Rapid fitness losses in mammalian RNA virus clones due to Muller's ratchet.

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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 replication 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.

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