This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G
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This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Transmission Dynamics of Avian Influenza A Virus Lu Lu Submitted for the degree of Doctor of Philosophy University of Edinburgh 2015 Declaration This thesis has been composed by my own. The work is my own work except where otherwise indicated in the text. The work has not been submitted for any other degree or professional qualification except as specified. Lu Lu 2014.12.18 Acknowledgements I appreciate my funding from the China Scholarship Council/University of Edinburgh Joint Scholarship. This work could not have been completed without it. I would like to thank many people who provided great help to not only my PhD study but the life in UK during the past three years. They have made it possible for me to complete this thesis. First of all, I am eternally grateful to my first and second supervisor: Prof. Andy J. Leigh Brown and Dr. Samantha J. Lycett, for providing me with the opportunity to undertake a PhD and for guidance during my PhD. They have put a considerable amount of time into meetings and discussions which were invaluable for the progress of my PhD. They have been incredibly patient and provided great encouragement when I met difficulties. They are the critical people to help me become confident and independent in my research. I also appreciate Prof. Andrew Rambaut, Prof. Ian White, Dr. Darren J Obbard for very helpful technical suggestions. It is a great pleasure to work in this friendly environment in the Ashworth Laboratories and I’d like to thank all my friends here. Especially, I appreciate all the numbers in the Leigh Brown group: Dr. Melissa Ward, Emma Hodcroft, Manon Ragonnet and Mojca Zelnikar. Their sincere friendship and selfless help make me feel extremely touched and warm. I also thank the numbers in virus group: Gytis Dudas, Matthew Hall and Dr. Jessica Hedge, Dr. Trevor Bedford, they always give me suggestions with patience. Finally, I thank my family for their great love, encouragement, and for the confidence they have placed in me from start to finish. Publications The following papers have arisen from this thesis: Lu Lu, Samantha J. Lycett, and Andrew J. Leigh Brown. Determining the genetic and phylogeographic origin of highly pathogenic avian influenza H7N3 in Mexico.PLos one. 2014, 9 doi: 10.1371/journal.pone.0107330 Lu Lu, Samantha J. Lycett, and Andrew J. Leigh Brown. Reassortment patterns of avian influenza viruses among different subtypes in internal segments. BMC Evolutionary Biology. 2014, 14:16 doi:10.1186/1471-2148-14-16 List of Abbreviations AI Association Index AIC Akaike's information criterion AIV Avian influenza A virus BEAST Bayesian Evolutionary Analysis by Sampling Trees BER Bohai Economic Rim BF Bayes Factor Cls Credible intervals CTMC Continuous-time Markov chain ED Economic divided zones ESS Effective sample size GLM Generalized linear model GTR General reversible model HKY Hasegawa-Kishino-Yano HME Harmonic mean estimator HPAI Highly Pathogenic Avian Influenza HPD Highest posterior density IP Inclusion probabilities LPAI Low Pathogenic Avian Influenza MC Maximum monophyletic clade size MCC Maximum Clade Credibility MCMC Markov chain Monte Carlo ML Maximum likelihood NCBI the National Centre for Biotechnology Information NIAID the National Institute of Allergy and Infectious Diseases NJ Neighbour-joining OIE World Organisation for Animal Health PRD Pan-Pearl River Delta PS Parsimony Score PS Path sampling RRW Relaxed random walk SA Sialic acid SIV Swine influenza A viruses SLAC Single Likelihood Ancestor Counting S-OIV H1N1 swine-originated H1N1 pandemic strain SS Stepping stone TMRCA the most recent common ancestor TR Traditional regions WHO World Health Organization YRD Yangtze River Delta Contents Declaration ............................................................................................................................... 2 Acknowledgements .................................................................................................................. 3 Publications .............................................................................................................................. 4 List of Abbreviations ............................................................................................................... 5 Abstract .................................................................................................................................. 12 Chapter 1 ................................................................................................................................ 14 Introduction ............................................................................................................................ 14 Chapter abstract ................................................................................................................. 15 1.1 Influenza viruses .......................................................................................................... 15 1.1.1 Virion structure and life cycle ............................................................................... 16 1.1.2 Mechanisms of Evolution: antigenic shift and drift .............................................. 17 1.2 Avian influenza viruses (AIV) ..................................................................................... 18 1.2.1 Pathogenicity of AIV ............................................................................................ 18 1.2.2 AIV in wild birds .................................................................................................. 20 1.2.3 AIV in domestic birds ........................................................................................... 22 1.2.4 Inter-species and cross-species transmission ........................................................ 23 1.2.5 Epidemics and Reassortment of AIV .................................................................... 24 1.2.6 Phylodynamics studies of AIV ............................................................................. 32 1.3 Objective of this study ................................................................................................. 33 Chapter 2 ................................................................................................................................ 35 Methods ................................................................................................................................. 35 Chapter Abstract ................................................................................................................ 36 2.1 Models of molecular evolution .................................................................................... 37 2.2 Phylogenetic methods .................................................................................................. 39 2.2.1 Neighbour joining and maximum likelihood phylogenetics ................................. 39 2.2.2 Bayesian phylogenetics ......................................................................................... 40 2.2.3 Molecular clock models ........................................................................................ 43 2.3.4 Tree priors (the coalescent models) ...................................................................... 44 2.3 Model selection ............................................................................................................ 45 2.4 Ancestral state reconstruction under a Bayesian framework ....................................... 47 6 2.5 AIV dataset .................................................................................................................. 50 2.6 Phylogenetic analysis ................................................................................................... 52 Chapter 3 ................................................................................................................................ 55 Reassortment patterns of avian influenza virus internal segments among different subtypes 55 Chapter Abstract ................................................................................................................ 56 3.1 Introduction .................................................................................................................. 57 3.2 Methods........................................................................................................................ 60 3.2.1 Data preparation and Preliminary phylogenetic analysis ...................................... 60 3.2.2 Time-scaled phylogenetic analysis ....................................................................... 62 3.2.3 Discrete trait mapping and estimation of reassortment rates ...............................