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Assessing in vivo mutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus.

ABSTRACT: Like many viruses, Hepatitis C Virus (HCV) has a high mutation rate, which helps the virus adapt quickly, but mutations come with fitness costs. Fitness costs can be studied by different approaches, such as experimental or frequency-based approaches. The frequency-based approach is particularly useful to estimate in vivo fitness costs, but this approach works best with deep sequencing data from many hosts are. In this study, we applied the frequency-based approach to a large dataset of 195 patients and estimated the fitness costs of mutations at 7957 sites along the HCV genome. We used beta regression and random forest models to better understand how different factors influenced fitness costs. Our results revealed that costs of nonsynonymous mutations were three times higher than those of synonymous mutations, and mutations at nucleotides A or T had higher costs than those at C or G. Genome location had a modest effect, with lower costs for mutations in HVR1 and higher costs for mutations in Core and NS5B. Resistance mutations were, on average, costlier than other mutations. Our results show that in vivo fitness costs of mutations can be site and virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes.

SUBMITTER: Tisthammer KH

PROVIDER: S-EPMC9113599 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Within-patient mutation frequencies reveal fitness costs of CpG dinucleotides and drastic amino acid changes in HIV.

Project description:HIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutations in vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of the pol gene in 160 patients, allowing us to determine the cost of these mutations. As expected, we found high costs for non-synonymous and nonsense mutations as compared to synonymous mutations. In addition, we found that non-synonymous mutations that lead to drastic amino acid changes are twice as costly as those that do not and mutations that create new CpG dinucleotides are also twice as costly as those that do not. We also found that G→A and C→T mutations are more costly than A→G mutations. We anticipate that our new in vivo frequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.

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Plasmid fitness costs are caused by specific genetic conflicts enabling resolution by compensatory mutation.

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A comprehensive, high-resolution map of a gene's fitness landscape.

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Compensating the fitness costs of synonymous mutations

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2016-03-11 | PXD003495 | Pride

Inferring Genome-Wide Correlations of Mutation Fitness Effects between Populations.

Project description:The effect of a mutation on fitness may differ between populations depending on environmental and genetic context, but little is known about the factors that underlie such differences. To quantify genome-wide correlations in mutation fitness effects, we developed a novel concept called a joint distribution of fitness effects (DFE) between populations. We then proposed a new statistic w to measure the DFE correlation between populations. Using simulation, we showed that inferring the DFE correlation from the joint allele frequency spectrum is statistically precise and robust. Using population genomic data, we inferred DFE correlations of populations in humans, Drosophila melanogaster, and wild tomatoes. In these species, we found that the overall correlation of the joint DFE was inversely related to genetic differentiation. In humans and D. melanogaster, deleterious mutations had a lower DFE correlation than tolerated mutations, indicating a complex joint DFE. Altogether, the DFE correlation can be reliably inferred, and it offers extensive insight into the genetics of population divergence.

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Fitness costs associated with a GABA receptor mutation conferring dieldrin resistance in Aedes albopictus.

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In vitro and in vivo fitness costs associated with Mycobacterium tuberculosis RpoB mutation H526D.

Project description:AimThere is controversy regarding the potential fitness costs of rifampicin (RIF) resistance-conferring mutations in the Mycobacterium tuberculosis (Mtb) rpoB gene. We characterized the pathogenicity of an Mtb RpoB H526D mutant.Materials & methodsA mutant containing the RpoB H526D mutation was isolated from wild-type Mtb grown on RIF-containing plates and complemented for determination of in vitro and in vivo fitness costs.ResultsThe RpoB H526D mutant showed reduced survival relative to control strains during progressive hypoxia and delayed growth following resuscitation from nutrient starvation (p < 0.05), which was associated with reduced expression of the resuscitation-promoting factor genes rpfB, rpfC and rpfE. Relative to the isogenic wild-type strain, the mutant showed significantly attenuated growth and long-term survival as well as reduced inflammation in mouse lungs. Conclusion & future perspective: Our data suggest that RpoB H526D mutation confers a fitness cost during growth-limiting conditions in vitro and in mouse lungs.

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<i>In vivo</i> mutation rates and the landscape of fitness costs of HIV-1.

Project description:Mutation rates and fitness costs of deleterious mutations are difficult to measure in vivo but essential for a quantitative understanding of evolution. Using whole genome deep sequencing data from longitudinal samples during untreated HIV-1 infection, we estimated mutation rates and fitness costs in HIV-1 from the dynamics of genetic variation. At approximately neutral sites, mutations accumulate with a rate of 1.2 × 10-5 per site per day, in agreement with the rate measured in cell cultures. We estimated the rate from G to A to be the largest, followed by the other transitions C to T, T to C, and A to G, while transversions are less frequent. At other sites, mutations tend to reduce virus replication. We estimated the fitness cost of mutations at every site in the HIV-1 genome using a model of mutation selection balance. About half of all non-synonymous mutations have large fitness costs (>10 percent), while most synonymous mutations have costs <1 percent. The cost of synonymous mutations is especially low in most of pol where we could not detect measurable costs for the majority of synonymous mutations. In contrast, we find high costs for synonymous mutations in important RNA structures and regulatory regions. The intra-patient fitness cost estimates are consistent across multiple patients, indicating that the deleterious part of the fitness landscape is universal and explains a large fraction of global HIV-1 group M diversity.

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