scholarly journals In-vivo mutation rates and fitness landscape of HIV-1

2016 ◽  
Author(s):  
Fabio Zanini ◽  
Vadim Puller ◽  
Johanna Brodin ◽  
Jan Albert ◽  
Richard Neher
Keyword(s):  
Temporal Dynamics ◽  
Fitness Landscape ◽  
Large Fraction ◽  
Fitness Cost ◽  
Mutation Rates ◽  
Sequencing Data ◽  
Fitness Costs ◽  
Synonymous Mutations ◽  
Hiv 1

Mutation rates and fitness costs of deleterious mutations are difficult to measurein vivobut 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 temporal dynamics of genetic variation. At approximately neutral sites, mutations accumulate with a rate of 1.2 x 10-5per site per day, in agreement with the rate measured in cell cultures. The rate from G to A is largest, followed by the other transitions C to T, T to C, and A to G, while transversions are more rare. At non-neutral sites, most mutations reduce virus replication; using a model of mutation selection balance, we estimated the fitness cost of mutations at every site in the HIV-1 genome. About half of all nonsynonymous mutations have large fitness costs (greater than 10%), while most synonymous mutations have costs below 1%. The cost of synonymous mutations is especially low in most of gag and pol, while much higher costs are observed in important RNA structures and regulatory regions. The intrapatient fitness cost estimates are consistent across multiple patients, suggesting that the deleterious part of the fitness landscape is universal and explains a large fraction of global HIV-1 group M diversity.

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

2016 ◽  
Author(s):  
Kristof Theys ◽  
Alison F. Feder ◽  
Maoz Gelbart ◽  
Marion Hartl ◽  
Adi Stern ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mutation Rate ◽  
Fitness Landscape ◽  
Fitness Costs ◽  
Nonsense Mutations ◽  
Cpg Dinucleotides ◽  
Synonymous Mutations ◽  
The Cost ◽  
Patient Mutation

AbstractHIV has a high mutation rate, which contributes to its ability to evolve quickly. However, we know little about the fitness costs of individual HIV mutationsin vivo, their distribution and the different factors shaping the viral fitness landscape. We calculated the mean frequency of transition mutations at 870 sites of thepolgene 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 newin vivofrequency-based approach will provide insights into the fitness landscape and evolvability of not only HIV, but a variety of microbes.Author summaryHIV’s high mutation rate allows it to evolve quickly. However, most mutations probably reduce the virus’ ability to replicate – they are costly to the virus. Until now, the actual cost of mutations is not well understood. We used within-patient mutation frequencies to estimate the cost of 870 HIV mutationsin vivo. As expected, we found high costs for non-synonymous and nonsense mutations. In addition, we found surprisingly high costs for mutations that lead to drastic amino acid changes, mutations that create new CpG sites (possibly because they trigger the host’s immune system), and G→A and C→T mutations. Our results demonstrate the power of analyzing mutant frequencies fromin vivoviral populations to study costs of mutations. A better understanding of fitness costs will help to predict the evolution of HIV.

scholarly journals In vivo mutation rates and the landscape of fitness costs of HIV-1

2017 ◽  
Vol 3 (1) ◽  
Author(s):  
Fabio Zanini ◽  
Vadim Puller ◽  
Johanna Brodin ◽  
Jan Albert ◽  
Richard A. Neher
Keyword(s):  
Mutation Rates ◽  
Fitness Costs ◽  
Hiv 1

scholarly journals Biased Pol II fidelity contributes to conservation of functional domains in the Potato spindle tuber viroid genome

2020 ◽  
Vol 16 (12) ◽  
pp. e1009144
Author(s):  
Jian Wu ◽  
David M. Bisaro
Keyword(s):  
Rna Polymerase Ii ◽  
De Novo ◽  
Potato Spindle Tuber Viroid ◽  
Mutation Rates ◽  
Wild Type ◽  
Pol Ii ◽  
Synonymous Mutations ◽  
Novel Strategy ◽  
Critical Regions

Accurate calculation of mutation rates for viruses and viroids is necessary for evolutionary studies and to evaluate adaptation potential. However, estimation of in vivo mutation rates is complicated by selection, which leads to loss or proliferation of certain mutations. To minimize this concern, lethal mutations, including nonsense and non-synonymous mutations, have been used to determine mutation rates for several viruses and viroids, including Potato spindle tuber viroid (PSTVd). However, this approach has limitations, including focus on a relatively small number of genome sites and the possibility that mutations may not actually be lethal or may be maintained by wild type individuals. To avoid selection bias altogether, we sequenced minus-strand PSTVd dimers from concatemeric replication intermediates. The underlying rationale is that mutations found in only one of the monomers were likely generated de novo during RNA polymerase II (Pol II) transcription of the circular plus-strand RNA genome. This approach yielded an apparent Pol II error rate of ~1/1837 nucleotides per transcription cycle, and an estimated mutation rate of ~1/919 nucleotides for a single replication cycle. Remarkably, de novo mutations were nearly absent from the most conserved, replication-critical regions of the PSTVd genome, suggesting that sequence conservation is a consequence of both essential function and template optimization for greater Pol II fidelity. Such biased fidelity may constitute a novel strategy to ensure population success while allowing abundant sampling of sequence space in other genome regions. Comparison with variants in progeny populations derived from a cloned, wild type PSTVd master sequence revealed that most de novo mutations were lost through selection.

scholarly journals Codon optimality is the primary contributor to the exceptional mutational sensitivity of CcdA antitoxin in its operonic context

2022 ◽  
Author(s):  
Soumyanetra Chandra ◽  
Kritika Gupta ◽  
Shruti Khare ◽  
Pehu Kohli ◽  
Aparna Asok ◽  
...  
Keyword(s):  
Large Fraction ◽  
Point Mutations ◽  
Saturation Mutagenesis ◽  
Loss Of Function ◽  
Active Site Residues ◽  
Synonymous Mutations ◽  
Protein Levels ◽  
Intrinsically Disordered ◽  
Usage Frequency

Deep mutational scanning studies suggest that single synonymous mutations are typically silent and that most exposed, non active-site residues are tolerant to mutations. Here we show that the ccdA antitoxin component of the E.coli ccdAB toxin-antitoxin operonic system is unusually sensitive to mutations when studied in the operonic context. A large fraction (~80%) of single codon mutations, including many synonymous mutations in the ccdA gene show inactive phenotypes that are correlated with the E.coli codon usage frequency but retain native-like binding affinity towards cognate toxin, CcdB. Therefore, the observed phenotypic effects are largely not due to alterations in protein structure or stability, consistent with the fact that a large region of CcdA is intrinsically disordered. In select cases, proteomics studies reveal altered ratios of CcdA:CcdB protein levels in vivo, suggesting that these mutations likely alter relative translation efficiencies of the two genes in the operon. We extend these results by predicting and validating single synonymous mutations that lead to loss of function phenotypes in the relBE operon upon introduction of rarer codons. Thus, in their native context, genes are likely to be more sensitive to both synonymous and non-synonymous point mutations than inferred from previous saturation mutagenesis studies.

scholarly journals Atypical meiosis can be adaptive in outcrossed S. pombe due to wtf meiotic drivers

2020 ◽  
Author(s):  
María Angélica Bravo Núñez ◽  
Ibrahim M. Sabbarini ◽  
Lauren E. Eide ◽  
Robert L. Unckless ◽  
Sarah E. Zanders
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fitness Landscape ◽  
Fitness Cost ◽  
Fitness Costs ◽  
Diploid Gametes ◽  
Selection Of

AbstractKiller meiotic drivers are genetic parasites that destroy ‘sibling’ gametes lacking the driver allele. The fitness costs of drive can lead to selection of unlinked suppressors. This suppression could involve evolutionary tradeoffs that compromise gametogenesis and contribute to infertility. Schizosaccharomyces pombe, an organism containing numerous gamete-killing wtf drivers, offers a tractable system to test this hypothesis. Here, we demonstrate that in scenarios analogous to outcrossing, wtf drivers generate a fitness landscape in which atypical gametes, such as aneuploids and diploids, are advantageous. In this context, wtf drivers can decrease the fitness cost of mutations that disrupt meiotic fidelity and, in some circumstances, can even make such mutations beneficial. Moreover, we find that S. pombe isolates vary greatly in their ability to make haploid gametes, with some isolates generating more than 25% aneuploid or diploid gametes. This work empirically demonstrates the potential for meiotic drivers to shape the evolution of gametogenesis.

scholarly journals Globally Defining the Effects of Amino Acid Mutations across a Picornavirus Capsid

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 111
Author(s):  
Florian Mattenberger ◽  
Ron Geller
Keyword(s):  
Amino Acid ◽  
Rna Viruses ◽  
Large Fraction ◽  
Protein Structures ◽  
Single Amino Acid ◽  
Relative Fitness ◽  
Mutation Rates ◽  
Phenotypic Data ◽  
Synonymous Mutations ◽  
Amino Acid Mutations

RNA viruses are characterized by their extreme mutation rates, which play key roles in their biology and give them the ability to rapidly adapt to new environments. However, non-synonymous mutations tend to be largely deleterious to protein function, raising the question of how the proteins of RNA viruses maintain functionality in the face of high mutation rates. This is of particular relevance to the capsids of non-enveloped RNA viruses, which form highly complex protein structures that assemble from numerous subunits, interact with cellular host factors to mediate entry and uncoating, and are under strong immune selection. To better understand how viral capsids accommodate mutations, we generated viral populations harboring a large fraction of all possible single amino acid mutations in a picornavirus capsid. We then used high-fidelity next-generation sequencing to derive the relative fitness of these mutations compared to the wildtype sequence. Combining our results with available structural, genetic, and phenotypic data, we are able to provide a comprehensive understanding of the ability of a viral capsid to accommodate mutations.

scholarly journals Modelling and in vitro testing of the HIV-1 Nef fitness landscape

2019 ◽  
Vol 5 (2) ◽  
Author(s):  
John P Barton ◽  
Erasha Rajkoomar ◽  
Jaclyn K Mann ◽  
Dariusz K Murakowski ◽  
Mako Toyoda ◽  
...  
Keyword(s):  
Clinical Data ◽  
Fitness Landscape ◽  
Effective Vaccine ◽  
In Vitro Testing ◽  
Multifunctional Protein ◽  
Model Predictions ◽  
The Cost ◽  
Hiv 1

Abstract An effective vaccine is urgently required to curb the HIV-1 epidemic. We have previously described an approach to model the fitness landscape of several HIV-1 proteins, and have validated the results against experimental and clinical data. The fitness landscape may be used to identify mutation patterns harmful to virus viability, and consequently inform the design of immunogens that can target such regions for immunological control. Here we apply such an analysis and complementary experiments to HIV-1 Nef, a multifunctional protein which plays a key role in HIV-1 pathogenesis. We measured Nef-driven replication capacities as well as Nef-mediated CD4 and HLA-I down-modulation capacities of thirty-two different Nef mutants, and tested model predictions against these results. Furthermore, we evaluated the models using 448 patient-derived Nef sequences for which several Nef activities were previously measured. Model predictions correlated significantly with Nef-driven replication and CD4 down-modulation capacities, but not HLA-I down-modulation capacities, of the various Nef mutants. Similarly, in our analysis of patient-derived Nef sequences, CD4 down-modulation capacity correlated the most significantly with model predictions, suggesting that of the tested Nef functions, this is the most important in vivo. Overall, our results highlight how the fitness landscape inferred from patient-derived sequences captures, at least in part, the in vivo functional effects of mutations to Nef. However, the correlation between predictions of the fitness landscape and measured parameters of Nef function is not as accurate as the correlation observed in past studies for other proteins. This may be because of the additional complexity associated with inferring the cost of mutations on the diverse functions of Nef.

scholarly journals Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease

2019 ◽  
Author(s):  
Tian-hao Zhang ◽  
Lei Dai ◽  
John P. Barton ◽  
Yushen Du ◽  
Yuxiang Tan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Fitness Landscape ◽  
Sequence Data ◽  
Fitness Cost ◽  
Resistance Mutations ◽  
Human T Cells ◽  
Multiple Cycles ◽  
Replication Fitness ◽  
Hiv 1

AbstractDrug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.

scholarly journals Determinants of HIV-1 Mutational Escape From Cytotoxic T Lymphocytes

2003 ◽  
Vol 197 (10) ◽  
pp. 1365-1375 ◽  
Author(s):  
Otto O. Yang ◽  
Phuong Thi Nguyen Sarkis ◽  
Ayub Ali ◽  
Jason D. Harlow ◽  
Christian Brander ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Immune Escape ◽  
Selective Pressure ◽  
Escape Mutation ◽  
Resistance Mutations ◽  
Fitness Costs ◽  
Hiv 1

CD8+ class I–restricted cytotoxic T lymphocytes (CTLs) usually incompletely suppress HIV-1 in vivo, and while analogous partial suppression induces antiretroviral drug-resistance mutations, epitope escape mutations are inconsistently observed. However, escape mutation depends on the net balance of selective pressure and mutational fitness costs, which are poorly understood and difficult to study in vivo. Here we used a controlled in vitro system to evaluate the ability of HIV-1 to escape from CTL clones, finding that virus replicating under selective pressure rapidly can develop phenotypic resistance associated with genotypic changes. Escape varied between clones recognizing the same Gag epitope or different Gag and RT epitopes, indicating the influence of the T cell receptor on pressure and fitness costs. Gag and RT escape mutations were monoclonal intra-epitope substitutions, indicating limitation by fitness constraints in structural proteins. In contrast, escape from Nef-specific CTL was more rapid and consistent, marked by a polyclonal mixture of epitope point mutations and upstream frameshifts. We conclude that incomplete viral suppression by CTL can result in rapid emergence of immune escape, but the likelihood is strongly determined by factors influencing the fitness costs of the particular epitope targeted and the ability of responding CTL to recognize specific epitope variants.

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