RAPID FITNESS LOSSES IN MAMMALIAN RNA VIRUS CLONES DUE TO MULLER RATCHET
RAPID FITNESS LOSSES IN MAMMALIAN RNA VIRUS CLONES DUE TO MULLER RATCHET
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DOI：
10.1073/pnas.89.13.6015
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发表时间：
1992-07-01
影响因子：
11.1
通讯作者：
HOLLAND, J
中科院分区：
文献类型：
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作者：
DUARTE, E;CLARKE, D;HOLLAND, J
Muller棘轮是群体遗传学中的一个重要概念。它预测，当突变率很高，并且相当大比例的突变是有害的，一种不可逆的棘轮机制将逐渐降低无性生物小种群的平均适应度。相反，有性重组可以通过重组修复遗传损伤来阻止或逆转这种突变棘轮。穆勒棘轮的实验支持先前已获得原生动物和三方RNA噬菌体。我们现在有明确的证据表明，穆勒棘轮可以对动物和人类的非节段性非重组致病性RNA病毒起作用。我们做了遗传瓶颈通道（空斑到空斑转移）的水泡性体炎病毒（VSV），然后定量的相对健身的瓶颈克隆允许直接复制竞争混合感染细胞培养。我们的文件变量健身下降（一些严重）后，只有20斑块斑块转移VSV。在一些克隆中，没有观察到适合度的变化（或仅观察到不显著的变化）。令人惊讶的是，最经常和严重的健身损失发生在病毒传代期间的一个新的宿主细胞类型。这些结果再次证明了RNA病毒种群的极端遗传和生物变异性。穆勒棘轮可能对病毒爆发期间疾病严重程度的变化具有重要意义，因为在呼吸道飞沫传播和低产量RNA病毒从一个身体部位传播到另一个身体部位（如人类免疫缺陷病毒）期间，遗传瓶颈通常会发生。同样，在自然界中RNA病毒重复的遗传瓶颈转移过程中，较低概率的适应性增加克隆的产生也可能影响感染个体和宿主群体的疾病发病机制。每当RNA病毒的遗传瓶颈发生时，可能导致病毒亚群之间的生物学差异增强。
Muller's ratchet is an important concept in population genetics. It predicts that when mutation rates are high and a significant proportion of mutations are deleterious, a kind of irreversible ratchet mechanism will gradually decrease the mean fitness of small populations of asexual organisms. In contrast, sexual recombination may stop or reverse this mutational ratchet by recombinational repair of genetic damage. Experimental support for Muller's ratchet has previously been obtained in protozoa and in a tripartite RNA bacteriophage. We now show clear evidence that Muller's ratchet can operate on a nonsegmented nonrecombining pathogenic RNA virus of animals and humans. We did genetic bottleneck passages (plaque-to-plaque transfers) of vesicular somatitis virus (VSV) and then quantitated relative fitness of the bottleneck clones by allowing direct replicative competition in mixed infections in cell culture. We document variable fitness drops (some severe) following only 20 plaque-to-plaque transfers of VSV. In some clones no fitness changes (or only insignificant changes) were observed. Surprisingly, the most regular and severe fitness losses occurred during virus passages on a new host cell type. These results again demonstrate the extreme genetic and biological variability of RNA virus populations. Muller's ratchet could have significant implications for variability of disease severity during virus outbreaks, since genetic bottlenecks must often occur during respiratory droplet transmissions and during spread of low-yield RNA viruses from one body site to another (as with human immunodeficiency virus). Likewise, the lower-probability generation of increased-fitness clones during repeated genetic bottleneck transfers of RNA viruses in nature might also affect disease pathogenesis in infected individuals and in host populations. Whenever genetic bottlenecks of RNA viruses occur, enhanced biological differences among viral subpopulations may result.