Genetic and ecological determinants of coronavirus recombination

冠状病毒重组的遗传和生态决定因素

• 批准号: 10614440
• 负责人: Simon J Anthony
• 金额: $ 53.35万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-17 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614440
• 关键词: Animals; Automobile Driving; Cell Line; Chiroptera; Coronavirus; Country; Data; Databases; Daughter; Detection; Environmental Impact; Event; Frequencies; Genbank; Genes; Genetic; Genetic Materials; Genetic Recombination; Genetic Variation; Genome; Goals; Hot Spot; Human; Laboratories; Laboratory Study; Logistic Models; Maps; Methods; Modeling; Natural Selections; Nature; Observational Study; Parents; Pattern; Phylogenetic Analysis; Probability; Process; Proteins; Public Health; Recombinants; Recording of previous events; Reporting; Risk; Risk Estimate; Role; Series; Site; Spatial Distribution; Statistical Models; Surveys; Testing; Virus; Work; comparative genomics; cross-species transmission; experimental study; genomic locus; human coronavirus; improved; laboratory experiment; mathematical model; nanopore; novel coronavirus; pressure; programs; public database; single molecule; surveillance data; tissue tropism; trend

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.

项目概要： 重组是两种病毒交换部分遗传物质以产生新病毒的过程 对于冠状病毒（CoV）来说，它是一个重要的进化机制。 产生遗传变异，但它也是人类宿主转换的重要驱动因素。 人们认为起源于动物（特别是蝙蝠），并且有证据表明它们在进化过程中发生了重组 尽管与公共卫生相关，但重组的机制、驱动因素和局限性仍然存在。 结合实验室实验、比较基因组学和数学模型，我们得出结论。 将检验两个 CoV 之间重组的概率是遗传距离的函数的假设， 并且这种概率会受到生态或进化效应的进一步修改，换句话说，就是发生的可能性。 随着亲本菌株之间遗传距离的增加，重组会减少（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 两种 CoV 实际上会同时发生或进化选择压力。我们将测试三个目标：在目标 1 中，我们将测试。 采用实验室研究，并在系统发育梯度上用成对的 Co​​V 共同感染人类和蝙蝠细胞系。 这将测试重组的概率是否与父母之间的遗传距离有关，并且将 还显示重组是否在整个基因组中随机发生，或者在目标 2 中的特定“热点”中发生。 我们将使用公共数据库中提供的基因组或我们自己以前的基因组来评估自然发生的冠状病毒 据推测，天然存在的重组体将是任何遗传限制（例如遗传）的结果。 距离），加上任何生态或进化修饰因素（例如自然选择）。 通过实验室（目标 1）和观察（目标 2）研究，我们可以开始识别仍不清楚的模式 仅凭实验数据，我们就可以理清遗传和生态因素的贡献 任何两种病毒重组的概率可以用来改进预测。 最后，我们将推断这些效应的产生。 估计世界不同地区出现重组冠状病毒风险的空间模型（目标 3）。 整合我们独特的全球冠状病毒监测数据（来自超过 25 个国家的超过 31,000 只动物接受了冠状病毒调查） 将生成一个风险图，预测世界上最有可能发生重组的区域。