Final Report Summary - MTB VARIATION (High throughput sequencing to reveal the causes and consequences of Mycobacterium tuberculosis genomic variation) The MTB Variation_272086 project funded by the FP7 was focused on the application of next generation sequencing technologies to understand the global genomic diversity and evolution of the tuberculosis bacillus. There is a growing body of evidence showing that these different lineages are associated to different in vitro, clinical and epidemiological manifestations of the disease. However until now the genetic basis of these differences were unknown partly because we had no information on the genomic diversity of the bacteria at a global scale. The present MTB_variation IEF has filled this knowledge gap and provided a large amount of data that can potentially lead to new insights on the pathogenesis, evolution and epidemiology of the bacteria. Tuberculosis is a pathogen with two faces. Its natural history has characteristics that reminds at the same time to an acute disease and to a chronic disease. We want to add some new light to the evolutionary puzzle of the tuberculosis virulence. How did these different characteristics arise? Did they change over time? With this aim we collected 259 isolates representative of all known lineages and geographic areas and made use of Illumina sequencing technology. The comparative genomic analyses of the strain collection revealed more than thirty thousand single nucleotide polymorphisms (SNPs). These genetic changes are a valuable resource for the tuberculosis community as they can be used to design more universal vaccines and treatments. The evolutionary analyses found strong parallels between the bacteria and human populations suggesting that tuberculosis may have been infecting humans before they left Africa. To date the association of tuberculosis and humans we made used of state-of-the-art dating approaches. The most plausible scenario in our hands was an estimated most recent common ancestor of human tuberculosis strains of 70 thousand years We found a nearly perfect correlation between the bacterial and human population migration and dynamics. We found that human population success during the Neolithic was also tuberculosis population success and the platform for its actual global domination. The most striking results from these analyses was to find out that TB was able to infect and survive in small bands of hunter-gatherers during a long period. How tuberculosis managed to maintain cycles of infection in small bands of a few dozens of people? We suggests a two-step model of virulence for tuberculosis strains. At the beginning due to the low number of available hosts and to avoid its own extinction less virulent strains dominated. When host availability was not anymore a limitation during the population expansion during Neolithic and later on during the industrial revolution. We think this led to more virulent strains able to re-activate quicker and therefore to spread and infect more persons. We are now looking for some of the genetic determinants that could mediate this transition. In that way we think we could find the Achilles' heel of this constant companion of the humankind.Career development: The fellow have been awarded a Ramón y Cajal Research position to start a new group on tuberculosis research in Spain.