Domingo E, Holland J J
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Spain.
Annu Rev Microbiol. 1997;51:151-78. doi: 10.1146/annurev.micro.51.1.151.
RNA viruses exploit all known mechanisms of genetic variation to ensure their survival. Distinctive features of RNA virus replication include high mutation rates, high yields, and short replication times. As a consequence, RNA viruses replicate as complex and dynamic mutant swarms, called viral quasispecies. Mutation rates at defined genomic sites are affected by the nucleotide sequence context on the template molecule as well as by environmental factors. In vitro hypermutation reactions offer a means to explore the functional sequence space of nucleic acids and proteins. The evolution of a viral quasispecies is extremely dependent on the population size of the virus that is involved in the infections. Repeated bottleneck events lead to average fitness losses, with viruses that harbor unusual, deleterious mutations. In contrast, large population passages result in rapid fitness gains, much larger than those so far scored for cellular organisms. Fitness gains in one environment often lead to fitness losses in an alternative environment. An important challenge in RNA virus evolution research is the assignment of phenotypic traits to specific mutations. Different constellations of mutations may be associated with a similar biological behavior. In addition, recent evidence suggests the existence of critical thresholds for the expression of phenotypic traits. Epidemiological as well as functional and structural studies suggest that RNA viruses can tolerate restricted types and numbers of mutations during any specific time point during their evolution. Viruses occupy only a tiny portion of their potential sequence space. Such limited tolerance to mutations may open new avenues for combating viral infections.
RNA病毒利用所有已知的遗传变异机制来确保自身的生存。RNA病毒复制的显著特征包括高突变率、高产量和短复制时间。因此，RNA病毒以复杂且动态的突变群体形式进行复制，即所谓的病毒准种。特定基因组位点的突变率受模板分子上的核苷酸序列背景以及环境因素的影响。体外超突变反应为探索核酸和蛋白质的功能序列空间提供了一种手段。病毒准种的进化极大地依赖于参与感染的病毒群体大小。反复的瓶颈事件会导致平均适应性损失，病毒会携带异常的有害突变。相比之下，大量群体传代则会导致适应性快速增加，比目前在细胞生物体中所记录到的增加幅度大得多。在一种环境中的适应性增加往往会导致在另一种环境中的适应性损失。RNA病毒进化研究中的一个重要挑战是将表型特征归因于特定突变。不同的突变组合可能与相似的生物学行为相关。此外，最近的证据表明表型特征表达存在关键阈值。流行病学以及功能和结构研究表明，RNA病毒在其进化过程中的任何特定时间点都只能容忍有限类型和数量的突变。病毒仅占据其潜在序列空间的一小部分。这种对突变的有限耐受性可能为对抗病毒感染开辟新途径。
