Tradeoffs between fitness costs and transfer rates in horizontal gene transfer

水平基因转移中适应度成本和转移率之间的权衡

• 批准号: 10585969
• 负责人: LINGCHONG YOU
• 金额: $ 42.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585969
• 关键词: Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Biology; Biotechnology; Cell division; Clinical; Complex; DNA biosynthesis; Drug resistance; Engineering; Enterobacteriaceae; Environment; Environmental Risk Factor; Epidemiology; Escherichia coli; Evolution; Extended-spectrum β-lactamase; Fostering; Foundations; Gene Expression; Gene Expression Profile; Gene Transfer; Genes; Genomics; Goals; Growth; High Prevalence; Horizontal Disease Transmission; Horizontal Gene Transfer; Intervention; Investments; Libraries; Link; Measurement; Measures; Mediating; Medical; Metabolic; Mobile Genetic Elements; Modernization; Molecular; Nature; Parasites; Phenotype; Plasmids; Play; Population; Prevalence; Process; Publishing; Research; Resistance; Role; Study models; Testing; Vertical Transmission; Work; World Health Organization; cell growth; cost; design; drug resistant pathogen; effective intervention; fitness; gene product; gut microbiome; insight; interest; microbial community; microbiome; next generation sequencing; pathogen; pathogenic bacteria; phenomics; prevent; resistance gene; risk minimization; synthetic construct; trait; transcriptomics; transmission process

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.

摘要 移动的遗传元件（MGE）通过水平基因转移（HGT）的传播可以影响植物的遗传多样性。 微生物群落的动态、功能和存活。HGT的一个主要机制是接合， 在病原菌抗生素耐药性的获得和传播中起关键作用。结合高- 通过表型定量和基因组测序，我们最近发现，>200例临床病例中，>25%的病例 表达超广谱β-内酰胺酶（ESBLs）的细菌分离株可有效地转移其耐药性 通过共轭。可转移质粒的广泛存在引起了关于 其持续性的决定因素以及如何逆转。过去的研究表明， 一个质粒的稳定性取决于两个关键性状-质粒的适应性效应和它的转移速率。初步 在这项工作中，我们发现质粒负荷和接合之间存在稳健的阈值线性相关性 效率大多数质粒不会经历显著的负荷增加，除非它们的接合 效率达到阈值。超过阈值，这两个方面之间出现了重大权衡： 质粒转移越快，对宿主造成的负担就越大。这种权衡对以下方面有影响： 质粒在微生物群落中的持久性和进化。在我们出版的基础上， 工作和初步结果，拟议的研究的中心目标是审查这一定量 根据其潜在的分子机制和其一般适用性的相关性（不同的质粒， 细菌宿主和生长环境）。我们还将研究生态和进化 后果为了实现这一目标，我们将量化这种相关性，以获得广泛的可转移的 不同细菌宿主中的质粒，检查与质粒相关的基因的表达模式， 宿主，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前所未有的，定量测量调制 HGT受抗生素和其他环境因素的影响。