Tradeoffs between fitness costs and transfer rates in horizontal gene transfer

摘要 可移动遗传元件(MGE)通过水平基因转移(HGT)的传播可以影响 微生物群落的动态、功能和生存。HGT的一个主要机制，即结合，发挥着 在病原菌中获得和传播抗生素耐药性的关键作用。通过结合高- 通过表型定量和基因组测序，我们最近发现&gt；25%的临床&gt；200 表达超广谱β-内酰胺酶(ESBL S)的细菌能有效地转移耐药性 通过共轭。可转移质粒的广泛存在引发了关于 其持久性的决定因素以及如何扭转这种状况。过去的研究已经证实，坚持不懈 一个质粒的大小取决于两个关键特性--该质粒的适合度和它的转移率。在预赛中 在这项工作中，我们发现了一个稳健的阈值--质粒负荷和接合之间的线性关联 效率。大多数质粒不会经历显著的负担增加，除非它们接合 效率达到了一个门槛。超出门槛后，在这两个方面之间会出现一个重要的权衡： 质粒转移越快，对宿主造成的负担就越大。这种权衡产生了以下影响 微生物群落中质粒的持久性和进化。在我们出版的基础上 工作和初步结果，建议研究的中心目标是检验这一量化 就其潜在的分子机制和其普遍适用性而言的相关性(不同的质粒， 细菌宿主和生长环境)。我们还将调查生态和进化 后果。为了实现这一目标，我们将量化这种相关性，以实现广泛的可转让 不同细菌宿主中的质粒，检测与质粒相关的基因的表达模式和 宿主使用测序，并预测和测量这些质粒在不同实验条件下的持久性 条件。拟议的研究将产生史无前例的、定量的调制测量 HGT受抗生素等环境因素影响。

Abstract The spread of mobile genetic elements (MGEs) through horizontal gene transfer (HGT) can influence the dynamics, function, and survival of microbial communities. A major mechanism of HGT, conjugation, plays a critical role in the acquisition and spread of antibiotic resistance in pathogenic bacteria. By combining high- throughput phenotypic quantification and genomic sequencing, we recently showed that >25% of >200 clinical bacterial isolates expressing extended spectrum ß-lactamases (ESBLs) can effectively transfer their resistance through conjugation. The widespread of transferable plasmids raises fundamental questions regarding the determinants of their persistence and how it can be reversed. Past studies have established that the persistence of a plasmid depends on two critical traits – the fitness effect of the plasmid and its transfer rate. In preliminary work, we discovered a robust threshold-linear correlation between plasmid burden and conjugation efficiency. Most of the plasmids do not experience a significant increase in burden unless their conjugation efficiency reaches a threshold. Beyond the threshold, a significant tradeoff emerges between the two aspects: the faster a plasmid transfer, the greater the burden it causes to the host. This tradeoff has implications for the persistence and evolution of plasmids in microbial communities. Building on the foundation of our published work and the preliminary results, the central goal of the proposed research is to examine this quantitative correlation in terms of its underlying molecular mechanisms and its general applicability (different plasmids, bacterial hosts, and growth environments). We will also investigate the ecological and evolutionary consequences. To achieve this goal, we will quantify this correlation for a broad spectrum of transferable plasmids in different bacterial hosts, examine the expression patterns of genes associated with plasmids and hosts using sequencing, and predict and measure persistence of these plasmids under different experimental conditions. The proposed research will generate unprecedented, quantitative measurements of modulation of HGT by antibiotics and other environmental factors.