Abstract
Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to −9.5×10−4 (95% CI −1.1×10−3 to −6.8×10−4); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620–1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts.
Highlights
Mycobacterium tuberculosis (M.tb) is among a group of highly virulent bacteria that exhibit extremely low levels of population genetic diversity [1]
Countries of origin for M.tb isolates included in this study and a Bayesian phylogeny based on M.tb genomic data are shown in Figure 1, along with a global human phylogeny based on Y
Our results suggest that growth of M.tb populations parallels that of its human host population, and that complex influences lead to emergence and maintenance of adaptive traits in M.tb
Summary
Mycobacterium tuberculosis (M.tb) is among a group of highly virulent bacteria that exhibit extremely low levels of population genetic diversity [1]. Our goal here was to test M.tb population genomic data for signatures of both positive and negative selection, to identify regional differences in the strength and type of selection on the M.tb genome, and to quantify fitness effects of new mutations among natural populations of M.tb. We performed these analyses on whole genome sequence data from a globally representative sample of M.tb and related pathogenic mycobacteria
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