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Abstract:
Background Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor (MRCA) followed human migrations out of Africa ~70,000 years before present (BP). However, studies using ancient genomes as calibration points have yielded much younger MRCA dates of less than 6,000 years. Here we aim to address this discrepancy through the analysis of the highest-coverage and highest quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605 – d. 1697).Results A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Subsequent genomic enrichment enabled the reconstruction of a 141-fold coverage M. tuberculosis genome. In utilizing this high-quality, high-coverage 17th century M. tuberculosis genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent.Conclusions The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate an MRCA date for the MTBC of 3683 BP (2253-5821 BP) and for Lineage 4 of 1651 BP (946-2575 BP) using multiple models, confirming a Neolithic emergence for the MTBC.
