Dynamics of viral host range evolution

 描述（由申请人提供） 影响人类健康的新病毒的出现是一个重大威胁，艾滋病毒、SARS和埃博拉就是最近的例子。新病毒不是自发产生的，而是通过获得对新宿主的偏好而从现存的病毒群体中产生的。然而，这种情况发生的机制仍然知之甚少，病毒的宿主偏好的变化也不容易预测。噬菌体是解决病毒宿主范围进化问题的一个强有力的模型系统。噬菌体群体是巨大的、动态的和古老的，它们在环境碳周转和细菌致病性中起关键作用。噬菌体研究提供了许多好处，包括生物技术工具、细菌感染诊断、噬菌体治疗、合成生物学、微生物计算机和微生物电池。噬菌体群体的巨大遗传多样性，新的噬菌体可以被分离的容易性，它们的宿主范围操纵，以及它们的噬菌体基因分析，提出了一个易于处理的实验系统。噬菌体基因组与其细菌宿主相比通常较小，然而噬菌体基因组序列的定义远远落后于其较大宿主基因组的定义。此外，噬菌体基因组中丰富的新基因表明，它们代表了生物圈中最大的未开发序列库，我们一直在缓慢开发。噬菌体基因组和基因的多样性可能是由宿主与其感染病毒之间30 - 40亿年的战争驱动的，其中抗性宿主的压力持续存在，噬菌体共同进化以获得新宿主。因此，了解宿主偏好的作用和特定基因在特定宿主中生长的需求，将为新病毒如何出现提供关键线索，并为解释噬菌体和细菌基因组提供背景。800个完整测序的噬菌体基因组的大集合感染一个共同的宿主菌株，耻垢分枝杆菌mc 2155显示他们是高度多样化的。不相关基因组的种类繁多，相关基因组间的变异也很大，GC%在50- 70%之间。我们建议，这种多样性是由一个不同的范围内可能的细菌宿主的可用性，连同切换主机偏好的能力，我们预测，从类似的环境中分离的其他主机的切换将显示类似程度的多样性。为了探索病毒宿主范围进化的动力学，我们将描述放线菌目内的宿主范围。将分离和测序个体的DNA，并使用靶向宏基因组策略更广泛地探索这些DNA的基因组多样性。这些寄生虫的宿主范围将被确定，宿主范围变异体将在几个宿主中进化。将建立病毒在不同细菌宿主中生长的遗传要求，生物信息学分析将表征正选择下的基因、重组率、遗传交换的障碍以及宿主偏好的贡献。

 DESCRIPTION (provided by applicant) The emergence of new viruses impacting human health represents an important threat, with HIV, SARS and Ebola as recent examples. New viruses do not spontaneously generate, but arise from the extant viral population by acquisition of preferences for new hosts. However, the mechanisms by which this occurs remain poorly understood, and changes in the host preferences of viruses are not readily predictable. Bacteriophages represent a powerful model system for addressing questions of viral host range evolution. The phage population is vast, dynamic, and old, and they play key roles in environmental carbon turnover and bacterial pathogenicity. Phage studies provide a multitude of benefits, ranging biotechnology tools, diagnostics for bacterial infections, phage therapy, synthetic biology, microbial computers, and microbial batteries. The great genetic diversity of the phage population, the ease with which novel phages can be isolated, their host range manipulated, and their phage genes analyzed, presents a tractable experimental system. Phage genomes are typically small compared to their bacterial hosts, and yet the definition of phage genome sequences lags far behind that of their larger host genomes. Moreover, the abundance of novel genes within phage genomes shows they represent the largest unexplored reservoir of sequences in the biosphere, which we have been slow to tap. The diversity of phage genomes and genes is likely driven by 3-4 billion years of warfare between the hosts and their infecting viruses, with constant pressure for resistant hosts, and phage co- evolution to access new hosts. Thus, understanding the role of host preferences and the demands for specific genes to growth in specific hosts, will provide critical clues as to how new viruses emerge, and a context to interpreting both phage and bacterial genomes. A large collection of 800 completely sequenced phage genomes infecting a common host strain, Mycobacterium smegmatis mc2155 shows them to be highly diverse. Not only are there many types of unrelated genomes, but great variation among related genomes, and the GC% ranges from 50-70%. We propose that this diversity is generated by the availability of a diverse range of possible bacterial hosts, together with the ability of the phages to switch host preferences, and we predict that phages of other hosts that are isolated from similar environments will show similar degrees of diversity. To explore the dynamics of viral host range evolution we will characterize the phages of hosts within the Order Actinomycetales. Individual phages will be isolated and sequenced, and the genome diversity of these phages explored more broadly using targeted metagenomic strategies. The host ranges of these phages will be determined and host range variants evolved across several hosts. The genetic requirements for viral growth in different bacterial hosts will be established, and bioinformatic analyses will characterize genes under positive selection, recombination rates, the barriers to genetic exchange, and the contributions of host preferences.