Phenotypic heterogeneity promotes adaptive evolution.
Phenotypic heterogeneity promotes adaptive evolution.
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DOI：
10.1371/journal.pbio.2000644
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发表时间：
2017-05
期刊：
影响因子：
9.8
通讯作者：
Pál C
中科院分区：
文献类型：
--
作者：
Bódi Z;Farkas Z;Nevozhay D;Kalapis D;Lázár V;Csörgő B;Nyerges Á;Szamecz B;Fekete G;Papp B;Araújo H;Oliveira JL;Moura G;Santos MAS;Székely T Jr;Balázsi G;Pál C
基因相同的细胞在基因表达、细胞形态和生理上经常表现出实质性的异质性。表型异质性（或可塑性）通过快速产生具有新表型特征的亚种群，加速了面临极端环境挑战的种群的适应性进化速度。这个问题很重要，因为细胞间表型异质性可能启动耐药性和癌症进展的微生物进化的关键步骤。在这里，我们研究了细胞状态之间的随机转换如何影响酵母对应激环境的进化适应。我们开发了可诱导的合成基因回路，产生不同程度的抗真菌抗性基因的表达随机性。我们通过将相应的种群暴露在逐渐增加的抗真菌胁迫下，对携带不同版本遗传电路的基因型进行了实验室进化实验。表型异质性通过改变基因型与适应度相关的适应性景观，改变了进化动力学。具体来说，它通过细胞间变异和遗传变异之间的协同作用增强了有益突变的适应价值。我们的研究表明，当种群面临长期的选择压力时，表型异质性是一种不断进化的特征。它在基因组水平上塑造了进化轨迹，并促进了从不断恶化的环境压力中进行进化拯救。基因相同细胞的表型异质性可以在群体中产生不可遗传的变异。这种异质性对微生物有利吗？在不断变化的环境中，答案是肯定的。虽然学者们认为，随机产生的变异先于遗传变化，从而促进了复杂性状的进化，但这一观点仍然存在争议，尤其是因为缺乏实验研究。我们通过整合合成生物学，实验室实验进化和基因组分析来解决这个长期存在且有争议的问题。我们明确测试了表型异质性可能促进进化的机制。我们的研究表明，表型异质性通过产生异常高适应性的个体，促进了从不断恶化的环境压力中进行进化拯救。值得注意的是，表型异质性的升高是对应激的直接反应，因此它促进了罕见突变组合的进化。这些结果表明，表型异质性可能在关键创新的进化中发挥重要作用。
Genetically identical cells frequently display substantial heterogeneity in gene expression, cellular morphology and physiology. It has been suggested that by rapidly generating a subpopulation with novel phenotypic traits, phenotypic heterogeneity (or plasticity) accelerates the rate of adaptive evolution in populations facing extreme environmental challenges. This issue is important as cell-to-cell phenotypic heterogeneity may initiate key steps in microbial evolution of drug resistance and cancer progression. Here, we study how stochastic transitions between cellular states influence evolutionary adaptation to a stressful environment in yeast Saccharomyces cerevisiae. We developed inducible synthetic gene circuits that generate varying degrees of expression stochasticity of an antifungal resistance gene. We initiated laboratory evolutionary experiments with genotypes carrying different versions of the genetic circuit by exposing the corresponding populations to gradually increasing antifungal stress. Phenotypic heterogeneity altered the evolutionary dynamics by transforming the adaptive landscape that relates genotype to fitness. Specifically, it enhanced the adaptive value of beneficial mutations through synergism between cell-to-cell variability and genetic variation. Our work demonstrates that phenotypic heterogeneity is an evolving trait when populations face a chronic selection pressure. It shapes evolutionary trajectories at the genomic level and facilitates evolutionary rescue from a deteriorating environmental stress. Phenotypic heterogeneity of genetically identical cells can generate nonheritable variation in a population. Is this heterogeneity favorable for microbes? In a changing environment, the answer is a definite yes. While scholars have argued that stochastically generated variation precedes genetic changes and thereby facilitate the evolution of complex traits, this idea has remained disputed, not least because of the shortage of experimental studies. We address this long-standing and controversial issue by integrating synthetic biology, laboratory experimental evolution, and genomic analyses. We explicitly tested the mechanisms whereby phenotypic heterogeneity may promote evolvability. Our work demonstrates that phenotypic heterogeneity facilitates evolutionary rescue from deteriorating environmental stress by generating individuals with exceptionally high fitness. Remarkably, elevated phenotypic heterogeneity evolves as a direct response to stress and thereby it promotes evolution of rare combinations of mutations. These results indicate that phenotypic heterogeneity might have an important role in the evolution of key innovations.