A seventeenth-centuryMycobacterium tuberculosisgenome supports a Neolithic emergence of theMycobacterium tuberculosiscomplex

Abstract

BackgroundAlthough tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modernMycobacterium tuberculosiscomplex (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).ResultsA 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 coverageM. tuberculosisgenome. In utilizing this high-quality, high-coverage 17thcenturyM. tuberculosisgenome 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.ConclusionsThe 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.

Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia

“…Our results connect M.tb migration to major historical events in human history that altered patterns of connectivity in Africa and Eurasia. These findings provide context for a recent evolutionary origin of the MRCA of M.tb (Bos et al, ; Kay et al, ; Pepperell et al, ; Sabin et al, ), which represents yet another paradigm shift in our understanding of the history and origin of this successful pathogen.…”

“…These findings provide context for a recent evolutionary origin of the MRCA of M.tb (Bos et al, 2014;Kay et al, 2015;Pepperell et al, 2013;Sabin et al, 2019), which represents yet another paradigm shift in our understanding of the history and origin of this successful pathogen.…”

“…When calibrated with ancient DNA, the estimates of the time to most recent common ancestor (TMRCA) for the MTBC are <6,000 years before present (Bos et al, 2014;Kay et al, 2015;Sabin et al, 2019). This is not necessarily the time period over which TB first emerged, as it is possible, particularly given the apparent absence of recombination among M.tb (Pepperell et al, 2013), that the global population has undergone clonal replacement events that displaced ancient diversity from the species.…”

The Recovery, Interpretation and Use of Ancient Pathogen Genomes

“…Sequence data collected from rapidly evolving RNA viruses over a few years are usually sufficiently informative to allow their evolutionary rate to be estimated. In contrast, for more slowly evolving bacteria such as M. tuberculosis, an ancient genome is sometimes essential to obtain sufficient temporal signal to estimate an evolutionary rate and timescale [101,102].…”

“…Unfortunately, estimating this date can be seriously misled by the effects of purifying selection and misspecification of the evolutionary model. In particular, the removal of deleterious genetic variants by purifying selection can produce a timedependent bias in evolutionary rate estimates, leading to underestimation of deep divergence times [102,104]. Adding ancient genomes to the data set widens the sampling period, potentially allowing for better inference of the evolutionary rate of the pathogen.…”