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.

项目总结： 重组是两种病毒交换部分遗传物质以产生 在基因上是不同的‘女儿’菌株。对于冠状病毒(CoV)来说，这是一种重要的进化机制 产生遗传变异，但它也是主机切换的重要驱动因素。人类的大多数冠状病毒都是 认为起源于动物(特别是蝙蝠)，并在其进化过程中有重组的证据 历史。尽管重组与公共健康相关，但重组的机制、驱动因素和限制仍然存在 不清楚。利用实验室实验、比较基因组学和数学建模的组合，我们 将检验两个冠状病毒之间的重组概率是遗传距离的函数的假设， 生态或进化的影响进一步改变了这种可能性。换句话说， 随着亲本菌株之间遗传距离的增加，重组减少(推测是因为 遗传或结构不相容)，但也受到生态过程的影响，例如 两个CoV实际上会同时出现或进化选择的压力。我们将测试三个目标：在目标1中，我们将 利用实验室研究并在系统发育梯度上用成对的冠状病毒共同感染人类和蝙蝠细胞系。 这将测试重组的可能性是否与双亲之间的遗传距离有关，并将 还可以显示重组是否在整个基因组中随机发生，或者特别是“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以前的基因组来评估自然产生的CoV 工作。据推测，自然产生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物(例如，自然选择)。因此，通过比较 通过实验室(目标1)和观察性(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，我们就能理清遗传因素和生态因素的作用 任何两种病毒重新组合的可能性。这种理解可以用来改进预测。 冠状病毒重组的可能性和可能性。最后，我们将外推这些影响以生成 估计世界不同地区出现的重组冠状病毒的风险的空间模型(目标3)。通过 整合我们独特的全球冠状病毒监测数据(针对冠状病毒对25个国家和地区的31,000只动物进行调查)，我们 将生成一张风险地图，预测世界上最有可能重组的地区。