Bacterial Genomic Diversity

这项工作将探索人类行为在现实世界中变异的遗传基础。 病原体在个体人类和整个人群的感染过程中。重点将放在两个革兰阴性 病原体，类鼻疽伯克霍尔德氏菌和志贺氏菌，这两种病原体都引起传染性 与人类的大量死亡相关的疾病。B。类鼻疽是一种机会致病菌， 引起类鼻疽，一种主要见于东南亚和北方澳大利亚的疾病;它已被分类为 作为一种选择剂，因为它被认为具有生物战剂的潜力。S.菌痢 流行病，主要发生在发展中国家，造成大量死亡，特别是儿童死亡。 这项工作的基本假设是，在个体B. 类鼻疽感染或在S.寄生虫的流行将揭示对人类的选择性压力， 这些物种作为宿主防御，治疗的结果，并在S. The dynamic 流行病在其中传播的宿主人口特征的变化。更好的 了解这些遗传效应的分子基础可能会为临床治疗提供新的方法。 以及疾病的公共卫生管理。该项目有一个主要的技术组成部分， 尽管新一代测序技术为这类研究提供了机会， 尽管如此，该技术的关键方面仍然不发达。我们特别着重 提高新的碱基对准确的完成的基因组序列的速度， 为特定感染或流行病的指示菌株而生产。这些参考序列是 在实验和计算方法中的作用，用于检测发生在 传染病和流行病。

The proposed work will explore the genetic basis for real-world variability in the behavior of human pathogens during infections of individual humans and whole populations. The focus will be on two gramnegative pathogens, Burkholderia pseudomallei and Shigella dysenteriae, both of which cause infectious diseases associated with substantial mortality in humans. B. pseudomallei is an opportunistic pathogen that causes melioidosis, a disease largely found in Southeast Asia and Northern Australia; it has been classified as a select agent because of its perceived potential as a biowarfare agent. S. dysenteriae causes dysentery epidemics, predominantly in developing countries, which cause substantial mortality, particular in children. The basic hypothesis behind the proposed work is that genetic changes occurring during individual B. pseudomallei infections or during S. dysenteriae epidemics will reveal the selective pressures operating on these species as a result of host defenses, treatment, and¿in the case of S. dysenteriae¿the dynamic changes in the characteristics of the host population within which the epidemic is spreading. A better understanding of the molecular basis for these genetic effects may suggest new approaches to the clinical and public-health management of the diseases. The project has a major technical component since, although new-generation-sequencing technology is opening up the opportunity for studies of the type proposed, key aspects of the technology remain underdeveloped. We place particular emphasis on improvements in the rapidity with which new base-pair-accurate, finished genome sequences can be produced for the index strains of particular infections or epidemics. These reference sequences play a key in role in the experimental and computational methods used to detect the genetic changes that occur during infections and epidemics.