Dataset Information

Variation in RNA virus mutation rates across host cells.

ABSTRACT: It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10(-6) to 10(-4) substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10(-5) s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1-21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature.

SUBMITTER: Combe M

PROVIDER: S-EPMC3900646 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Variation in RNA virus mutation rates across host cells.

Combe Marine M Sanjuán Rafael R

PLoS pathogens 20140123 1

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10(-6) to 10(-4) substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on ...[more]

PMID: 24465205

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Project description:The causes and consequences of spatiotemporal variation in mutation rates remain to be explored in nearly all organisms. Here we examine relationships between local mutation rates and replication timing in three bacterial species whose genomes have multiple chromosomes: Vibrio fischeri, Vibrio cholerae, and Burkholderia cenocepacia Following five mutation accumulation experiments with these bacteria conducted in the near absence of natural selection, the genomes of clones from each lineage were sequenced and analyzed to identify variation in mutation rates and spectra. In lineages lacking mismatch repair, base substitution mutation rates vary in a mirrored wave-like pattern on opposing replichores of the large chromosomes of V. fischeri and V. cholerae, where concurrently replicated regions experience similar base substitution mutation rates. The base substitution mutation rates on the small chromosome are less variable in both species but occur at similar rates to those in the concurrently replicated regions of the large chromosome. Neither nucleotide composition nor frequency of nucleotide motifs differed among regions experiencing high and low base substitution rates, which along with the inferred ~800-kb wave period suggests that the source of the periodicity is not sequence specific but rather a systematic process related to the cell cycle. These results support the notion that base substitution mutation rates are likely to vary systematically across many bacterial genomes, which exposes certain genes to elevated deleterious mutational load.IMPORTANCE That mutation rates vary within bacterial genomes is well known, but the detailed study of these biases has been made possible only recently with contemporary sequencing methods. We applied these methods to understand how bacterial genomes with multiple chromosomes, like those of Vibrio and Burkholderia, might experience heterogeneous mutation rates because of their unusual replication and the greater genetic diversity found on smaller chromosomes. This study captured thousands of mutations and revealed wave-like rate variation that is synchronized with replication timing and not explained by sequence context. The scale of this rate variation over hundreds of kilobases of DNA strongly suggests that a temporally regulated cellular process may generate wave-like variation in mutation risk. These findings add to our understanding of how mutation risk is distributed across bacterial and likely also eukaryotic genomes, owing to their highly conserved replication and repair machinery.

Project description:BackgroundAlthough mitochondrial DNA (mtDNA) of many animals tends to mutate at higher rates than nuclear DNA (nuDNA), a recent survey of mutation rates of various animal groups found that the gastropod family Bradybaenidae (suborder Helicina) shows a nearly 40-fold difference in mutation rates of mtDNA ([Formula: see text]m) and nuDNA ([Formula: see text]n), while other gastropod taxa exhibit only two to five-fold differences. To determine if Bradybaenidae represents an outlier within Gastropoda, I compared estimated values of [Formula: see text]m/[Formula: see text]n of additional gastropod groups. In particular, I reconstructed mtDNA and nuDNA gene trees of 121 datasets that include members of various clades contained within the gastropod subclasses Caenogastropoda, Heterobranchia, Patellogastropoda, and Vetigastropoda and then used total branch length estimates of these gene trees to infer [Formula: see text]m/[Formula: see text]n.ResultsEstimated values of [Formula: see text]m/[Formula: see text]n range from 1.4 to 91.9. Datasets that exhibit relatively large values of [Formula: see text]m/[Formula: see text]n (i.e., > 20), however, show relatively lower estimates of [Formula: see text]n (and not elevated [Formula: see text]m) in comparison to groups with lower values. These datasets also tend to contain sequences of recently diverged species. In addition, datasets with low levels of phylogenetic breadth (i.e., contain members of single genera or families) exhibit higher values of [Formula: see text]m/[Formula: see text]n than those with high levels (i.e., those that contain representatives of single superfamilies or higher taxonomic ranks).ConclusionsGastropods exhibit considerable variation in estimates of [Formula: see text]m/[Formula: see text]n. Large values of [Formula: see text]m/[Formula: see text]n that have been calculated for Bradybaenidae and other gastropod taxa may be overestimated due to possible sampling artifacts or processes that depress estimates of total molecular divergence of nuDNA in groups that recently diversified.

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Variation in RNA virus mutation rates across host cells.

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Variation in RNA virus mutation rates across host cells.

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