Proteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance
Proteostasis Environment Shapes Higher-Order Epistasis Operating on Antibiotic Resistance
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DOI：
10.1534/genetics.119.302138
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发表时间：
2019-06-01
期刊：
影响因子：
3.3
通讯作者：
Ogbunugafor, C. Brandon
中科院分区：
文献类型：
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作者：
Guerrero, Rafael F.;Scarpino, Samuel, V;Ogbunugafor, C. Brandon
最近的研究证实，高阶上位性是普遍存在的，对复杂性状有很大的影响。然而，我们缺乏理解上位相互作用如何受到细胞生理学中心特征影响的框架。在这项研究中，我们评估了蛋白质质量控制机制-细胞生理学的一个关键组成部分-如何影响与细菌对抗生素耐药性相关的不同性状的上位性。具体来说，我们分析了不同蛋白质质量控制遗传背景和两组突变之间的相互作用：(i)与必需细菌酶（二氢叶酸还原酶，或DHFR）中抗生素耐药性相关的snp； （ii）不同DHFR细菌物种特异性氨基酸背景序列（大肠杆菌、李斯特菌和muridarum衣原体）。在此过程中，我们通过讨论如何通过必需酶突变和与蛋白质静止环境相关的基因之间的特定相互作用来部分解释上位性模式，从而改进了上位性普遍存在的一般观察结果。这些发现说明了环境和基因型背景在调节高阶上位中的作用，对进化理论、基因修饰技术和管理抗菌素耐药性的努力具有直接意义。
Recent studies have affirmed that higher-order epistasis is ubiquitous and can have large effects on complex traits. Yet, we lack frameworks for understanding how epistatic interactions are influenced by central features of cell physiology. In this study, we assess how protein quality control machinery-a critical component of cell physiology-affects epistasis for different traits related to bacterial resistance to antibiotics. Specifically, we disentangle the interactions between different protein quality control genetic backgrounds and two sets of mutations: (i) SNPs associated with resistance to antibiotics in an essential bacterial enzyme (dihydrofolate reductase, or DHFR) and (ii) differing DHFR bacterial species-specific amino acid background sequences (Escherichia coli, Listeria grayi, and Chlamydia muridarum). In doing so, we improve on generic observations that epistasis is widespread by discussing how patterns of epistasis can be partly explained by specific interactions between mutations in an essential enzyme and genes associated with the proteostasis environment. These findings speak to the role of environmental and genotypic context in modulating higher-order epistasis, with direct implications for evolutionary theory, genetic modification technology, and efforts to manage antimicrobial resistance.