V CONSIDERAÇÕES FINAIS

Ao longo das últimas décadas, o avanço das tecnologias de sequenciamento associadas ao aumento de poder computacional levou ao crescimento nunca antes observado no volume de dados genômicos, transcritômicos e proteômicos de diversos grupos taxonômicos, o que abriu novas fronteiras para as análises biológicas comparativas. Neste contexto, a filogenômica tem o potencial de conectar a diversidade genômica à biologia evolutiva, estabelecendo relações entre os domínios da vida e contribuindo para a aprimoração da anotação funcional de genes e proteínas. Esta abordagem tem impacto ainda maior no que diz respeito à análises genômicas de parasitos, visto que à luz da evolução é possível revelar características espécie-específicas com potencial aplicação em biomedicina e biotecnologia. Ao utilizar a abordagem filogenômica para analisar o proteoma predito de S. mansoni, em comparação com outros organismos parasitos e de vida livre, nós "iluminamos" os processos evolutivos que modelaram as interações parasito- hospedeiro ao longo do tempo evolutivo e identificamos e testamos experimentalmente potenciais alvos para o desenvolvimento de novas drogas contra a esquistossomose. Dando continuidade a este trabalho, análises comparativas envolvendo dados genômicos, transcritômicos e proteômicos de outros helmintos e vetores, assim como a caracterização experimental de outros alvos promissores, aumentarão nosso conhecimento sobre a biologia parasitária rumo à prevenção do progresso da doença.

VI - REFERÊNCIAS

ü Andrade LF, Nahum LA, Avelar LG, Silva LL, Zerlotini A, Ruiz JC, Oliveira G. Eukaryotic protein kinases (ePKs) of the helminth parasite Schistosoma mansoni. BMC Genomics, v.12, 215, 2011.

ü Berriman M, Haas BJ, LoVerde PT, Wilson RA, Dillon GP, Cerqueira GC, Mashiyama ST, Al- Lazikani B, Andrade LF, Ashton PD, Aslett MA, Bartholomeu DC, Blandin G, Caffrey CR, Coghlan A, Coulson R, Day TA, Delcher A, DeMarco R, Djikeng A, Eyre T, Gamble JA, Ghedin E, Gu Y, Hertz-Fowler C, Hirai H, Hirai Y, Houston R, Ivens A, Johnston DA, Lacerda D, Macedo CD, McVeigh P, Ning Z, Oliveira G, Overington JP, Parkhill J, Pertea M, Pierce RJ, Protasio AV, Quail MA, Rajandream MA, Rogers J, Sajid M, Salzberg SL, Stanke M, Tivey AR, White O, Williams DL, Wortman J, Wu W, Zamanian M, Zerlotini A, Fraser-Liggett CM, Barrell BG, El-Sayed NM. The genome of the blood fluke Schistosoma mansoni. Nature, v.460, p. 352–358, 2009.

ü Bolton E, Wang Y, Thiessen PA, Bryant SH. PubChem: Integrated Platform of Small Molecules and Biological Activities. In Annual Reports in Computational Chemistry. American Chemical Society, Washington, DC, 2008. cap. 12.

ü Botros SS, Bennett JL. Praziquantel resistance. Expert Opinion on Drug Discovery, v. 2, p. S35-S40, 2007.

ü Boyle SN, Koleske AJ. Dissecting kinase signaling pathways. Drug Discov Today 2007; 12(17-18):717-724.

ü Brown D, Sjolander K. Functional classification using phylogenomics inference. PLoS Computational Biology, v. 2, e. 77, 2006.

ü Carroll L. Through the looking-glass. 1872.

ü Criscione CD, Valentim CL, Hirai H, LoVerde PT, Anderson TJ. Genomic linkage map of the human blood fluke Schistosoma mansoni. Genome Biology, v. 10, R71, 2009.

ü DeMarco R, Mathieson W, Dillon GP, Wilson RA. Schistosome albumin is of host, not parasite, origin. International Journal for Parasitology, v. 37, p. 1201-8, 2007.

ü Dunne DW, Webster M, Smith P, Langley JG, Richardson BA, et al. The isolation of a 22 kDa band after SDS-PAGE of Schistosoma mansoni adult worms and its use to demonstrate that IgE responses against the antigen(s) it contains are associated with human resistance to reinfection. Parasite Immunol. v.19, p: 79–89, 1997.

ü Eisen JA, Kaiser D, Myers RM. Gastrogenomic delights: a movable feast. Nature Medicine, v. 3, p. 1076-1078, 1997.

ü Eisen JA, Wu M. Phylogenetic analysis and gene functional predictions: phylogenomics in action. Theoretical Population Biology, v. 61, p. 481–487, 2002.

ü Felsenstein J. Phylogenies and the comparative method. Am Nat, v. 125, p. 1-15, 1985. ü Fitzpatrick JM, Peak E, Perally S, Chalmers IW, Barrett J, Yoshino TP, Ivens AC, Hoffmann

KF. Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses. PLoS Neglected Tropical Diseases, v. 3, e. 543, 2009.

ü Fitzsimmons CM, Jones FM, Stearn A, Chalmers IW, Hoffmann KF, Wawrzyniak J, Wilson S, Kabatereine NB, Dunne DW. The Schistosoma mansoni tegumental-allergen-like (TAL) protein family: influence of developmental expression on human IgE responses. PLoS Negl Trop Dis v.6, e1593, 2012.

ü Gabaldón T. Comparative Genomics-Based Prediction of Protein Function. Genomics Protocols, v. 439, p. 387-401, 2008.

ü Gabaldón T, Huynen MA. Prediction of protein function and pathways in the genome era. Cellular and Molecular Life Sciences, v.61, p. 930-44, 2004.

ü Galperin MY, Koonin EV. Who's your neighbor? New computational approaches for functional genomics. Nature Biotechnology, v. 18, p. 609-13, 2000.

ü Greenberg RM. New approaches for understanding mechanisms of drug resistance in schistosomes. Parasitology. 2013 Apr 3:1-13. [Epub ahead of print] PubMed PMID: 23552512.

ü Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet, v. 368, p. 1106-18, 2006.

ü Han ZG, Brindley PJ, Wang SY, Chen Z. Schistosoma genomics: new perspectives on schistosome biology and host-parasite interaction. Annu Rev Genomics Hum Genet, v. 10, p. 211-240, 2009.

ü Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 1988; 241(4861):42-52.

ü Hardison RC. Comparative genomics. PLoS Biol, v. 1, e58, 2003.

ü Hawkins T, Kihara D. Function prediction of uncharacterized proteins. Journal of Bioinformatics and Computacional Biology, v.5, p. 1-30, 2007.

ü Hood L. Systems biology: integrating technology, biology, and computation. Mechanisms of Ageing and Development, v. 124, p. 9-16, 2003.

ü Huerta-Cepas J, Dopazo H, Dopazo J, Gabaldón T. The human phylome. Genome Biology, v. 8, R109, 2007.

ü Huerta-Cepas J, Marcet-Houben M, Pignatelli M, Moya A, Gabaldón T. The pea aphid phylome: a complete catalogue of evolutionary histories and arthropod orthology and paralogy relationships for Acyrthosiphon pisum genes. Insect Molecular Biology, v. 19, p. 13- 21, 2010.

ü Jones MK, Gobert GN, Zhang L, Sunderland P, McManus DP. The cytoskeleton and motor proteins of human schistosomes and their roles in surface maintenance and host-parasite interactions. Bioessays v.26, p: 752-65, 2004.

ü Kasný M, Mikes L, Hampl V, Dvorák J, Caffrey CR, Dalton JP, Horák P. Chapter 4. Peptidases of trematodes. Adv Parasitol v. 69, p. 205-297, 2009.

ü Lambertucci JR. Acute schistosomiasis mansoni: revisited and reconsidered. Memorias do Instituto Oswaldo Cruz, v. 105, p. 422–435, 2010.

ü Lawton SP, Hirai H, Ironside JE, Johnston DA, Rollinson D. Genomes and geography: genomic insights into the evolution and phylogeography of the genus Schistosoma. Parasit Vectors, v. 7, 131, 2011.

ü Liang YS, Dai JR, Zhu YC, Coles GC, Doenhoff MJ. Genetic analysis of praziquantel resistance in Schistosoma mansoni. The Southeast Asian Journal of Tropical Medicine and Public Health, v. 34, p. 274-80, 2003.

ü LoVerde PT, Hirai H, Merrick JM, Lee NH, El-Sayed N. Schistosoma mansoni genome project: an update. Parasitology International, v. 53, p. 183-92, 2004.

ü Marques Jr ETA, Ichikawa Y, Strand M, August JT, Hart GW, Schnaar RL. Fucosyltransferases in Schistosoma mansoni development. Glycobiology, v. 11, p. 249-59, 2001.

ü McKerrow JH, Caffrey C, Kelly B, Loke P, Sajid M 2006. Proteases in parasitic diseases. Annu Rev Pathol 1: 497-536.

ü McManus DP, Loukas A. Current status of vaccines for schistosomiasis. Clinical Microbiology Reviews, v. 21, p. 225-42, 2008.

ü Medina M. Genomes, phylogeny, and evolutionary systems biology. Proceedings of the National Academy of Sciences, v. 102, p. 6630-6635, 2005.

ü Melman SD, Steinauer ML, Cunningham C, Kubatko LS, Mwangi IN, Wynn NB, Mutuku MW, Karanja DM, Colley DG, Black CL, Secor WE, Mkoji GM, Loker ES. Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of Schistosoma mansoni. PLoS Neglected Tropical Disease, v. 3, e. 504, 2009.

ü Mulvenna J, Moertel L, Jones MK, Nawaratna S, Lovas EM, Gobert GN, Colgrave M, Jones A, Loukas A, McManus DP. Exposed proteins of the Schistosoma japonicum tegument. Int J Parasitol. v.40, p: 543-54, 2010.

ü Nahum LA, Goswami S, Serres MH: Protein families reflect the metabolic diversity of organisms and provide support for functional prediction. Physiol Genomics, v. 38, p:250–260, 2009.

ü Nahum LA, Mourão MM, Oliveira G. New frontiers in schistosoma genomics and transcriptomics. J Parasitol Res, v. 2012, 849132, 2012.

ü Nahum LA, Pereira SL. Phylogenomics, Protein Family Evolution, and the Tree of Life: An Integrated Approach between Molecular Evolution and Computational Intelligence. In: Smolinski TG, Milanova MG, Hassanien A-E (eds), Studies in Computational Intelligence (SCI) 122. Springer-Verlag Berlin Heidelberg, 2008. cap. 11, p. 259–279.

ü Pica-Mattoccia L, Cioli D. Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. International Journal for Parasitology, v. 34, p. 527- 33, 2004.

ü Pinot de Moira A, Fulford AJ, Kabatereine NB, Ouma JH, Booth M, et al. Analysis of complex patterns of human exposure and immunity to Schistosomiasis mansoni: the influence of age, sex, ethnicity and IgE. PLoS Negl Trop Dis v. 14, e820, 2010.

ü Plowman GD, Sudarsanam S, Bingham J, Whyte D, Hunter T. The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. Proc Natl Acad Sci U S A, v. 96, p. 13603-13610, 1999.

ü Protasio AV, Tsai IJ, Babbage A, Nichol S, Hunt M, Aslett MA, De Silva N, Velarde GS, Anderson TJ, Clark RC, Davidson C, Dillon GP, Holroyd NE, LoVerde PT, Lloyd C, McQuillan J, Oliveira G, Otto TD, Parker-Manuel SJ, Quail MA, Wilson RA, Zerlotini A, Dunne DW, Berriman M: A systematically improved high quality genome and transcriptome of the human blood fluke Schistosoma mansoni. PLoS Negl Trop Dis, v. 6, e1455, 2012.

ü Rokni MB: Schistosomiasis. Croatia: InTech, 2012. p. 322.

ü Sjölander K. Phylogenomic inference of protein molecular function: advances and challenges. Bioinformatics, v. 20, p. 170-179, 2004.

ü Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect Dis, v. 6, p. 411-25, 2006.

ü Subpipattana P, Grams R, Vichasri-Grams S. Analysis of a calcium-binding EF-hand protein family in Fasciola gigantica. Exp Parasitol. v.130, p: 364-73, 2012.

ü Swain MT, Larkin DM, Caffrey CR, Davies SJ, Loukas A, Skelly PJ, Hoffmann KF. Schistosoma comparative genomics: integrating genome structure, parasite biology and anthelmintic discovery. Trends Parasitol, v. 27, p. 555-64, 2011.

ü Touchman, J. Comparative Genomics. Nature Education Knowledge, v. 3, p. 13

ü Tran MH, Pearson MS, Bethony JM, Smyth DJ, Jones MK, Duke M, Don TA, McManus DP, Correa-Oliveira R, Loukas A. Tetraspanins on the surface of Schistosoma mansoni are protective antigens against schistosomiasis. Nature Medicine, v. 12, p. 835-40, 2006.

ü Tsai IJ, Zarowiecki M, Holroyd N, Garciarrubio A, Sanchez-Flores A, Brooks KL, Tracey A, Bobes RJ, Fragoso G, Sciutto E, Aslett M, Beasley H, Bennett HM, Cai J, Camicia F, Clark R, Cucher M, De Silva N, Day TA, Deplazes P, Estrada K, Fernández C, Holland PW, Hou J, Hu S, Huckvale T, Hung SS, Kamenetzky L, Keane JA, Kiss F, Koziol U, Lambert O, Liu K, Luo X, Luo Y, Macchiaroli N, Nichol S, Paps J, Parkinson J, Pouchkina-Stantcheva N, Riddiford N, Rosenzvit M, Salinas G, Wasmuth JD, Zamanian M, Zheng Y; Taenia solium Genome Consortium, Cai X, Soberón X, Olson PD, Laclette JP, Brehm K, Berriman M. The genomes of four tapeworm species reveal adaptations to parasitism. Nature, v. 496, p. 57- 63, 2013.

ü Van Valen L. A new evolutionary law. Evol. Theory, v. 1, p. 1-30, 1973.

ü Waknine-Grinberg JH, Gold D, Ohayon A, Flescher E, Heyfets A, Doenhoff MJ, Schramm G, Haas H, Golenser J. Schistosoma mansoni infection reduces the incidence of murine cerebral malaria. Malaria Journal, v. 9, 2010.

ü Webster JP, Oliviera G, Rollinson D, Gower CM. Schistosome genomes: a wealth of information. Trends in Parasitology, v. 26, p. 103-6, 2010.

ü Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J, v. 14, p. 2147-2157, 2000.

ü Webster M, Fulford AJ, Braun G, Ouma JH, Kariuki HC, et al. Human immunoglobulin E responses to a recombinant 22.6-kilodalton antigen from Schistosoma mansoni adult worms are associated with low intensities of reinfection after treatment. Infect Immun v.64, p: 4042– 4046, 1996.

ü WHO - World Health Organization: Schistosomiasis: number of people treated in 2009. Wkly Epidemiol Rec, v. 86, p. 73–80, 2011.

ü WHO - World Health Organization: Schistosomiasis: number of people treated in 2011. Wkly Epidemiol Rec, v. 88, p. 81-88, 2013.

ü Young ND, Jex AR, Li B, Liu S, Yang L, Xiong Z, Li Y, Cantacessi C, Hall RS, Xu X, Chen F, Wu X, Zerlotini A, Oliveira G, Hofmann A, Zhang G, Fang X, Kang Y, Campbell BE, Loukas A, Ranganathan S, Rollinson D, Rinaldi G, Brindley PJ, Yang H, Wang J, Gasser RB: Whole- genome sequence of Schistosoma haematobium. Nature Genetics, v. 44, p:221–225, 2012

ü Zerlotini A, Heiges M, Wang H, Moraes RL, Dominitini AJ, Ruiz JC, Kissinger JC, Oliveira G. SchistoDB: a Schistosoma mansoni genome resource. Nucleic Acids Research, v. 37, p. D579-82, 2009.

ü Zhang Z, Xu H, Gan W, Zeng S, Hu X. Schistosoma japonicum calcium-binding tegumental protein SjTP22.4 immunization confers praziquantel schistosomulumicide and antifecundity effect in mice. Vaccine v. 30, p: 5141-50, 2012.

ü Zhou Y, Zheng H, Chen Y, Zhang L, Wang K, Guo J, Huang Z, Zhang B, Huang W, Jin K, Dou T, Hasegawa M, Wang L, Zhang Y, Zhou J, Tao L, Cao Z, Li Y, Vinar T, Brejova B, Brown D, Li M, Miller DJ, Blair D, Zhong Y, Chen Z, Liu F, Hu W, Wang ZQ, Zhang QH, Song HD, Chen S, Xu X, Xu B, Ju C, Huang Y, Brindley PJ, McManus DP, Feng Z, Han ZG, Lu G, Ren S, Wang Y, Gu W, Kang H, Chen J, Chen X, Chen S, Wang L, Yan J, Wang B, Lv X, Jin L, Wang B, Pu S, Zhang X, Zhang W, Hu Q, Zhu G, Wang J, Yu J, Wang J, Yang H, Ning Z, Beriman M, Wei CL, Ruan Y, Zhao G, Wang S, Liu F, Zhou Y, Wang ZQ, Lu G, Zheng H, Brindley PJ, McManus DP, Blair D, Zhang QH, Zhong Y, Wang S, Han ZG, Chen Z, Wang S, Han ZG, Chen Z.. The Schistosoma japonicum genome reveals features of host-parasite interplay. Nature v.460, p: 345-351, 2009.