Genetic and ecological determinants of coronavirus recombination

项目概要： 病毒交换是两种病毒交换部分遗传物质以产生一种病毒的过程。 “子”系基因上不同。对于冠状病毒（CoV）， 产生遗传变异，但它也是宿主转换的重要驱动力。大多数人类的冠状病毒 被认为起源于动物（特别是蝙蝠），并有证据表明它们的进化过程中发生了重组。 历史尽管与公共卫生相关，但重组的机制，驱动因素和限制仍然存在 不清楚通过实验室实验、比较基因组学和数学建模的结合，我们 将检验两个冠状病毒之间重组的概率是遗传距离的函数的假设， 而且这种可能性还受到生态或进化效应的进一步影响。换句话说， 重组随着亲本菌株之间的遗传距离增加而减少（大概是因为 遗传或结构不相容性），但也受到生态过程的影响，例如 两个冠状病毒实际上会同时出现或进化选择压力。我们将测试三个目标：在目标1中，我们将 采用实验室研究，并在系统发育梯度上用成对的CoV共感染人类和蝙蝠细胞系。 这将检验重组的概率是否与亲本间的遗传距离有关， 还显示重组是否在整个基因组中随机发生或特别是“热点”。在目标2中， 我们将使用公共数据库中的基因组或我们自己以前的基因组来评估自然发生的CoV。 工作据推测，天然存在的重组体将是任何遗传限制的结果（例如，遗传 距离），加上任何生态或进化修饰符（例如，自然选择）。因此，通过比较 通过实验室研究（目标1）和观察性研究（目标2），我们可以开始识别尚不清楚的模式 仅凭实验数据，我们就可以理清遗传和生态因素的作用 任何两种病毒重组的概率。这种理解可以用来改进预测 冠状病毒重组的可能性和概率。最后，我们将推断这些影响， 一个空间模型，估计世界不同地区出现重组CoV的风险（目标3）。通过 整合我们独特的全球冠状病毒监测数据（来自>25个国家的> 31，000只动物接受冠状病毒调查）， 将产生一个风险图，预测世界上最有可能发生重组的地区。

PROJECT SUMMARY: Recombination is the process by which two viruses exchange part of their genetic material to produce a ‘daughter’ strain that is genetically distinct. For coronaviruses (CoVs), it is an important evolutionary mechanism for generating genetic variation, but it is also an important driver of host switching. Most CoVs in humans are thought to have originated in animals (in particular, bats) and have evidence of recombination in their evolutionary history. Despite the relevance to public health, the mechanism, drivers, and limitations to recombination remain unclear. Using a combination of laboratory experiments, comparative genomics, and mathematical modeling, we will test the hypothesis that the probability of recombination between two CoVs is a function of genetic distance, and that this probability is further modified by ecological or evolutionary effects. In other words, the likelihood of recombination decreases as the genetic distance between the parental strains increases (presumably because of genetic or structural incompatibilities), but is also impacted by ecological processes such as the chance that two CoVs will actually co-occur or evolutionary selection pressure. We will test three aims: In Aim 1, we will employ laboratory studies and co-infect human and bat cell lines with pairs of CoVs over a phylogenetic gradient. This will test whether the probability of recombination is related to genetic distance between the parents, and will also show whether recombination occurs randomly throughout the genome or in particular ‘hot-spots’. In Aim 2, we will evaluate naturally occurring CoVs using genomes available in public databases or from our own previous work. Presumably, naturally occurring recombinants will be the result of any genetic limitations (e.g., genetic distance), plus any ecological or evolutionary modifiers (e.g., natural selection). Thus, by comparing the laboratory (Aim 1) and observational (Aim 2) studies, we can begin to identify patterns that would remain unclear with experimental data alone, allowing us to disentangle the contributions of both genetic and ecological factors to the probability that any two viruses will recombine. This understanding can then be used to improve predictions of both the potential and probability of CoV recombination. Finally, we will extrapolate these effects to generate a spatial model that estimates of the risk of recombinant CoVs arising in different parts of the world (Aim 3). By integrating our unique global CoV surveillance data (>31,000 animals from >25 countries surveyed for CoVs) we will produce a risk map predicting regions of the world where recombination is most likely.