""4.8.3 Towards Routine Genomic Epidemiology""

""Preface""; ""Contents""; ""Contributors""; ""1 The Nature and Evolution of Genomic Diversity in the Mycobacterium tuberculosis Complex""; ""1.1 Introduction""; ""1.2 The Phylogeography of the Mycobacterium tuberculosis Complex""; ""1.3 The Origin of the MTBC as a Professional Pathogen""; ""1.3.1 The Transition from the Environment to an Obligate Pathogen""; ""1.3.2 Immune Subversion Instead of Immune Escape""; ""1.4 The Evolutionary Forces Driving MTBC Diversity""; ""1.4.1 Impact of Clonality and Genetic Drift""; ""1.4.2 Mutation Rates and Within-Host Evolution""

""1.4.3 Mutation Rates During Latency""""1.5 The Origin and Evolutionary History of the Human-Adapted MTBC""; ""1.5.1 From Promiscuity to Host Specialisation""; ""1.5.2 The MTBC Originated in Africa""; ""1.5.3 Human and MTBC Co-phylogenies""; ""1.5.4 Molecular Dating""; ""1.6 The Ecology of the Human-Adapted MTBC""; ""1.6.1 Local Adaptation""; ""1.6.2 Specialists and Generalists""; ""1.6.3 Evolution Towards Higher Virulence""; ""1.7 MTBC and Homo sapiens Gene-to-Gene Interactions""; ""1.8 Conclusions""; ""References""; ""2 The Biology and Epidemiology of Mycobacterium canettii""

""2.1 Introduction""""2.2 The Phylogeny and Epidemiology of M. canettii Strains""; ""2.3 The Smooth Morphotype of M. canettii""; ""2.4 Virulence Characteristics of M. canettii Strains""; ""2.5 The Recombination Cluster""; ""2.6 Other Genotypic Differences Between M. canettii Strains and the MTBC""; ""References""; ""3 The Evolution of Strain Typing in the Mycobacterium tuberculosis Complex""; ""3.1 Introduction: Need for Effective Genotyping of the MTBC""; ""3.2 Classical Genotyping""; ""3.2.1 General Overview""; ""3.2.2 IS6110 RFLP""; ""3.2.3 First- and Second-Generation Spoligotyping""

""3.2.4 MIRU-VNTR Typing""""3.2.5 Regions of Difference and Single Nucleotide Polymorphism Typing""; ""3.3 Whole-Genome-Based Typing""; ""3.3.1 DNA Extraction and Library Preparation""; ""3.3.2 Massively Parallel Sequencing""; ""3.3.3 Analysis of Sequencing Results by Reference Mapping and SNP Analysis""; ""3.3.4 Analysis of Sequencing Results by Genome-Wide MLST""; ""3.4 Molecular Cluster Definition by Classical Typing and WGS""; ""3.5 Practical Implications: What Method to Use in What Context and for What Question""; ""3.6 Concluding Remarks""; ""References""

""4 Genomic Epidemiology of Tuberculosis""""4.1 Introduction""; ""4.2 Next-Generation DNA Sequencing Applied to the Tubercle Bacilli""; ""4.3 The Genome as an Epidemiological Marker""; ""4.4 Population Scale Analysis of TB Transmission Using WGS""; ""4.5 Role of Within-Host Diversity in Transmission Inference""; ""4.6 Special Cases of Within-Host Diversity: Relapse, Re-infection and Co-infection""; ""4.7 Reconstructing Transmission""; ""4.8 Challenges of Genomic Epidemiology""; ""4.8.1 Understanding the Biology""; ""4.8.2 Beyond Distance Thresholds""

Until about 10 years ago, the general view in the field was that Mycobacterium tuberculosis, the causative agent of human tuberculosis was a "clone" with insufficient natural sequence variation between clinical strains to be considered biologically and epidemiologically "relevant". This view has now changed quite dramatically thanks to the -omics revolution, particularly the advent of next generation DNA sequencing. Large-scale comparative genomic studies over the last few years have revealed that M. tuberculosis clinical strains are more genetically diverse than appreciated previously. Moreover, an increasing number of experimental and epidemiological studies are showing that this genetic diversity also translates into important phenotypic variation. Taken together, these findings have led to a paradigm shift, such that currently phylogenetic diversity among M. tuberculosis clinical strains is being considered in the development of new tools to combat tuberculosis.  The purpose of this book is to bring together a series of contributions from some of the most influential groups working on various aspects of M. tuberculosis diversity, and which through their work have contributed to the this paradigm shift. This includes authors focusing on the evolution of M. tuberculosis in relation to other members of the M. tuberculosis complex adapted to animals, the co-evolution between M. tuberculosis and humans, the phenotypic consequences of strains diversity both from an experimental and epidemiological point of view, the ecology and evolution of drug resistant tuberculosis, the diversity and evolution of the BCG vaccine strains, and the use of mathematical modelling to study strain diversity and drug resistance in human tuberculosis. No such book has ever been published, and given the paradigm shift described above, this book will be a valuable resource both for established researchers as well as new scientists, clinicians and public health officials joining the growing field of tuberculosis research.

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