The role of selection in shaping diversity of natural M. tuberculosis populations.
The role of selection in shaping diversity of natural M. tuberculosis populations.
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DOI：
10.1371/journal.ppat.1003543
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发表时间：
2013-08
期刊：
影响因子：
6.7
通讯作者：
Feldman MW
中科院分区：
文献类型：
--
作者：
Pepperell CS;Casto AM;Kitchen A;Granka JM;Cornejo OE;Holmes EC;Birren B;Galagan J;Feldman MW
结核分枝杆菌（Mycobacterium tuberculosis，M.tb）是结核病（TB）的病因，估计每秒感染一个新的宿主。虽然对结核分枝杆菌自然种群遗传数据的分析强调了遗传漂变在形成多样性模式中的作用，但对自然选择对这种成功病原体的影响还不太了解。我们研究了自然选择对全球现存的63种结核分枝杆菌和相关致病分枝杆菌基因组多样性模式的影响。我们发现了强纯化选择的证据，估计全基因组选择系数等于−9.5×10−4（95%CI −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。我们还确定了不同类别的基因功能的变异模式。参与无机离子运输和代谢的基因表现出非常低水平的非同义多态性，相当于强净化选择下的类别（必需和抑制相关基因）。最高水平的非同义变异出现在一组转运蛋白基因中，可能是由于多样化选择或局部选择性扫描。除了选择之外，我们还发现了对结核分枝杆菌遗传多样性的其他重要影响，例如全球结核分枝杆菌种群的25倍扩张与人类种群的爆炸性增长相一致（估计时间为1684年，95% CI 1620-1713 C.E.）。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统计学历史，并表明选择对结核分枝杆菌的主要影响是去除新的变体，除了一组有趣的基因参与运输和防御。我们推测，宿主体内的恶劣环境对结核分枝杆菌的生理学提出了严格的要求，因此大多数新突变的适应性成本很高。在这方面，专性细菌病原体可能不同于其他宿主相关的微生物，如共生体。 结核分枝杆菌（Mycobacterium tuberculosis，M.tb）是结核病（tuberculosis，TB）的病原体，是人类的高度流行的病原体，估计感染世界上三分之一的人口。以前对结核分枝杆菌进化的研究强调了偶然事件对这些细菌种群的影响。为了理解为什么这种生物如此适应其生态位，我们试图描述自然选择对结核杆菌的影响。结核分枝杆菌群体的DNA序列数据似乎受到全基因组选择对有害突变的强烈影响。这种类型的选择在三个功能类别中特别明显：感染所必需的基因（在结核病动物模型中鉴定），参与蛋白质翻译的基因，以及参与无机离子运输和代谢的基因。相比之下，第四类（“防御”基因）表现出高水平的多样性，与有利突变的选择一致。除了选择对结核分枝杆菌基因组数据的影响外，我们还确定了结核分枝杆菌种群近期明显扩张的影响，这与世界各地人口的爆炸性增长相吻合。我们的研究结果表明，结核分枝杆菌种群的增长与其人类宿主种群的增长平行，复杂的影响导致结核分枝杆菌适应性特征的出现和维持。
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. Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis (TB), is a highly prevalent pathogen of humans, estimated to infect one-third of the world's population. Previous investigations of M.tb evolution have emphasized the influence of chance events on populations of these bacteria. To understand why this organism is so well adapted to its niche, we sought to characterize the influence of natural selection on M.tb. DNA sequence data from M.tb populations appeared to be strongly influenced by genome-wide selection against deleterious mutations. This type of selection was particularly evident in three functional categories: genes essential for infection (identified in an animal model of TB), genes involved in protein translation, and genes involved in trafficking and metabolism of inorganic ions. By contrast, a fourth category (‘defense’ genes) exhibited high levels of diversity, consistent with selection for advantageous mutations. In addition to effects of selection on M.tb genomic data, we identified the influence of a pronounced recent expansion in M.tb populations, coincident with explosive growth of human populations around the world. 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.
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