Peris, J. B., Davis, P., Cuevas, J. M., Nebot, M., & Sanjuan, R. (2010). Distribution of Fitness Effects Caused by Single-Nucleotide Substitutions in Bacteriophage f1. Genetics, 185(2), 603–U308.
Abstract: Empirical knowledge of the fitness effects of mutations is important for understanding many evolutionary processes, yet this knowledge is often hampered by several sources of measurement error and bias. Most of these problems can be solved using site-directed mutagenesis to engineer single mutations, an approach particularly suited for viruses due to their small genomes. Here, we used this technique to measure the fitness effect of 100 single-nucleotide substitutions in the bacteriophage f1, a filamentous single-strand DNA virus. We found that approximately one-fifth of all mutations are lethal. Viable ones reduced fitness by 11% on average and were accurately described by a log-normal distribution. More than 90% of synonymous substitutions were selectively neutral, while those affecting intergenic regions reduced fitness by 14% on average. Mutations leading to amino acid substitutions had an overall mean deleterious effect of 37%, which increased to 45% for those changing the amino acid polarity. Interestingly, mutations affecting early steps of the infection cycle tended to be more deleterious than those affecting late steps. Finally, we observed at least two beneficial mutations. Our results confirm that high mutational sensitivity is a general property of viruses with small genomes, including RNA and single-strand DNA viruses infecting animals, plants, and bacteria.
|
Sanjuan, R., Nebot, M., Chirico, N., Mansky, L. M., & Belshaw, R. (2010). Viral Mutation Rates. J. Virol., 84(19), 9733–9748.
Abstract: Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10(-8) to 10(-6) s/n/c for DNA viruses and from 10(-6) to 10(-4) s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut.
|
Sanjuan, R., Nebot, M., Peris, J. B., & Alcami, J. (2013). Immune Activation Promotes Evolutionary Conservation of T-Cell Epitopes in HIV-1. PLoS. Biol., 11(4), e1001523–10pp.
Abstract: The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (T-H cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when T-H cell infection is concomitant to epitope recognition (transinfection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved T-H epitopes may be counterproductive.
|
Morisi, S., Nebot, M., Patel, K. M., Peinado, E., & Valle, J. W. F. (2013). Quark-lepton mass relation and CKM mixing in an A(4) extension of the minimal supersymmetric standard model. Phys. Rev. D, 88(3), 036001–8pp.
Abstract: An interesting mass relation between down-type quarks and charged leptons has been recently predicted within a supersymmetric SU(3)(c) circle times SU(2)(L) circle times U(1)(Y) model based on the A(4) flavor symmetry. Here we propose a simple extension which provides an adequate full description of the quark sector. By adding a pair of vectorlike up quarks, we show how the CKM entries V-ub, V-cb, V-td and V-ts arise from deviations of the unitarity. We perform an analysis including the most relevant observables in the quark sector, such as oscillations and rare decays of kaons, B-d and B-s mesons. In the lepton sector, the model predicts an inverted hierarchy for the neutrino masses, leading to a potentially observable rate of neutrinoless double beta decay.
|
Bernabeu, J., Botella, F. J., & Nebot, M. (2014). Novel T-Violation observable open to any pair of decay channels at meson factories. Phys. Lett. B, 728, 95–98.
Abstract: Quantum entanglement between the two neutral mesons produced in meson factories has allowed the first indisputable direct observation of Time Reversal Violation in the time evolution of the neutral meson between the two decays. The exceptional meson transitions are directly connected to semileptonic and CP eigenstate decay channels. The possibility of extending the observable asymmetries to more decay channels confronts the problem of the “orthogonality condition”, which can be stated with this tonguetwister: Given a decay channel f, which is the decay channel f' such that the meson state not decaying to f is orthogonal to the meson state not decaying to f? In this Letter we propose an alternative T-Violation asymmetry at meson factories which allows its opening to any pair of decay channels. Instead of searching which is the pair of decay channels associated to the T-reverse meson transition, we build an asymmetry which tags the initial states of both the Reference and the T-reverse meson transitions. This observable filters the appropriate final states by means of two measurable survival probabilities. We discuss the methodology to be followed in the analysis of the new observable and the results expected in specific examples.
|
