Large-Scale Phylogenomic Analysis Reveals the Complex Evolutionary History of Rabies Virus in Multiple Carnivore Hosts

The natural evolution of rabies virus (RABV) provides a potent example of multiple host shifts and an important opportunity to determine the mechanisms that underpin viral emergence. Using 321 genome sequences spanning an unprecedented diversity of RABV, we compared evolutionary rates and selection pressures in viruses sampled from multiple primary host shifts that occurred on various continents. Two major phylogenetic groups, bat-related RABV and dog-related RABV, experiencing markedly different evolutionary dynamics were identified. While no correlation between time and genetic divergence was found in bat-related RABV, the evolution of dog-related RABV followed a generally clock-like structure, although with a relatively low evolutionary rate. Subsequent molecular clock dating indicated that dog-related RABV likely underwent a rapid global spread following the intensification of intercontinental trade starting in the 15th century. Strikingly, although dog RABV has jumped to various wildlife species from the order Carnivora, we found no clear evidence that these host-jumping events involved adaptive evolution, with RABV instead characterized by strong purifying selection, suggesting that ecological processes also play an important role in shaping patterns of emergence. However, specific amino acid changes were associated with the parallel emergence of RABV in ferret-badgers in Asia, and some host shifts were associated with increases in evolutionary rate, particularly in the ferret-badger and mongoose, implying that changes in host species can have important impacts on evolutionary dynamics.狂犬病病毒（Rabies virus, RABV）的自然演化，堪称多宿主转换现象的极具代表性案例，同时为解析病毒出现的核心机制提供了重要研究契机。本研究依托覆盖狂犬病病毒空前多样性的321条基因组序列，对不同大洲多次原发性宿主转换事件中分离的病毒的演化速率与选择压力开展了比较分析。研究鉴定出两大主要系统发育类群——蝙蝠相关狂犬病病毒与犬相关狂犬病病毒，二者呈现出显著迥异的演化动力学特征。蝙蝠相关狂犬病病毒未呈现出时间与遗传分化间的相关性，而犬相关狂犬病病毒的演化整体遵循分子钟式演化模式，尽管其演化速率相对较低。后续分子钟定年分析表明，自15世纪洲际贸易强化以来，犬相关狂犬病病毒或已实现快速的全球传播。值得注意的是，尽管犬相关狂犬病病毒已跨宿主感染食肉目（Carnivora）下的多种野生动物类群，但本研究未发现明确证据表明这些跨宿主转换事件伴随适应性演化；相反，狂犬病病毒呈现出强烈的纯化选择特征，这提示生态过程在塑造病毒出现模式中同样发挥着关键作用。不过，特定的氨基酸变异与亚洲鼬獾中狂犬病病毒的平行暴发存在关联；部分宿主转换事件还伴随演化速率的提升，尤以鼬獾与獴类宿主中最为显著，这意味着宿主物种的改变可对病毒演化动力学产生重要影响。