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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 金傳春(Chwan-Chuen King) | |
dc.contributor.author | Po-Hao Chou | en |
dc.contributor.author | 周柏豪 | zh_TW |
dc.date.accessioned | 2021-06-15T12:45:07Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-07-26 | |
dc.identifier.citation | Aly, M. M., A. Arafa, and M. K. Hassan. 2008. 'Epidemiological findings of outbreaks of disease caused by highly pathogenic H5N1 avian influenza virus in poultry in Egypt during 2006.' Avian Dis no. 52 (2):269-77. doi: 10.1637/8166-103007-Reg.1.
Aw, P. P., P. F. de Sessions, A. Wilm, L. T. Hoang, N. Nagarajan, O. M. Sessions, and M. L. Hibberd. 2014. 'Next-generation whole genome sequencing of dengue virus.' Methods Mol Biol no. 1138:175-95. doi: 10.1007/978-1-4939-0348-1_12. Barrero, P. R., M. Viegas, L. E. Valinotto, and A. S. Mistchenko. 2011. 'Genetic and phylogenetic analyses of influenza A H1N1pdm virus in Buenos Aires, Argentina.' J Virol no. 85 (2):1058-66. doi: 10.1128/JVI.00936-10. Bennett, S. 2004. 'Solexa Ltd.' Pharmacogenomics no. 5 (4):433-8. doi: 10.1517/14622416.5.4.433. Bertran, K., D. E. Swayne, M. J. Pantin-Jackwood, D. R. Kapczynski, E. Spackman, and D. L. Suarez. 2016. 'Lack of chicken adaptation of newly emergent Eurasian H5N8 and reassortant H5N2 high pathogenicity avian influenza viruses in the U.S. is consistent with restricted poultry outbreaks in the Pacific flyway during 2014-2015.' Virology no. 494:190-197. doi: 10.1016/j.virol.2016.04.019. Bourret, V., G. Croville, J. Mariette, C. Klopp, O. Bouchez, L. Tiley, and J. L. Guerin. 2013. 'Whole-genome, deep pyrosequencing analysis of a duck influenza A virus evolution in swine cells.' Infect Genet Evol no. 18:31-41. doi: 10.1016/j.meegid.2013.04.034. Butt, K. M., G. J. Smith, H. Chen, L. J. Zhang, Y. H. Leung, K. M. Xu, W. Lim, R. G. Webster, K. Y. Yuen, J. S. Peiris, and Y. Guan. 2005. 'Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003.' J Clin Microbiol no. 43 (11):5760-7. doi: 10.1128/JCM.43.11.5760-5767.2005. Cattoli, G., A. Fusaro, I. Monne, F. Coven, T. Joannis, H. S. El-Hamid, A. A. Hussein, C. Cornelius, N. M. Amarin, M. Mancin, E. C. Holmes, and I. Capua. 2011. 'Evidence for differing evolutionary dynamics of A/H5N1 viruses among countries applying or not applying avian influenza vaccination in poultry.' Vaccine no. 29 (50):9368-75. doi: 10.1016/j.vaccine.2011.09.127. Chang-Chun, Lee. 2006. Molecular Epidemiology of Avian Influenza Virus in A Live Bird Market in Taiwan during 2005-2006, National Taiwan University. Chang, C. F., C. C. King, C. H. Wan, Y. C. Chang, T. C. Chan, C. C. David Lee, P. H. Chou, Z. R. Li, Y. T. Li, T. J. Tseng, P. F. Lee, and C. H. Chang. 2016. 'Lessons from the Largest Epidemic of Avian Influenza Viruses in Taiwan, 2015.' Avian Dis no. 60 (1 Suppl):156-71. doi: 10.1637/11168-051915-Reg. Chen, H., Y. Li, Z. Li, J. Shi, K. Shinya, G. Deng, Q. Qi, G. Tian, S. Fan, H. Zhao, Y. Sun, and Y. Kawaoka. 2006. 'Properties and dissemination of H5N1 viruses isolated during an influenza outbreak in migratory waterfowl in western China.' J Virol no. 80 (12):5976-83. doi: 10.1128/JVI.00110-06. Chen, H., G. J. Smith, S. Y. Zhang, K. Qin, J. Wang, K. S. Li, R. G. Webster, J. S. Peiris, and Y. Guan. 2005. 'Avian flu: H5N1 virus outbreak in migratory waterfowl.' Nature no. 436 (7048):191-2. doi: 10.1038/nature03974. Chen, W., P. A. Calvo, D. Malide, J. Gibbs, U. Schubert, I. Bacik, S. Basta, R. O'Neill, J. Schickli, P. Palese, P. Henklein, J. R. Bennink, and J. W. Yewdell. 2001. 'A novel influenza A virus mitochondrial protein that induces cell death.' Nat Med no. 7 (12):1306-12. doi: 10.1038/nm1201-1306. Cheng, M. C., K. Soda, M. S. Lee, S. H. Lee, Y. Sakoda, H. Kida, and C. H. Wang. 2010. 'Isolation and characterization of potentially pathogenic H5N2 influenza virus from a chicken in Taiwan in 2008.' Avian Dis no. 54 (2):885-93. doi: 10.1637/9208-120609-Reg.1. de la Rosa-Zamboni, D., J. A. Vazquez-Perez, S. Avila-Rios, A. P. Carranco-Arenas, C. E. Ormsby, C. A. Cummings, M. Soto-Nava, V. A. Hernandez-Hernandez, C. O. Orozco-Sanchez, C. A. la Barrera, R. Perez-Padilla, and G. Reyes-Teran. 2012. 'Molecular characterization of the predominant influenza A(H1N1)pdm09 virus in Mexico, December 2011-February 2012.' PLoS One no. 7 (11):e50116. doi: 10.1371/journal.pone.0050116. Deng, G., D. Tan, J. Shi, P. Cui, Y. Jiang, L. Liu, G. Tian, Y. Kawaoka, C. Li, and H. Chen. 2013. 'Complex reassortment of multiple subtypes of avian influenza viruses in domestic ducks at the Dongting Lake Region of China.' J Virol no. 87 (17):9452-62. doi: 10.1128/JVI.00776-13. Drake, J. W. 1993. 'Rates of spontaneous mutation among RNA viruses.' Proc Natl Acad Sci U S A no. 90 (9):4171-5. Drake, J. W., and J. J. Holland. 1999. 'Mutation rates among RNA viruses.' Proc Natl Acad Sci U S A no. 96 (24):13910-3. Dudley, D. M., E. N. Chin, B. N. Bimber, S. S. Sanabani, L. F. Tarosso, P. R. Costa, M. M. Sauer, E. G. Kallas, and D. H. O'Connor. 2012. 'Low-cost ultra-wide genotyping using Roche/454 pyrosequencing for surveillance of HIV drug resistance.' PLoS One no. 7 (5):e36494. doi: 10.1371/journal.pone.0036494. Eid, J., A. Fehr, J. Gray, K. Luong, J. Lyle, G. Otto, P. Peluso, D. Rank, P. Baybayan, B. Bettman, A. Bibillo, K. Bjornson, B. Chaudhuri, F. Christians, R. Cicero, S. Clark, R. Dalal, A. Dewinter, J. Dixon, M. Foquet, A. Gaertner, P. Hardenbol, C. Heiner, K. Hester, D. Holden, G. Kearns, X. Kong, R. Kuse, Y. Lacroix, S. Lin, P. Lundquist, C. Ma, P. Marks, M. Maxham, D. Murphy, I. Park, T. Pham, M. Phillips, J. Roy, R. Sebra, G. Shen, J. Sorenson, A. Tomaney, K. Travers, M. Trulson, J. Vieceli, J. Wegener, D. Wu, A. Yang, D. Zaccarin, P. Zhao, F. Zhong, J. Korlach, and S. Turner. 2009. 'Real-time DNA sequencing from single polymerase molecules.' Science no. 323 (5910):133-8. doi: 10.1126/science.1162986. Fan, S., G. Deng, J. Song, G. Tian, Y. Suo, Y. Jiang, Y. Guan, Z. Bu, Y. Kawaoka, and H. Chen. 2009. 'Two amino acid residues in the matrix protein M1 contribute to the virulence difference of H5N1 avian influenza viruses in mice.' Virology no. 384 (1):28-32. doi: 10.1016/j.virol.2008.11.044. Fouchier, R. A., V. Munster, A. Wallensten, T. M. Bestebroer, S. Herfst, D. Smith, G. F. Rimmelzwaan, B. Olsen, and A. D. Osterhaus. 2005. 'Characterization of a novel influenza A virus hemagglutinin subtype (H16) obtained from black-headed gulls.' J Virol no. 79 (5):2814-22. doi: 10.1128/JVI.79.5.2814-2822.2005. Grard, G., J. N. Fair, D. Lee, E. Slikas, I. Steffen, J. J. Muyembe, T. Sittler, N. Veeraraghavan, J. G. Ruby, C. Wang, M. Makuwa, P. Mulembakani, R. B. Tesh, J. Mazet, A. W. Rimoin, T. Taylor, B. S. Schneider, G. Simmons, E. Delwart, N. D. Wolfe, C. Y. Chiu, and E. M. Leroy. 2012. 'A novel rhabdovirus associated with acute hemorrhagic fever in central Africa.' PLoS Pathog no. 8 (9):e1002924. doi: 10.1371/journal.ppat.1002924. Grinev, A., C. Chancey, G. Anez, C. Ball, V. Winkelman, P. Williamson, G. A. Foster, S. L. Stramer, and M. Rios. 2013. 'Genetic analysis of West Nile virus isolates from an outbreak in Idaho, United States, 2006-2007.' Int J Environ Res Public Health no. 10 (9):4486-506. doi: 10.3390/ijerph10094486. Henikoff, S., and J. G. Henikoff. 1992. 'Amino acid substitution matrices from protein blocks.' Proc Natl Acad Sci U S A no. 89 (22):10915-9. Herfst, S., E. J. Schrauwen, M. Linster, S. Chutinimitkul, E. de Wit, V. J. Munster, E. M. Sorrell, T. M. Bestebroer, D. F. Burke, D. J. Smith, G. F. Rimmelzwaan, A. D. Osterhaus, and R. A. Fouchier. 2012. 'Airborne transmission of influenza A/H5N1 virus between ferrets.' Science no. 336 (6088):1534-41. doi: 10.1126/science.1213362. Horimoto, T., and Y. Kawaoka. 2001. 'Pandemic threat posed by avian influenza A viruses.' Clin Microbiol Rev no. 14 (1):129-49. doi: 10.1128/CMR.14.1.129-149.2001. Huang, P. Y., C. C. Lee, C. H. Yip, C. L. Cheung, G. Yu, T. T. Lam, D. K. Smith, H. Zhu, and Y. Guan. 2016. 'Genetic characterization of highly pathogenic H5 influenza viruses from poultry in Taiwan, 2015.' Infect Genet Evol no. 38:96-100. doi: 10.1016/j.meegid.2015.12.006. Huang, Y., X. Li, H. Zhang, B. Chen, Y. Jiang, L. Yang, W. Zhu, S. Hu, S. Zhou, Y. Tang, X. Xiang, F. Li, W. Li, and L. Gao. 2015. 'Human infection with an avian influenza A (H9N2) virus in the middle region of China.' J Med Virol no. 87 (10):1641-8. doi: 10.1002/jmv.24231. Hui, P. 2014. 'Next generation sequencing: chemistry, technology and applications.' Top Curr Chem no. 336:1-18. doi: 10.1007/128_2012_329. Hulse-Post, D. J., K. M. Sturm-Ramirez, J. Humberd, P. Seiler, E. A. Govorkova, S. Krauss, C. Scholtissek, P. Puthavathana, C. Buranathai, T. D. Nguyen, H. T. Long, T. S. Naipospos, H. Chen, T. M. Ellis, Y. Guan, J. S. Peiris, and R. G. Webster. 2005. 'Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia.' Proc Natl Acad Sci U S A no. 102 (30):10682-7. doi: 10.1073/pnas.0504662102. Ji, H., Y. Li, M. Graham, B. B. Liang, R. Pilon, S. Tyson, G. Peters, S. Tyler, H. Merks, S. Bertagnolio, L. Soto-Ramirez, P. Sandstrom, and J. Brooks. 2011. 'Next-generation sequencing of dried blood spot specimens: a novel approach to HIV drug-resistance surveillance.' Antivir Ther no. 16 (6):871-8. doi: 10.3851/IMP1839. Kandun, I. N., H. Wibisono, E. R. Sedyaningsih, Yusharmen, W. Hadisoedarsuno, W. Purba, H. Santoso, C. Septiawati, E. Tresnaningsih, B. Heriyanto, D. Yuwono, S. Harun, S. Soeroso, S. Giriputra, P. J. Blair, A. Jeremijenko, H. Kosasih, S. D. Putnam, G. Samaan, M. Silitonga, K. H. Chan, L. L. Poon, W. Lim, A. Klimov, S. Lindstrom, Y. Guan, R. Donis, J. Katz, N. Cox, M. Peiris, and T. M. Uyeki. 2006. 'Three Indonesian clusters of H5N1 virus infection in 2005.' N Engl J Med no. 355 (21):2186-94. doi: 10.1056/NEJMoa060930. Kao, C. L., T. C. Chan, C. H. Tsai, K. Y. Chu, S. F. Chuang, C. C. Lee, Z. R. Li, K. W. Wu, L. Y. Chang, Y. H. Shen, L. M. Huang, P. I. Lee, C. Yang, R. Compans, B. T. Rouse, and C. C. King. 2012. 'Emerged HA and NA mutants of the pandemic influenza H1N1 viruses with increasing epidemiological significance in Taipei and Kaohsiung, Taiwan, 2009-10.' PLoS One no. 7 (2):e31162. doi: 10.1371/journal.pone.0031162. Kim, S. H., M. Hur, J. H. Suh, C. Woo, S. J. Wang, E. R. Park, J. Hwang, I. J. An, S. D. Jo, J. H. Shin, S. D. Yu, K. Choi, D. H. Lee, and C. S. Song. 2015. 'Molecular characterization of highly pathogenic avian influenza H5N8 viruses isolated from Baikal teals found dead during a 2014 outbreak in Korea.' J Vet Sci. Kobayashi, M., T. Toyoda, and A. Ishihama. 1996. 'Influenza virus PB1 protein is the minimal and essential subunit of RNA polymerase.' Arch Virol no. 141 (3-4):525-39. Lakdawala, S. S., A. Jayaraman, R. A. Halpin, E. W. Lamirande, A. R. Shih, T. B. Stockwell, X. Lin, A. Simenauer, C. T. Hanson, L. Vogel, M. Paskel, M. Minai, I. Moore, M. Orandle, S. R. Das, D. E. Wentworth, R. Sasisekharan, and K. Subbarao. 2015. 'The soft palate is an important site of adaptation for transmissible influenza viruses.' Nature no. 526 (7571):122-5. doi: 10.1038/nature15379. Lee, C. C., H. Zhu, P. Y. Huang, L. Peng, Y. C. Chang, C. H. Yip, Y. T. Li, C. L. Cheung, R. Compans, C. Yang, D. K. Smith, T. T. Lam, C. C. King, and Y. Guan. 2014. 'Emergence and evolution of avian H5N2 influenza viruses in chickens in Taiwan.' J Virol no. 88 (10):5677-86. doi: 10.1128/JVI.00139-14. Lee, M. S., P. C. Chang, J. H. Shien, M. C. Cheng, C. L. Chen, and H. K. Shieh. 2006. 'Genetic and pathogenic characterization of H6N1 avian influenza viruses isolated in Taiwan between 1972 and 2005.' Avian Dis no. 50 (4):561-71. doi: 10.1637/7640-050106R.1. Lee, M. S., L. H. Chen, Y. P. Chen, Y. P. Liu, W. C. Li, Y. L. Lin, and F. Lee. 2016. 'Highly pathogenic avian influenza viruses H5N2, H5N3, and H5N8 in Taiwan in 2015.' Vet Microbiol no. 187:50-7. doi: 10.1016/j.vetmic.2016.03.012. Lee, Y. J., H. M. Kang, E. K. Lee, B. M. Song, J. Jeong, Y. K. Kwon, H. R. Kim, K. J. Lee, M. S. Hong, I. Jang, K. S. Choi, J. Y. Kim, H. J. Lee, M. S. Kang, O. M. Jeong, J. H. Baek, Y. S. Joo, Y. H. Park, and H. S. Lee. 2014. 'Novel reassortant influenza A(H5N8) viruses, South Korea, 2014.' Emerg Infect Dis no. 20 (6):1087-9. doi: 10.3201/eid2006.140233. Li, Q., X. Sun, Z. Li, Y. Liu, C. J. Vavricka, J. Qi, and G. F. Gao. 2012. 'Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus.' Proc Natl Acad Sci U S A no. 109 (46):18897-902. doi: 10.1073/pnas.1211037109. Li, Q., L. Zhou, M. Zhou, Z. Chen, F. Li, H. Wu, N. Xiang, E. Chen, F. Tang, D. Wang, L. Meng, Z. Hong, W. Tu, Y. Cao, L. Li, F. Ding, B. Liu, M. Wang, R. Xie, R. Gao, X. Li, T. Bai, S. Zou, J. He, J. Hu, Y. Xu, C. Chai, S. Wang, Y. Gao, L. Jin, Y. Zhang, H. Luo, H. Yu, J. He, Q. Li, X. Wang, L. Gao, X. Pang, G. Liu, Y. Yan, H. Yuan, Y. Shu, W. Yang, Y. Wang, F. Wu, T. M. Uyeki, and Z. Feng. 2014. 'Epidemiology of human infections with avian influenza A(H7N9) virus in China.' N Engl J Med no. 370 (6):520-32. doi: 10.1056/NEJMoa1304617. Li, Y. T., H. Y. Ko, C. C. Lee, C. Y. Lai, C. L. Kao, C. Yang, W. B. Wang, and C. C. King. 2015. 'Phenotypic and Genetic Characterization of Avian Influenza H5N2 Viruses with Intra- and Inter-Duck Variations in Taiwan.' PLoS One no. 10 (8):e0133910. doi: 10.1371/journal.pone.0133910. Lin, H. T., C. H. Wang, L. L. Chueh, B. L. Su, and L. C. Wang. 2015. 'Influenza A(H6N1) Virus in Dogs, Taiwan.' Emerg Infect Dis no. 21 (12):2154-7. doi: 10.3201/eid2112.141229. Ma, W., Q. Liu, C. Qiao, G. del Real, A. Garcia-Sastre, R. J. Webby, and J. A. Richt. 2014. 'North American triple reassortant and Eurasian H1N1 swine influenza viruses do not readily reassort to generate a 2009 pandemic H1N1-like virus.' MBio no. 5 (2):e00919-13. doi: 10.1128/mBio.00919-13. Margulies, M., M. Egholm, W. E. Altman, S. Attiya, J. S. Bader, L. A. Bemben, J. Berka, M. S. Braverman, Y. J. Chen, Z. Chen, S. B. Dewell, L. Du, J. M. Fierro, X. V. Gomes, B. C. Godwin, W. He, S. Helgesen, C. H. Ho, G. P. Irzyk, S. C. Jando, M. L. Alenquer, T. P. Jarvie, K. B. Jirage, J. B. Kim, J. R. Knight, J. R. Lanza, J. H. Leamon, S. M. Lefkowitz, M. Lei, J. Li, K. L. Lohman, H. Lu, V. B. Makhijani, K. E. McDade, M. P. McKenna, E. W. Myers, E. Nickerson, J. R. Nobile, R. Plant, B. P. Puc, M. T. Ronan, G. T. Roth, G. J. Sarkis, J. F. Simons, J. W. Simpson, M. Srinivasan, K. R. Tartaro, A. Tomasz, K. A. Vogt, G. A. Volkmer, S. H. Wang, Y. Wang, M. P. Weiner, P. Yu, R. F. Begley, and J. M. Rothberg. 2005. 'Genome sequencing in microfabricated high-density picolitre reactors.' Nature no. 437 (7057):376-80. doi: 10.1038/nature03959. McAuley, J. L., F. Hornung, K. L. Boyd, A. M. Smith, R. McKeon, J. Bennink, J. W. Yewdell, and J. A. McCullers. 2007. 'Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia.' Cell Host Microbe no. 2 (4):240-9. doi: 10.1016/j.chom.2007.09.001. Nakajima, K. 1997. '[Influenza virus genome structure and encoded proteins].' Nihon Rinsho no. 55 (10):2542-6. Newman, R. M., T. Kuntzen, B. Weiner, A. Berical, P. Charlebois, C. Kuiken, D. G. Murphy, P. Simmonds, P. Bennett, N. J. Lennon, B. W. Birren, M. C. Zody, T. M. Allen, and M. R. Henn. 2013. 'Whole genome pyrosequencing of rare hepatitis C virus genotypes enhances subtype classification and identification of naturally occurring drug resistance variants.' J Infect Dis no. 208 (1):17-31. doi: 10.1093/infdis/jis679. Olsen, B., V. J. Munster, A. Wallensten, J. Waldenstrom, A. D. Osterhaus, and R. A. Fouchier. 2006. 'Global patterns of influenza a virus in wild birds.' Science no. 312 (5772):384-8. doi: 10.1126/science.1122438. Orton, R. J., C. F. Wright, M. J. Morelli, D. J. King, D. J. Paton, D. P. King, and D. T. Haydon. 2015. 'Distinguishing low frequency mutations from RT-PCR and sequence errors in viral deep sequencing data.' BMC Genomics no. 16:229. doi: 10.1186/s12864-015-1456-x. Pantin-Jackwood, M. J., and D. L. Suarez. 2013. 'Vaccination of domestic ducks against H5N1 HPAI: a review.' Virus Res no. 178 (1):21-34. doi: 10.1016/j.virusres.2013.07.012. Poon, L. L., T. Song, R. Rosenfeld, X. Lin, M. B. Rogers, B. Zhou, R. Sebra, R. A. Halpin, Y. Guan, A. Twaddle, J. V. DePasse, T. B. Stockwell, D. E. Wentworth, E. C. Holmes, B. Greenbaum, J. S. Peiris, B. J. Cowling, and E. Ghedin. 2016. 'Quantifying influenza virus diversity and transmission in humans.' Nat Genet no. 48 (2):195-200. doi: 10.1038/ng.3479. Quinones-Mateu, M. E., S. Avila, G. Reyes-Teran, and M. A. Martinez. 2014. 'Deep sequencing: becoming a critical tool in clinical virology.' J Clin Virol no. 61 (1):9-19. doi: 10.1016/j.jcv.2014.06.013. Redd, A. D., T. C. Quinn, and A. A. Tobian. 2013. 'Frequency and implications of HIV superinfection.' Lancet Infect Dis no. 13 (7):622-8. doi: 10.1016/S1473-3099(13)70066-5. Reinert, K., B. Langmead, D. Weese, and D. J. Evers. 2015. 'Alignment of Next-Generation Sequencing Reads.' Annu Rev Genomics Hum Genet no. 16:133-51. doi: 10.1146/annurev-genom-090413-025358. Rothberg, J. M., W. Hinz, T. M. Rearick, J. Schultz, W. Mileski, M. Davey, J. H. Leamon, K. Johnson, M. J. Milgrew, M. Edwards, J. Hoon, J. F. Simons, D. Marran, J. W. Myers, J. F. Davidson, A. Branting, J. R. Nobile, B. P. Puc, D. Light, T. A. Clark, M. Huber, J. T. Branciforte, I. B. Stoner, S. E. Cawley, M. Lyons, Y. Fu, N. Homer, M. Sedova, X. Miao, B. Reed, J. Sabina, E. Feierstein, M. Schorn, M. Alanjary, E. Dimalanta, D. Dressman, R. Kasinskas, T. Sokolsky, J. A. Fidanza, E. Namsaraev, K. J. McKernan, A. Williams, G. T. Roth, and J. Bustillo. 2011. 'An integrated semiconductor device enabling non-optical genome sequencing.' Nature no. 475 (7356):348-52. doi: 10.1038/nature10242. Sanger, F., and A. R. Coulson. 1975. 'A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase.' J Mol Biol no. 94 (3):441-8. Sanger, F., S. Nicklen, and A. R. Coulson. 1977. 'DNA sequencing with chain-terminating inhibitors.' Proc Natl Acad Sci U S A no. 74 (12):5463-7. Sanjuan, R., M. R. Nebot, N. Chirico, L. M. Mansky, and R. Belshaw. 2010. 'Viral mutation rates.' J Virol no. 84 (19):9733-48. doi: 10.1128/JVI.00694-10. Senne, D. A., B. Panigrahy, Y. Kawaoka, J. E. Pearson, J. Suss, M. Lipkind, H. Kida, and R. G. Webster. 1996. 'Survey of the hemagglutinin (HA) cleavage site sequence of H5 and H7 avian influenza viruses: amino acid sequence at the HA cleavage site as a marker of pathogenicity potential.' Avian Dis no. 40 (2):425-37. Sessions, O. M., A. Wilm, U. S. Kamaraj, M. M. Choy, A. Chow, Y. Chong, X. M. Ong, N. Nagarajan, A. R. Cook, and E. E. Ooi. 2015. 'Analysis of Dengue Virus Genetic Diversity during Human and Mosquito Infection Reveals Genetic Constraints.' PLoS Negl Trop Dis no. 9 (9):e0004044. doi: 10.1371/journal.pntd.0004044. Shi, W., Y. Shi, Y. Wu, D. Liu, and G. F. Gao. 2013. 'Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan.' Protein Cell no. 4 (11):846-53. doi: 10.1007/s13238-013-3083-0. Simen, B. B., J. F. Simons, K. H. Hullsiek, R. M. Novak, R. D. Macarthur, J. D. Baxter, C. Huang, C. Lubeski, G. S. Turenchalk, M. S. Braverman, B. Desany, J. M. Rothberg, M. Egholm, M. J. Kozal, and Aids Terry Beirn Community Programs for Clinical Research on. 2009. 'Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.' J Infect Dis no. 199 (5):693-701. doi: 10.1086/596736. Sims, L. D., J. Domenech, C. Benigno, S. Kahn, A. Kamata, J. Lubroth, V. Martin, and P. Roeder. 2005. 'Origin and evolution of highly pathogenic H5N1 avian influenza in Asia.' Vet Rec no. 157 (6):159-64. Styczynski, M. P., K. L. Jensen, I. Rigoutsos, and G. Stephanopoulos. 2008. 'BLOSUM62 miscalculations improve search performance.' Nat Biotechnol no. 26 (3):274-5. doi: 10.1038/nbt0308-274. Suarez-Lopez, P., and J. Ortin. 1994. 'An estimation of the nucleotide substitution rate at defined positions in the influenza virus haemagglutinin gene.' J Gen Virol no. 75 ( Pt 2):389-93. doi: 10.1099/0022-1317-75-2-389. Tan le, V., H. R. van Doorn, H. D. Nghia, T. T. Chau, T. P. Tu le, M. de Vries, M. Canuti, M. Deijs, M. F. Jebbink, S. Baker, J. E. Bryant, N. T. Tham, B. Krong NT, M. F. Boni, T. Q. Loi, T. Phuong le, J. T. Verhoeven, M. Crusat, R. E. Jeeninga, C. Schultsz, N. V. Chau, T. T. Hien, L. van der Hoek, J. Farrar, and M. D. de Jong. 2013. 'Identification of a new cyclovirus in cerebrospinal fluid of patients with acute central nervous system infections.' MBio no. 4 (3):e00231-13. doi: 10.1128/mBio.00231-13. Tellez-Sosa, J., M. H. Rodriguez, R. E. Gomez-Barreto, H. Valdovinos-Torres, A. C. Hidalgo, P. Cruz-Hervert, R. S. Luna, E. Carrillo-Valenzo, C. Ramos, L. Garcia-Garcia, and J. Martinez-Barnetche. 2013. 'Using high-throughput sequencing to leverage surveillance of genetic diversity and oseltamivir resistance: a pilot study during the 2009 influenza A(H1N1) pandemic.' PLoS One no. 8 (7):e67010. doi: 10.1371/journal.pone.0067010. Terregino, Calogero, and Ilaria Capua. 2009. 'Conventional Diagnosis of Newcastle Disease Virus Infection.' In Avian Influenza and Newcastle Disease: A Field and Laboratory Manual, edited by Ilaria Capua and Dennis J. Alexander, 123-125. Milano: Springer Milan. To, K. K., A. K. Tsang, J. F. Chan, V. C. Cheng, H. Chen, and K. Y. Yuen. 2014. 'Emergence in China of human disease due to avian influenza A(H10N8)--cause for concern?' J Infect no. 68 (3):205-15. doi: 10.1016/j.jinf.2013.12.014. Tong, S., Y. Li, P. Rivailler, C. Conrardy, D. A. Castillo, L. M. Chen, S. Recuenco, J. A. Ellison, C. T. Davis, I. A. York, A. S. Turmelle, D. Moran, S. Rogers, M. Shi, Y. Tao, M. R. Weil, K. Tang, L. A. Rowe, S. Sammons, X. Xu, M. Frace, K. A. Lindblade, N. J. Cox, L. J. Anderson, C. E. Rupprecht, and R. O. Donis. 2012. 'A distinct lineage of influenza A virus from bats.' Proc Natl Acad Sci U S A no. 109 (11):4269-74. doi: 10.1073/pnas.1116200109. Tong, S., X. Zhu, Y. Li, M. Shi, J. Zhang, M. Bourgeois, H. Yang, X. Chen, S. Recuenco, J. Gomez, L. M. Chen, A. Johnson, Y. Tao, C. Dreyfus, W. Yu, R. McBride, P. J. Carney, A. T. Gilbert, J. Chang, Z. Guo, C. T. Davis, J. C. Paulson, J. Stevens, C. E. Rupprecht, E. C. Holmes, I. A. Wilson, and R. O. Donis. 2013. 'New world bats harbor diverse influenza A viruses.' PLoS Pathog no. 9 (10):e1003657. doi: 10.1371/journal.ppat.1003657. Ungchusak, K., P. Auewarakul, S. F. Dowell, R. Kitphati, W. Auwanit, P. Puthavathana, M. Uiprasertkul, K. Boonnak, C. Pittayawonganon, N. J. Cox, S. R. Zaki, P. Thawatsupha, M. Chittaganpitch, R. Khontong, J. M. Simmerman, and S. Chunsutthiwat. 2005. 'Probable person-to-person transmission of avian influenza A (H5N1).' N Engl J Med no. 352 (4):333-40. doi: 10.1056/NEJMoa044021. Vey, M., M. Orlich, S. Adler, H. D. Klenk, R. Rott, and W. Garten. 1992. 'Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R.' Virology no. 188 (1):408-13. Villarreal, C. 2009. 'Avian influenza in Mexico.' Rev Sci Tech no. 28 (1):261-5. Wang, C., Y. Mitsuya, B. Gharizadeh, M. Ronaghi, and R. W. Shafer. 2007. 'Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance.' Genome Res no. 17 (8):1195-201. doi: 10.1101/gr.6468307. Wang, H., Z. Feng, Y. Shu, H. Yu, L. Zhou, R. Zu, Y. Huai, J. Dong, C. Bao, L. Wen, H. Wang, P. Yang, W. Zhao, L. Dong, M. Zhou, Q. Liao, H. Yang, M. Wang, X. Lu, Z. Shi, W. Wang, L. Gu, F. Zhu, Q. Li, W. Yin, W. Yang, D. Li, T. M. Uyeki, and Y. Wang. 2008. 'Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China.' Lancet no. 371 (9622):1427-34. doi: 10.1016/S0140-6736(08)60493-6. Webster, R. G., W. J. Bean, O. T. Gorman, T. M. Chambers, and Y. Kawaoka. 1992. 'Evolution and ecology of influenza A viruses.' Microbiol Rev no. 56 (1):152-79. Wei, S. H., J. R. Yang, H. S. Wu, M. C. Chang, J. S. Lin, C. Y. Lin, Y. L. Liu, Y. C. Lo, C. H. Yang, J. H. Chuang, M. C. Lin, W. C. Chung, C. H. Liao, M. S. Lee, W. T. Huang, P. J. Chen, M. T. Liu, and F. Y. Chang. 2013. 'Human infection with avian influenza A H6N1 virus: an epidemiological analysis.' Lancet Respir Med no. 1 (10):771-8. doi: 10.1016/S2213-2600(13)70221-2. Wood, G. W., J. W. McCauley, J. B. Bashiruddin, and D. J. Alexander. 1993. 'Deduced amino acid sequences at the haemagglutinin cleavage site of avian influenza A viruses of H5 and H7 subtypes.' Arch Virol no. 130 (1-2):209-17. Wu, H. S., J. R. Yang, M. T. Liu, C. H. Yang, M. C. Cheng, and F. Y. Chang. 2014. 'Influenza A(H5N2) virus antibodies in humans after contact with infected poultry, Taiwan, 2012.' Emerg Infect Dis no. 20 (5):857-60. doi: 10.3201/eid2005.131393. Xu, W., H. Li, and L. Jiang. 2016. 'Human infection with a highly pathogenic avian influenza A (H5N6) virus in Yunnan province, China.' Infect Dis (Lond) no. 48 (6):477-82. doi: 10.3109/23744235.2015.1135253. Xu, Y., H. Cao, H. Liu, H. Sun, B. Martin, Y. Zhao, Q. Wang, G. Deng, J. Xue, Y. Zong, J. Zhu, F. Wen, L. P. Long, S. S. Wong, N. Zhao, X. Fu, M. Liao, G. Hu, R. Webby, G. F. Gao, and X. F. Wan. 2015. 'Identification of the source of A (H10N8) virus causing human infection.' Infect Genet Evol no. 30:159-63. doi: 10.1016/j.meegid.2014.12.026. Yin, L., L. Liu, Y. Sun, W. Hou, A. C. Lowe, B. P. Gardner, M. Salemi, W. B. Williams, W. G. Farmerie, J. W. Sleasman, and M. M. Goodenow. 2012. 'High-resolution deep sequencing reveals biodiversity, population structure, and persistence of HIV-1 quasispecies within host ecosystems.' Retrovirology no. 9:108. doi: 10.1186/1742-4690-9-108. Yu, X., T. Jin, Y. Cui, X. Pu, J. Li, J. Xu, G. Liu, H. Jia, D. Liu, S. Song, Y. Yu, L. Xie, R. Huang, H. Ding, Y. Kou, Y. Zhou, Y. Wang, X. Xu, Y. Yin, J. Wang, C. Guo, X. Yang, L. Hu, X. Wu, H. Wang, J. Liu, G. Zhao, J. Zhou, J. Pan, G. F. Gao, R. Yang, and J. Wang. 2014. 'Influenza H7N9 and H9N2 viruses: coexistence in poultry linked to human H7N9 infection and genome characteristics.' J Virol no. 88 (6):3423-31. doi: 10.1128/JVI.02059-13. Yuan, J., L. Zhang, X. Kan, L. Jiang, J. Yang, Z. Guo, and Q. Ren. 2013. 'Origin and molecular characteristics of a novel 2013 avian influenza A(H6N1) virus causing human infection in Taiwan.' Clin Infect Dis no. 57 (9):1367-8. doi: 10.1093/cid/cit479. Zhou, B., M. E. Donnelly, D. T. Scholes, K. St George, M. Hatta, Y. Kawaoka, and D. E. Wentworth. 2009. 'Single-reaction genomic amplification accelerates sequencing and vaccine production for classical and Swine origin human influenza a viruses.' J Virol no. 83 (19):10309-13. doi: 10.1128/JVI.01109-09. Zhu, X., H. Yang, Z. Guo, W. Yu, P. J. Carney, Y. Li, L. M. Chen, J. C. Paulson, R. O. Donis, S. Tong, J. Stevens, and I. A. Wilson. 2012. 'Crystal structures of two subtype N10 neuraminidase-like proteins from bat influenza A viruses reveal a diverged putative active site.' Proc Natl Acad Sci U S A no. 109 (46):18903-8. doi: 10.1073/pnas.1212579109. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50537 | - |
dc.description.abstract | 禽流行性感冒(簡稱禽流感)病毒防治已視為重要議題。許多嚴重的禽流感疫情在台灣家禽養殖場爆發,不僅造成鉅大經濟損失,也加劇暴露民眾感染禽流感病毒的風險。事實上,以傳統桑格定序法(Sanger sequencing)所建立的禽流感病毒監測系統在台灣已實施多年,依然無法完善地盡早預警與防治禽流感疫情。近年,次世代定序(next generation sequencing, NGS) - 此新穎的DNA定序方法已被廣用於許多病毒的偵測,若啟用於偵測禽流感病毒,將能比傳統桑格定序法提供更多不同次病毒群的些微序列變化資訊;運用此新穎法至田野流行病學所得禽流感病毒,並研發次世代定序後的大量序列數據之一系列分析流程,遂顯得格外重要。因此,本研究的目標為: (1)研發並建立次世代定序分析流程法,以檢測與評估禽流感病毒的細微核甘酸與胺基酸突變;(2)在混合H5與H6不同亞型的禽流感病毒中,以此新分析流程法探尋其可能具有流行病學重要性的特殊病毒核甘酸變異模式,如找出兩不同次病毒群含有致病分子標幟(即基因重組的前兆);(3)評估其未來應用於禽流感病毒偵測系統的適用性;及(4)進行公共衛生風險評估。
針對第一、二目標,做法上是使用2013年台灣家鴨的三禽流感病毒株,各被鑑定為H5N2(DV10955病毒株)、H6N1(DV11011病毒株)和H6N1與H5N2兩亞型混合(DV11018病毒株,並非混合DV11011與 DV10955),以進行次世代定序,並研究分析產出的高通量病毒序列資料。為了評估檢測禽流感病毒中細微的核甘酸與胺基酸突變與兩不同次病毒群是否含有不同亞型禽流感病毒特殊位點的核甘酸變異百分比;先以統計軟體R研發新分析流程法,包括排序、移除定序實驗中曾用引子(primers)與聚合酵素鏈反應(polymerase chain reaction, PCR)可能造成的偏差干擾後,一方面分析禽流感病毒每位點的核甘酸與胺基酸突變百分比;另方面也假定次世代定序中產生的定序誤差發生次數符合卜瓦松分佈(Poisson distribution),並利用卜瓦松累積分布函數檢定此次世代定序過程可能產生的定序誤差而致其影響最小化。最後,仔細深入分析各病毒核苷酸與胺基酸位點間的差異在11種不同的病毒蛋白之變化,並比較此三株不同亞型病毒在次病毒群的核甘酸變異於混合型與單一亞型之異處。此外,為了以次世代定序建立禽流感病毒偵測系統的預警機制並評估其在公共衛生的風險,特別將2013年三株鴨流感病毒中細微的胺基酸突變和過去相同亞型的病毒株(18株H5N2, 52株H6N1)比較,找出過去未曾在台灣出現過的胺基酸突變,而後將這些胺基酸突變和2015年禽流感大疫情63株台灣雞地方性流行H5N2禽流感病毒與clade 2.3.4.4 H5病毒 (H5N2、H5N8、H5N3)的胺基酸進行比較,期望找到潛藏在2013年病毒株中為過去未見的細微胺基酸突變卻又出現在引發2015年台灣禽流感大疫情的病毒序列而有預警性。在公共衛生風險評估上,是依據美國疾管與預防中心提供可能會提高禽流感病毒在哺乳類感染或致病力的66個胺基酸突變,期能於病毒檢體中尋找曾以弱勢存在卻能提高病毒對於哺乳類感染或致病力的胺基酸突變。 研究結果顯示三株鴨流感核苷酸位點遺傳變異百分比的平均值均小於4%。然而,H5N2 DV10955病毒株核甘酸與胺基酸變異的95百分位數卻高於其他兩株病毒;顯示此H5N2 DV10955病毒株可能具有較高的基因突變潛能與引發流行的風險。另方面,混合亞型的禽流感病毒一向被認為是其基因重組的前兆,研究中發現以次世代定序新分析法也可偵測並辨認混合亞型禽流感病毒特殊位點的核苷酸變異百分比。另自此三株病毒中,發現PB1和PB1-F2兩病毒基因之核苷酸變異百分比明顯高於病毒的其他基因外,在病毒各位點的核甘酸比較上,也發現此三株病毒基因均在PB1的核甘酸位點100到1300區域有較高的變異。另外,共發現36個基因突變不僅以弱勢[0.3%-14.6%]存在於2013年此三株病毒,另也出現在引發2015年台灣禽流感大疫情的病毒序列中[1%-90.6%],且此且此三株2013年鴨流感病毒中具有三個共同的細微突變,如M2的胺基酸位點13上天冬醯胺(Asparagine)突變為羥丁胺酸(threonine)。同時,也在病毒中HA切割位上發現一些已證實會在感染雞隻後具較高致死力(lethality)的細微突變 [谷胺酸(Glutamate)突變為離胺酸(lysine)],促使演化為高致病性病毒。 公共衛生風險評估的結果顯示,2013年的臺灣三株鴨流感病毒(H5N2 DV10955、H6N1 DV11011、H6N1與H5N2兩亞型混合DV11018)中確實存在一些已證實會增加病毒對哺乳類致病力的細微胺基酸突變,包括:(1) PB2位點627分別發現了0.28%、0.13% 與0.18%的賴胺酸(lysine)突變,(2) PB2位點701各有0.31%、0.51%及0.13%的天冬醯胺(Asparagine)突變;此外兩H5鴨病毒在HA 222位點各有0.05%及0%的白胺酸(Leucine)突變,與224位點各有0.06%及0.35%的絲胺酸(Serine)突變。最重要的是這些結果證實可以藉由次世代定序協助預測病毒進化的未來走向與下一次可能發生禽流感疫情的風險,同時也可以結合相關的禽流感病毒研究成果進行公共衛生風險評估。 綜言之,本研究致力研發一套合適分析禽流感病毒次世代定序資料的方法,並以新角度研究台灣禽流感病毒的核甘酸與胺基酸變異。結果顯示可以次世代定序法:追蹤台灣禽場的禽流感病毒間或許具有共同的微觀核甘酸與胺基酸變異;並檢視特殊位點、高致病性及公共衛生風險相關胺基酸的隨時間變化,來評估禽流感病毒增加流行潛力之分子標幟,以提早執行防治措施:更重要的是分析2003年12月台灣雞流感H5N2病毒在無菌雞胚傳代以模擬流行情形,也發現除了HA切割位之外,另伴隨PB1較其他7段基因有最多的核甘酸變異,顯示不僅HA還須考慮其他基因在雞流感病毒的致病角色。未來希望以此新開發的方法分析更多台灣田野的禽流感病毒次世代定序序列,整合微觀的分子變異與巨觀的病毒變異群群體變異,將徹底明瞭禽流感病毒的動態演變趨勢,藉以推動最佳防治策略。 | zh_TW |
dc.description.abstract | Prevention of avian influenza viruses (AIVs) has become an important issue in recent years. Several severe outbreaks of AIVs in poultry farms of Taiwan leading to tremendous economic loss and increasing human risk of acquiring infection with AIVs. In fact, virological surveillance system has relied on traditional method using Sanger sequencing, but it has still struggled to guide early warning for successful preventing outbreaks of AIVs. Recently, next-generation sequencing (NGS), a novel method of DNA sequencing, has been widely applied to virological surveillance for many viruses, especially providing more information on viral subtitle sequence variations of different sub-populations of AIVs than Sanger sequencing. Applying this novel approach to AIV isolates obtained from field epidemiology and developing a series of workflow to analyze massive NGS sequence data becomes crucially important. Therefore, the specific aims of this study were: (1) to establish a new analysis method of NGS data for monitoring minor mutations of nucleotides and amino acids that might be possibly present in AIVs, (2) to identify special patterns in variations of nucleotides with epidemiological significance that would be existed in mixed or single subtypes AIVs, thus providing early clues for viral genetic reassortment or recombination; (3) to evaluate its application to future surveillance system of AIVs after best optimization of NGS approach; and (4) to search for possibilities for public health risk assessment using viral population data from NGS.
For the 1st and 2nd aims, the three duck isolates of AIVs obtained from 9- to 11-day embryonated chicken eggs through virological surveillance at a live-poultry market in Taiwan in 2013 were used for getting NGS data. They were identified as H5N2 (ID#DV10955), H6N1 (ID#DV11011), and mixed subtypes of H5N2 and H6N1 (ID#DV11018, not mixing DV11011 with DV10955), respectively. To evaluate minor variations of nucleotides and amino acids of AIVs as well as changing patterns in minor mutations of nucleotides in mixed subtypes of AIVs; a new analysis workflow [such as mapping the sequencing reads, removing the bias caused by the primers and polymerase chain reaction (PCR) process, and analyzing the percentage of variations in nucleotides and amino acids at each position of AIV] was firstly developed by the R software. Subsequently, a statistical test assuming the frequencies of sequencing errors in NGS process following the Poisson distribution and thus using its cumulative distribution function to examine and minimize inaccuracy of sequencing errors existed in the NGS data. Finally, similarities and differences in variations in nucleotides and amino acids of each of the 11 viral proteins of the three studied duck AIVs were analyzed. For the 3rd and 4th aims, to establish an early warning mechanism for AIVs surveillance system using the NGS approach, the minor mutations of amino acids in the 2013 Taiwan three duck influenza virus were compared with their same subtype of AIVs before 2013 (18 strains of H5N2, 52 strains of H6N1) to find out the novel mutations of amino acids that had not appeared in the past Taiwan AIV. These novel mutations of amino acids identified in our studied the three AIVs in 2013 were then compared with the 63 strains of enzootic H5N2 AIVs and clades 2.3.4.4 H5 AIVs (H5N2, H5N8, H5N3) to search for these minor mutations that had never been present in the past but were hidden in the AIVs in 2013 did also occur in strains of AIV that caused large outbreaks in 2015 with better predictability for early warning. Public health risk assessment was based on the 66 mutations of amino acids that may increase the virulence and infectivity of mammalian hosts listed by the Centers for Disease Control and Prevention in the United States (US-CDC), to find out whether the minor mutations of amino acids with increasing virulence and infectivity to mammalian might be present in the studied 2013 AIVs. The results showed that the means of nucleotide variations in the three AIV isolates were lower than 4%. However, the 95th percentile of nucleotide variations of Dk-H5N2-#DV10955 was higher than other two AIV isolates, indicating that certain positions of this H5N2 virus contained higher variations of nucleotide. It implies that the H5N2 had higher potential in genetic variations and risk for leading to outbreaks. On the other hand, the NGS data was capable to differentiate the mixed subtypes of H5N2 and H6N1 from single subtype of AIV by examining the nucleotide variations at specific positions. Such mixed subtypes have been thought with potentiality of gene reassortment or genetic recombination resulting in a novel influenza virus with higher pathogenicity is an important virological surveillance target of AIVs. Among the nucleotide variations of the tested AIVs’ 11 viral proteins, PB1 and PB1-F2 (encoded from PB1 gene) ranked the highest, particularly in the common regions at positions of 100-1300 nucleotides of PB1 presented with highly genetic variations than other viral genes were identified in all the three tested AIV isolates. In addition, the 36 minor mutations of amino acids that were not only hiddenly present in the three 2013 studied AIVs [0.3%-14.6%] but also can be identified in the 2015 Taiwan AIVs [1%-90.6%] during outbreaks. Furthermore, three common minor mutations were found in the 2013 three duck influenza viruses, including a mutation from asparagine (D) to threonine (T) at position 13 of M2. Besides, the minor mutations - the lysine (K) at the HA cleavage site were observed in the two H5 related studied viruses exhibiting greater lethality in chickens. Public health risk assessment shows that the minor mutations of amino acids with higher infectivity and pathogenicity to mammals indeed did exist in the 2013 Taiwan three duck influenza virus (H5N2 DV10955, H6N1 DV11011, H6N1 and H5N2 mixing two subtypes DV11018), including: (1) 0.28%, 0.13% and 0.18% mutations of lysine (K) at position 627 of the PB2; (2) 0.31%, 0.51% and 0.13% the mutation of asparagine (N) at position 701 of the PB2. In addition, the two duck H5 viruses had 0.05% and 0% mutations of leucine (L) at position 222 of the HA, and 0.06% and 0.35% mutations of serine (S) at position 224 of the HA, respectively. Most importantly, these results supported that the NGS can help not only to predict further viral evolution of AIVs and the risk for next possible outbreak, but also to assess public health risk after integrating with related scientific results on molecular signatures of AIVs. In conclusion, this study develop a framework to analyze the NGS data of AIVs and to provide a novel approach to study the genetic variations of AIVs obtained from surveillance and field epidemiology. Our results suggested that NGS approach can: (1) detect the common minor variations being present in different AIV isolates at the micro level in Taiwan field, (2) provide information on minor mutations of amino acids with epidemiological significance that might increase viral pathogenicity and epidemic potentiality of AIVs for early prevention; and (3) offer scientific evidence on changing of those important amino acids over time for better public health risk assessment. Most importantly, serial passages of Taiwan 2003 chicken H5N2 LPAIVs in specific pathogen free eggs found that amino acid changes at the HA cleavage site accompanied with the highest diversities of PB1 nucleotides than other gene segments, implying the significant role of PB1 in addition to HA in viral pathogenicity in chicken influenza viruses. Future studies need to increase more field specimens for NGS data of AIVs. To fully understand the dynamic changes and evolutionary trend in AIVs, obtaining minor mutations at micro-level as well as viral quasispecies population changes at macro-level can certainly help formulate the best prevention and control strategies of AIVs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T12:45:07Z (GMT). No. of bitstreams: 1 ntu-105-R03849026-1.pdf: 2743096 bytes, checksum: 8a989e663cbf600b5e05704f5dc93a4e (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 誌謝(Acknowledgement) i
中文摘要 ii Abstract vi LIST OF FIGURES xvi LIST OF TABLES xviii Chapter 1 Introduction 1 Chapter 2 Literature Review 5 2.1 Avian influenza virus 5 2.1.1 Structure and characteristics of influenza virus 5 2.1.2 Epidemiology of avian influenza 6 2.1.3 Molecular markers for pathogenesis of avian influenza virus 7 2.2 Epidemiology of avian influenza in Taiwan 8 2.2.1 H6N1 AIVs in Taiwan 9 2.2.2 H5N2 AIVs in Taiwan 11 2.2.3 Clade 2.3.4.4 H5 viruses in Taiwan 13 2.3 Next generation sequencing 14 2.4 Applications of next generation sequencing in virological studies 16 2.4.1 Molecular epidemiology 17 2.4.2 Detection of minor variants in viral gene 17 2.5 Common problems of NGS data 18 2.5 Problems in Virological Surveillance of AIVs and the Remained Scientific Questions Common problems of NGS data 19 Chapter 3 Objectives and Specific Aims 21 3.1 Objectives 21 3.2 Specific aims 21 Chapter 4 Materials and Methods 22 4.1 Viruses 22 4.1.1 Studied Taiwan H5 and H6 AIVs through virological surveillance 22 4.1.2 Sample selection of AIVs for next generation sequencing 23 4.2 NGS sample preparation for NGS 23 4.3 Next generation sequencing 24 4.4 Bioinformatics analysis of viral NGS data 24 4.4.1 Mapping of the sequencing reads 24 4.4.2 Genetic variations of PB1-F2 26 4.4.3 Identification of the major sequences and minor mutations in the studied viruses 27 4.4.4 Elimination of the bias caused by multiple RT-PCR 27 4.4.5 Comparison of genetic variation within studied viruses 28 4.4.6 Statistical test 28 4.5 Sequence comparison 30 4.6 Public health risk assessment 31 Chapter 5 Results 32 5.1 Overview of mapping results 32 5.2 Viral variants 33 5.2.1 Genetic variations in different AIV subtypes 33 5.2.2 Genetic variations in different viral proteins of AIVs 33 5.2.3 Genetic variations at different positions of nucleotides 35 5.3 Different patterns in the AIV with mixed H5/H6 subtypes 35 5.4 Viral variations supported with statistical tests 37 5.5 Prospective examination of viral sequences of AIVs obtained in Taiwan, 2015. 38 5.6 Detection of specific molecular signatures in amino acids with higher pathogenicity in the studied AIVs 39 5.7 Detection of specific molecular signatures in the studied AIVs with higher risk of viral infectivity to humans 40 Chapter 6 Discussion 42 6.1 Quality assessment of method to map sequencing read 42 6.2 Genetic variations of AIVs in Taiwan 44 6.2.1 Higher nucleotide variation of H5N2 44 6.2.2 Higher nucleotide variation of PB1 gene 44 6.2.3 Relationship between genetic variation and virulence variation 45 6.3 Applicability of AIVs’ surveillance system that conducted by NGS approach 46 6.3.1 Diagnosis of mixed subtypes AIVs 46 6.3.2 Prediction of pandemic 47 6.3.3 Risk assessment of public health 48 6.4 Limitations 49 6.5 Recommendations and future perspectives 50 REFERENCES 52 FIGURES 63 TABLES 72 Appendix 87 | |
dc.language.iso | en | |
dc.title | 建立禽流感病毒株變異群的次世代定序分析流程-備妥未來病毒偵測與流行潛力趨增之前瞻預警 | zh_TW |
dc.title | Establish an Analysis Framework for Detecting Sub-populations of Avian Influenza Virus Variants by Next Generation Sequencing for Better Preparedness and Early Warning of Viral Variants with Increasing Epidemic Potential through Virological Surveillance | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林菀俞(Wan-Yu Lin),林詩舜(Shih-Shun Lin),張淑媛(Sui-Yuan Chang),游卓遠(Chao-Yuan Yu),劉力瑜(Li-Yu Daisy Liu) | |
dc.subject.keyword | 禽流感病毒,病毒監測,次世代定序,病毒基因變異分析,流行潛力趨增,臺灣, | zh_TW |
dc.subject.keyword | Avian Influenza Virus,Virological surveillance,Next Generation Sequencing,Genetic variation analysis,Increasing epidemic potential,Taiwan, | en |
dc.relation.page | 113 | |
dc.identifier.doi | 10.6342/NTU201601031 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-07-26 | |
dc.contributor.author-college | 公共衛生學院 | zh_TW |
dc.contributor.author-dept | 流行病學與預防醫學研究所 | zh_TW |
顯示於系所單位: | 流行病學與預防醫學研究所 |
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