant G, Calderwood MA, et al. (2012) Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature487: 491–495. doi: 10.1038/nature11288
46. Gulbahce N, Yan H, Dricot A, Padi M, Byrdsong D, et al. (2012) Viral perturbations of host networks reflect disease etiology. PLoS Comput Biol8: e1002531. doi: 10.1371/journal.pcbi.1002531
47. Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, et al. (2008) CTCF physically links cohesin to chromatin. Proc Natl Acad Sci USA105: 8309–8314. doi: 10.1073/pnas.0801273105
48. Network TCGA (2012) Comprehensive molecular portraits of human breast tumours. Nature490: 61–70. doi: 10.1038/nature11412
49. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, et al. (2011) The mutational landscape of head and neck squamous cell carcinoma. Science333: 1157–1160. doi: 10.1126/science.1208130
50. Cancer Genome Atlas Research NKandoth C, Schultz N, Cherniack AD, Akbani R, et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature497: 67–73. doi: 10.1038/nature12113
51. Hirasawa K, Nishikawa SG, Norman KL, Alain T, Kossakowska A, et al. (2002) Oncolytic reovirus against ovarian and colon cancer. Cancer Res62: 1696–1701.
52. Nie ZL, Pan YQ, He BS, Gu L, Chen LP, et al. (2012) Gene therapy for colorectal cancer by an oncolytic adenovirus that targets loss of the insulin-like growth factor 2 imprinting system. Mol Cancer11: 86. doi: 10.1186/1476-4598-11-86
53. Molyneux SD, Waterhouse PD, Shelton D, Shao YW, Watling CM, et al. (2014) Human somatic cell mutagenesis creates genetically tractable sarcomas. Nat Genet46: 964–972. doi: 10.1038/ng.3065
54. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, et al. (2008) DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res36: D901–906. doi: 10.1093/nar/gkm958
55. Zhu F, Shi Z, Qin C, Tao L, Liu X, et al. (2012) Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res40: D1128–1136. doi: 10.1093/nar/gkr797
56. Hernandez-Boussard T, Whirl-Carrillo M, Hebert JM, Gong L, Owen R, et al. (2008) The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge. Nucleic Acids Res36: D913–918. doi: 10.1093/nar/gkm1009
57. He S, Lin B, Chu V, Hu Z, Hu X, et al. (2015) Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Sci Transl Med7: 282ra249. doi: 10.1126/scitranslmed.3010286
58. Guendel I, Agbottah ET, Kehn-Hall K, Kashanchi F, (2010) Inhibition of human immunodeficiency virus type-1 by cdk inhibitors. AIDS Res Ther7: 7. doi: 10.1186/1742-6405-7-7
59. Szlavik L, Gyuris A, Minarovits J, Forgo P, Molnar J, et al. (2004) Alkaloids from Leucojum vernum and antiretroviral activity of Amaryllidaceae alkaloids. Planta Med70: 871–873. doi: 10.1055/s-2004-827239
60. Tan GT, Pezzuto JM, Kinghorn AD, Hughes SH, (1991) Evaluation of natural products as inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. J Nat Prod54: 143–154
61. Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, et al. (2006) Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol80: 10109–10116. doi: 10.1128/JVI.01157-06
62. Volchkov VE, Feldmann H, Volchkova VA, Klenk HD, (1998) Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci USA95: 5762–5767
63. Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM, (2005) Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science308: 1643–1645. doi: 10.1126/science.1110656
64. Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, et al. (2015) Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science347: 995–998.
65. Fish JM, Antzelevitch C, (2004) Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm1: 210–217. doi: 10.1016/j.hrthm.2004.03.061
66. Endsley MA, Somasunderam AD, Li G, Oezguen N, Thiviyanathan V, et al. (2014) Nuclear trafficking of the HIV-1 pre-integration complex depends on the ADAM10 intracellular domain. Virology454–455: 60–66. doi: 10.1016/j.virol.2014.02.006
67. Marcato P, Dean CA, Giacomantonio CA, Lee PW, (2009) Oncolytic reovirus effectively targets breast cancer stem cells. Mol Ther17: 972–979. doi: 10.1038/mt.2009.58
68. Norman KL, Coffey MC, Hirasawa K, Demetrick DJ, Nishikawa SG, et al. (2002) Reovirus oncolysis of human breast cancer. Hum Gene Ther13: 641–652. doi: 10.1089/10430340252837233
69. Twigger K, Roulstone V, Kyula J, Karapanagiotou EM, Syrigos KN, et al. (2012) Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway. BMC Cancer12: 368. doi: 10.1186/1471-2407-12-368
70. Holdorf MM, Cooper SB, Yamamoto KR, Miranda JJ, (2011) Occupancy of chromatin organizers in the Epstein-Barr virus genome. Virology415: 1–5. doi: 10.1016/j.virol.2011.04.004
71. Hughes DJ, Marendy EM, Dickerson CA, Yetming KD, Sample CE, et al. (2012) Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency. J Virol86: 1034–1045. doi: 10.1128/JVI.05923-11
72. Duan Q, Flynn C, Niepel M, Hafner M, Muhlich JL, et al. (2014) LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures. Nucleic Acids Res42: W449–460. doi: 10.1093/nar/gku476
73. Hicks GG, Shi EG, Li XM, Li CH, Pawlak M, et al. (1997) Functional genomics in mice by tagged sequence mutagenesis. Nature Genetics16: 338–344. doi: 10.1038/ng0897-338
74. Ivie SE, Fennessey CM, Sheng J, Rubin DH, McClain MS, (2011) Gene-trap mutagenesis identifies mammalian genes contributing to intoxication by Clostridium perfringens epsilon-toxin. PLoS One6: e17787. doi: 10.1371/journal.pone.0017787
75. Organ EL, Sheng J, Ruley HE, Rubin DH, (2004) Discovery of mammalian genes that participate in virus infection. BMC Cell Biol5: 41. doi: 10.1186/1471-2121-5-41
76. Sheng J, Organ EL, Hao C, Wells KS, Ruley HE, et al. (2004) Mutations in the IGF-II pathway that confer resistance to lytic reovirus infection. BMC Cell Biol5: 32. doi: 10.1186/1471-2121-5-32
77. Dziuba N, Ferguson MR, O'Brien WA, Sanchez A, Prussia AJ, et al. (2012) Identification of Cellular Proteins Required for Replication of Human Immunodeficiency Virus Type 1. AIDS Res Hum Retroviruses28: 1329–1339.
78. Murray JL, McDonald NJ, Sheng J, Shaw MW, Hodge TW, et al. (2012) Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis. Antivir Chem Chemother22: 205–215. doi: 10.3851/IMP2080
79. Murray JL, Sheng J, Rubin DH, (2014) A role for H/ACA and C/D small nucleolar RNAs in viral replication. Mol Biotechnol56: 429–437. doi: 10.1007/s12033-013-9730-0
80. Radin JN, Gonzalez-Rivera C, Frick-Cheng AE, Sheng J, Gaddy JA, et al. (2014) Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect Immun82: 423–432. doi: 10.1128/IAI.00827-13
81. Knox C, Law V, Jewison T, Liu P, Ly S, et al. (2011) DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res39: D1035–1041. doi: 10.1093/nar/gkq1126
82. Bodenreider O, (2004) The Unified Medical Language System (UMLS): integrating biomedical terminology. Nucleic Acids Res32: D267–270. doi: 10.1093/nar/gkh061
83. Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, et al. (2013) Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep3: 2650. doi: 10.1038/srep02650
84. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr.et al. (2013) Cancer genome landscapes. Science339: 1546–1558. doi: 10.1126/science.1235122
85. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, et al. (2013) Mutational landscape and significance across 12 major cancer types. Nature502: 333–339. doi: 10.1038/nature12634
86. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, et al. (2014) Discovery and saturation analysis of cancer genes across 21 tumour types. Nature505: 495–501. doi: 10.1038/nature12912
87. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, et al. (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res39: D945–950. doi: 10.1093/nar/gkq929
88. Hamosh A, Scott AF, Amberger JS, Bocchini CA, McKusick VA, (2005) Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res33: D514–517.
89. Zhang M, Zhu C, Jacomy A, Lu LJ, Jegga AG, (2011) The orphan disease networks. Am J Hum Genet88: 755–766. doi: 10.1016/j.ajhg.2011.05.006
90. Dear JW, Lilitkarntakul P, Webb DJ, (2006) Are rare diseases still orphans or happily adopted? The challenges of developing and using orphan medicinal products. Br J Clin Pharmacol62: 264–271. doi: 10.1111/j.1365-2125.2006.02654.x
91. Hirsh AE, Fraser HB, Wall DP, (2005) Adjusting for selection on synonymous sites in estimates of evolutionary distance. Mol Biol Evol22: 174–177. doi: 10.1093/molbev/msh265
92. Bezginov A, Clark GW, Charlebois RL, Dar VU, Tillier ER, (2013) Coevolution reveals a network of human proteins originating with multicellularity. Mol Biol Evol30: 332–346. doi: 10.1093/molbev/mss218
93. Capra JA, Williams AG, Pollard KS, (2012) ProteinHistorian: tools for the comparative analysis of eukaryote protein origin. PLoS Comput Biol8: e1002567. doi: 10.1371/journal.pcbi.1002567
94. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, et al. (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics25: 1091–1093. doi: 10.1093/bioinformatics/btp101