The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations

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.

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis

“…These two studies yielded similar rate estimates, despite including data from very different time periods. The substitution rate estimates of ∼5 × 10 −8 substitutions/site/year (s/s/y) obtained in these aDNA studies are slightly lower than estimates from epidemiologic studies and other studies based on contemporaneous sampling, all of which produced rate estimates around 0.7 × 10 −7 -1.3 × 10 −7 s/s/y, corresponding to 0.3-0.5 substitutions/genome/ year (6,(13)(14)(15)(16)(17)(18).…”

“…It has been suggested that a high degree of congruence between human and Mtb phylogenies supports a scenario of codivergence for the two organisms, and thus that the age of the MRCA of Mtb mirrors the timing of the migrations of anatomically modern humans out of Africa approximately 40,000-70,000 y ago (9). However, another study failed to identify such a congruence in phylogenies and did not find support for a codivergence scenario when using a host of formal tests (16). When it comes to the Beijing lineage, age estimates range from approximately 6,000 y (2, 9) to 30,000 y (1); however, the two studies using aDNA to calibrate MTBC phylogenies both estimated an age of approximately 6,000 y for the TMRCA of all extant Mtb (11,12).…”

“…(11,12) and human-Mtb codivergence (9) for calibration are annotated separately. The other studies used tip dating (6,13,14) or historical information (16), or counted mutations in paired isolates (15) or serial isolates (17).…”

Methodological and Clinical Aspects of the Molecular Epidemiology of Mycobacterium tuberculosis and Other Mycobacteria

“…It can also be helpful in exploring important questions about the biology of mycobacteria, including evolutionary mechanisms shaping mycobacterial populations (219)(220)(221), antibiotic resistance (222)(223)(224)(225), or virulence and immunogenicity (54, 226,227).…”

Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis

“…The age of the association between humans and MTBC remains controversial: some studies estimate the most recent common ancestor (MRCA) of MTCB existed less than 6,000 y ago (17)(18)(19), whereas others have obtained a figure of around 70,000 y ago (20)(21)(22). Regardless of which estimate is more…”