Departments of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
PLoS Pathog. 2013 Aug;9(8):e1003543. doi: 10.1371/journal.ppat.1003543. Epub 2013 Aug 15.
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.
结核分枝杆菌（M.tb）是结核病（TB）的病原体，据估计，每秒钟就会有一个新宿主被感染。尽管对 M.tb 自然种群的遗传数据分析强调了遗传漂变在塑造多样性模式方面的作用，但自然选择对这种成功病原体的影响却知之甚少。我们研究了自然选择对 63 个全球现存 M.tb 和相关致病性分枝杆菌基因组多样性模式的影响。我们发现了强烈的纯化选择的证据，估计全基因组选择系数等于-9.5×10(-4)（95%置信区间-1.1×10(-3)至-6.8×10(-4)）；这比最近对真核生物和原核生物的估计高出几个数量级。我们还发现了不同类别的基因功能的变异模式。涉及无机离子运输和代谢的基因表现出非常低的非同义多态性水平，相当于强烈纯化选择的类别（必需和翻译相关的基因）。在一组转运基因中观察到最高水平的非同义变异，这可能是由于多样化选择或局部选择清扫。除了选择，我们还确定了其他对 M.tb 遗传多样性有重要影响的因素，例如与人类人口爆炸同时发生的全球 M.tb 种群的 25 倍扩张（估计时间为公元 1684 年，95%置信区间为公元 1620-1713 年）。这些结果强调了这种专性病原体及其人类宿主的平行人口历史，并表明选择对 M.tb 的主要影响是去除新变体，在涉及运输和防御的一组有趣的基因中存在例外。我们推测，宿主内的恶劣环境对 M.tb 生理学提出了严格要求，因此大多数新突变都有很大的适应成本。在这方面，专性细菌病原体可能与其他与宿主相关的微生物（如共生体）不同。
