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一个关键突变阻碍了间日疟原虫耐药性适应性景观中的反向进化。

A pivot mutation impedes reverse evolution across an adaptive landscape for drug resistance in Plasmodium vivax.

作者信息

Ogbunugafor C Brandon, Hartl Daniel

机构信息

Department of Biology, University of Vermont, Burlington, VT, USA.

Vermont Complex Systems Center, The University of Vermont, Burlington, VT, USA.

出版信息

Malar J. 2016 Jan 25;15:40. doi: 10.1186/s12936-016-1090-3.

Abstract

BACKGROUND

The study of reverse evolution from resistant to susceptible phenotypes can reveal constraints on biological evolution, a topic for which evolutionary theory has relatively few general principles. The public health catastrophe of antimicrobial resistance in malaria has brought these constraints on evolution into a practical realm, with one proposed solution: withdrawing anti-malarial medication use in high resistance settings, built on the assumption that reverse evolution occurs readily enough that populations of pathogens may revert to their susceptible states. While past studies have suggested limits to reverse evolution, there have been few attempts to properly dissect its mechanistic constraints.

METHODS

Growth rates were determined from empirical data on the growth and resistance from a set of combinatorially complete set of mutants of a resistance protein (dihydrofolate reductase) in Plasmodium vivax, to construct reverse evolution trajectories. The fitness effects of individual mutations were calculated as a function of drug environment, revealing the magnitude of epistatic interactions between mutations and genetic backgrounds. Evolution across the landscape was simulated in two settings: starting from the population fixed for the quadruple mutant, and from a polymorphic population evenly distributed between double mutants.

RESULTS

A single mutation of large effect (S117N) serves as a pivot point for evolution to high resistance regions of the landscape. Through epistatic interactions with other mutations, this pivot creates an epistatic ratchet against reverse evolution towards the wild type ancestor, even in environments where the wild type is the most fit of all genotypes. This pivot mutation underlies the directional bias in evolution across the landscape, where evolution towards the ancestor is precluded across all examined drug concentrations from various starting points in the landscape.

CONCLUSIONS

The presence of pivot mutations can dictate dynamics of evolution across adaptive landscape through epistatic interactions within a protein, leaving a population trapped on local fitness peaks in an adaptive landscape, unable to locate ancestral genotypes. This irreversibility suggests that the structure of an adaptive landscape for a resistance protein should be understood before considering resistance management strategies. This proposed mechanism for constraints on reverse evolution corroborates evidence from the field indicating that phenotypic reversal often occurs via compensatory mutation at sites independent of those associated with the forward evolution of resistance. Because of this, molecular methods that identify resistance patterns via single SNPs in resistance-associated markers might be missing signals for resistance and compensatory mutation throughout the genome. In these settings, whole genome sequencing efforts should be used to identify resistance patterns, and will likely reveal a more complicated genomic signature for resistance and susceptibility, especially in settings where anti-malarial medications have been used intermittently. Lastly, the findings suggest that, given their role in dictating the dynamics of evolution across the landscape, pivot mutations might serve as future targets for therapy.

摘要

背景

对从抗性表型到敏感表型的逆向进化的研究,可以揭示生物进化的限制因素,而进化理论在这个主题上的一般原则相对较少。疟疾中抗菌药物耐药性这一公共卫生灾难,已将这些进化限制因素带入了实际领域,其中一个提议的解决方案是:在高耐药性环境中停止使用抗疟药物,其依据的假设是逆向进化足够容易发生,以至于病原体种群可能恢复到敏感状态。虽然过去的研究表明逆向进化存在局限性,但很少有人尝试恰当地剖析其机制限制。

方法

根据间日疟原虫中一种耐药蛋白(二氢叶酸还原酶)的一组组合完整的突变体的生长和耐药性的经验数据,确定生长速率,以构建逆向进化轨迹。计算单个突变的适应性效应作为药物环境的函数,揭示突变与遗传背景之间上位性相互作用的大小。在两种情况下模拟景观中的进化:从固定有四重突变体的种群开始,以及从双突变体之间均匀分布的多态种群开始。

结果

一个具有较大效应的单一突变(S117N)作为进化到景观高抗性区域的一个关键点。通过与其他突变的上位性相互作用,这个关键点形成了一个上位性棘轮,阻止向野生型祖先的逆向进化,即使在野生型是所有基因型中最适应的环境中也是如此。这个关键突变是景观中进化方向偏差的基础,从景观中的各种起始点出发,在所有检测的药物浓度下,向祖先的进化都被排除。

结论

关键突变的存在可以通过蛋白质内的上位性相互作用决定适应性景观中的进化动态,使种群被困在适应性景观中的局部适应性峰值上,无法找到祖先基因型。这种不可逆性表明,在考虑耐药性管理策略之前,应该了解耐药蛋白适应性景观的结构。这种提出的逆向进化限制机制,证实了来自该领域的证据,即表型逆转通常通过与耐药性正向进化无关的位点的补偿性突变发生。因此,通过耐药相关标记中的单核苷酸多态性识别耐药模式的分子方法,可能会遗漏整个基因组中耐药和补偿性突变的信号。在这些情况下,应该使用全基因组测序来识别耐药模式,并且可能会揭示出更复杂的耐药和敏感基因组特征,特别是在间歇性使用抗疟药物的环境中。最后,研究结果表明,鉴于关键突变在决定景观中进化动态方面的作用,它们可能成为未来的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d608/4727274/23eee9d3bc65/12936_2016_1090_Fig1_HTML.jpg

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