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Palaeopopulation genomics of Mycobacterium tuberculosis
A research project of the Department of Archaeology.
Tuberculosis (TB) is a re-emerging infectious disease that has afflicted the human population for at least the last 8000 years and possibly for much longer. A disease of poverty, the first clear historical account of TB dates to 2700 BC in China and the first convincing archaeological evidence derives from Italy at 5800±90 BP. TB was widespread during the classical period, being described by Hippocrates, Aristotle and Galen. It increased rapidly in Europe during the 17th century, giving rise to the White Plague (named because of the pallor associated with the disease) which by the 19th century was causing up to one quarter of the deaths in London according to the Bills of Mortality. Its prevalence at this time was almost certainly promoted by the higher population densities associated with urbanization, which provide ideal conditions for transmission of an airborne pathogen. Modern vaccination programmes and chemotherapies were thought to have brought the disease under control by the late 1980s9, but its frequency began to rise again in the early 1990s, to the extent that the World Health Organization declared TB to be a global emergency in 1993. One third of the world population has latent TB, and after HIV it kills more people than any other infectious agent. In 2011 it was estimated that 8.7 million people contracted TB and there were 1.4 million deaths.
The main human pathogen, Mycobacterium tuberculosis is now globally distributed and displays biogeographical diversity, caused by genome sequence variations that result in strains that have differing virulence and immunological properties. The emergence of new strains, and changes in the geographical distributions of existing ones, has been recorded during the modern clinical era, and similar events presumably occurred in the past. However, the link between past changes in the population genetics of the bacterium and the evolution of the disease in prehistoric and historic human populations is largely unexplored. The materials for such a study exist, in the form of excavated and curated archaeological skeletons displaying lesions associated with TB. Palaeopathological information on TB from human remains can then be supplemented with genetic data if ancient DNA (aDNA) from the infecting bacteria is preserved in the lesions or other parts of the skeleton.
This Natural Environmental Research Council funded project based at the University of Manchester awarded to Professor Terry Brown, with Professor Charlotte Roberts, Durham, as Co-I, and Romy Müller, University of Manchester, as postdoctoral research assistant (September 2013-September 2016: £486,419 with £44,500 to Durham) exploits the outcomes of a previous NERC grant awarded to Professors Brown and Roberts (Biomolecular archaeology of ancient tuberculosis in Britain and Europe, NE/E018564/1, 2007– 2011). In that project we screened 491 archaeological skeletons, from across Britain and Europe and dating back to the Roman period, for the presence of Mycobacterium tuberculosis aDNA. With those samples containing the best preserved aDNA, we used the polymerase chain reaction (PCR) to type a small number of single nucleotide polymorphisms (SNPs) whose identities enable strains to be placed into broad population groupings recognized in modern M. tuberculosis. We also established the proof of principle on which the new proposal is based: that next generation sequencing (NGS) can be used to type substantially greater numbers of SNPs in M. tuberculosis aDNA than is possible by PCR, and that the genotypes resulting from NGS allow detailed examination of the evolutionary relationships between historic and extant types of TB.
The specific objective of the current project is to test the hypothesis that hybridization capture and Next Generation Sequencing of M. tuberculosis aDNA can provide sufficient genotype data from enough archaeological skeletons for palaeopopulation genomics of TB to become a reality. To test this hypothesis we will attempt to obtain genotype information from samples from British and European skeletons.
Further hypotheses that will be tested include:
- Different strains of TB were present in Britain at different periods in the past
- Within Britain, different strains of TB were associated with different geographical regions, as is indicated for modern TB on a global scale
- The evolutionary dynamics of TB were different in urban and rural locations and
- The evolution of M. tuberculosis in Britain paralleled equivalent events in Europe because of contacts, via trade and other activities, between the human populations
The anticipated achievement is establishment of the utility of palaeopopulation genomics in studies of TB; the outputs will include sequence and genotype information relating to the strains of M. tuberculosis in the skeletons that we will study.