HIV Protease and Integrase Empirical Substitution Models of Evolution: Protein-Specific Models Outperform Generalist Models.
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ABSTRACT:
SUBMITTER: Del Amparo R
PROVIDER: S-EPMC8774313 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Comparative sequence analyses, including such fundamental bioinformatics techniques as similarity searching, sequence alignment and phylogenetic inference, have become a mainstay for researchers studying type 1 Human Immunodeficiency Virus (HIV-1) genome structure and evolution. Implicit in comparative analyses is an underlying model of evolution, and the chosen model can significantly affect the results. In general, evolutionary models describe the probabilities of replacing one amino acid character with another over a period of time. Most widely used evolutionary models for protein sequences have been derived from curated alignments of hundreds of proteins, usually based on mammalian genomes. It is unclear to what extent these empirical models are generalizable to a very different organism, such as HIV-1-the most extensively sequenced organism in existence. We developed a maximum likelihood model fitting procedure to a collection of HIV-1 alignments sampled from different viral genes, and inferred two empirical substitution models, suitable for describing between-and within-host evolution. Our procedure pools the information from multiple sequence alignments, and provided software implementation can be run efficiently in parallel on a computer cluster. We describe how the inferred substitution models can be used to generate scoring matrices suitable for alignment and similarity searches. Our models had a consistently superior fit relative to the best existing models and to parameter-rich data-driven models when benchmarked on independent HIV-1 alignments, demonstrating evolutionary biases in amino-acid substitution that are unique to HIV, and that are not captured by the existing models. The scoring matrices derived from the models showed a marked difference from common amino-acid scoring matrices. The use of an appropriate evolutionary model recovered a known viral transmission history, whereas a poorly chosen model introduced phylogenetic error. We argue that our model derivation procedure is immediately applicable to other organisms with extensive sequence data available, such as Hepatitis C and Influenza A viruses.
| S-EPMC1876811 | biostudies-literature
Project description:UnlabelledHIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ?1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ?0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ?0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ?10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS.ImportanceMost antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN.
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Project description:Bird pollination systems are dominated by specialist nectarivores, such as hummingbirds in the Americas and sunbirds in Africa. Opportunistic (generalist) avian nectarivores such as orioles, weavers and bulbuls have also been implicated as plant pollinators, but their effectiveness as agents of pollen transfer is poorly known. Here, we compare the single-visit effectiveness of specialist and opportunistic avian nectarivores as pollinators of Aloe ferox, a plant that relies almost exclusively on birds for seed production. We found that the number of pollen grains on stigmas of flowers receiving single visits by opportunistic avian nectarivores was approximately threefold greater than on those receiving single visits by specialist sunbirds and about twofold greater than on those that received single visits by honeybees. The number of pollen grains on stigmas of flowers visited by sunbirds was similar to that on stigmas of unvisited flowers. These results show that opportunistic birds are highly effective pollinators of A. ferox, supporting the idea that some plants are specialized for pollination by opportunistic birds.
| S-EPMC6684984 | biostudies-literature
Project description:To assess compatibility in sequence analysis we compared results from Sanger sequencing (with sequencing threshold >15%) and Next Generation Sequencing (with sequencing treshold >5%). Totally, there were 60 patients included in this part of the study. Here we demonstrate how reliable tool for fast and accurate identification of low-level viral quasispecies is deep-sequencing.
2023-11-30 | E-MTAB-13563 | biostudies-arrayexpress
Project description:To assess compatibility in sequence analysis we compared results from Sanger sequencing (with sequencing threshold >15%) and Next Generation Sequencing (with sequencing treshold >5%). Totally, there were 48 patients included in this part of the study but sequencing for one sample failed. Here we demonstrate how reliable tool for fast and accurate identification of low-level viral quasispecies is deep-sequencing.
2019-07-29 | E-MTAB-8153 | biostudies-arrayexpress
Project description:BACKGROUND: Codon substitution probabilities are used in many types of molecular evolution studies such as determining Ka/Ks ratios, creating ancestral DNA sequences or aligning coding DNA. Until the recent dramatic increase in genomic data enabled construction of empirical matrices, researchers relied on parameterized models of codon evolution. Here we present the first empirical codon substitution matrix entirely built from alignments of coding sequences from vertebrate DNA and thus provide an alternative to parameterized models of codon evolution. RESULTS: A set of 17,502 alignments of orthologous sequences from five vertebrate genomes yielded 8.3 million aligned codons from which the number of substitutions between codons were counted. From this data, both a probability matrix and a matrix of similarity scores were computed. They are 64 x 64 matrices describing the substitutions between all codons. Substitutions from sense codons to stop codons are not considered, resulting in block diagonal matrices consisting of 61 x 61 entries for the sense codons and 3 x 3 entries for the stop codons. CONCLUSION: The amount of genomic data currently available allowed for the construction of an empirical codon substitution matrix. However, more sequence data is still needed to construct matrices from different subsets of DNA, specific to kingdoms, evolutionary distance or different amount of synonymous change. Codon mutation matrices have advantages for alignments up to medium evolutionary distances and for usages that require DNA such as ancestral reconstruction of DNA sequences and the calculation of Ka/Ks ratios.
| S-EPMC1173088 | biostudies-other
Project description:Proteins evolve under a myriad of biophysical selection pressures that collectively control the patterns of amino acid substitutions. These evolutionary pressures are sufficiently consistent over time and across protein families to produce substitution patterns, summarized in global amino acid substitution matrices such as BLOSUM, JTT, WAG, and LG, which can be used to successfully detect homologs, infer phylogenies, and reconstruct ancestral sequences. Although the factors that govern the variation of amino acid substitution rates have received much attention, the influence of thermodynamic stability constraints remains unresolved. Here we develop a simple model to calculate amino acid substitution matrices from evolutionary dynamics controlled by a fitness function that reports on the thermodynamic effects of amino acid mutations in protein structures. This hybrid biophysical and evolutionary model accounts for nucleotide transition/transversion rate bias, multi-nucleotide codon changes, the number of codons per amino acid, and thermodynamic protein stability. We find that our theoretical model accurately recapitulates the complex yet universal pattern observed in common global amino acid substitution matrices used in phylogenetics. These results suggest that selection for thermodynamically stable proteins, coupled with nucleotide mutation bias filtered by the structure of the genetic code, is the primary driver behind the global amino acid substitution patterns observed in proteins throughout the tree of life.
| S-EPMC8442976 | biostudies-literature
Project description:Identification of minority resistance mutations in the HIV-1 integrase gene using Next Generation Sequencing
| PRJEB9552 | ENA
Project description:Calculating amino-acid substitution models that are specific for individual protein data sets is often difficult due to the computational burden of estimating large numbers of rate parameters. In this study, we tested the computational efficiency and accuracy of five methods used to estimate substitution models, namely Codeml, FastMG, IQ-TREE, P4 (maximum likelihood), and P4 (Bayesian inference). Data-specific substitution models were estimated from simulated alignments (with different lengths) that were generated from a known simulation model and simulation tree. Each of the resulting data-specific substitution models was used to calculate the maximum likelihood score of the simulation tree and simulated data that was used to calculate the model, and compared with the maximum likelihood scores of the known simulation model and simulation tree on the same simulated data. Additionally, the commonly-used empirical models, cpREV and WAG, were assessed similarly. Data-specific models performed better than the empirical models, which under-fitted the simulated alignments, had the highest difference to the simulation model maximum-likelihood score, clustered further from the simulation model in principal component analysis ordination, and inferred less accurate trees. Data-specific models and the simulation model shared statistically indistinguishable maximum-likelihood scores, indicating that the five methods were reasonably accurate at estimating substitution models by this measure. Nevertheless, tree statistics showed differences between optimal maximum likelihood trees. Unlike other model estimating methods, trees inferred using data-specific models generated with IQ-TREE and P4 (maximum likelihood) were not significantly different from the trees derived from the simulation model in each analysis, indicating that these two methods alone were the most accurate at estimating data-specific models. To show the benefits of using data-specific protein models several published data sets were reanalysed using IQ-TREE-estimated models. These newly estimated models were a better fit to the data than the empirical models that were used by the original authors, often inferred longer trees, and resulted in different tree topologies in more than half of the re-analysed data sets. The results of this study show that software availability and high computation burden are not limitations to generating better-fitting data-specific amino-acid substitution models for phylogenetic analyses.
| S-EPMC10416777 | biostudies-literature
Project description:Human immunodeficiency virus (HIV) therapy has evolved over the last 20 years from mono-drug therapy given five times daily to regimens consisting of three or four drugs combined in a single-tablet dosed once daily. To allow once-daily administration, several drugs require pharmacokinetic boosting by a concomitantly administered P-glycoprotein and cytochrome P450 inhibitor such as ritonavir. The availability of cobicistat provides an alternative to ritonavir to those who are intolerant to this drug, and the opportunity for co-formulated single-tablet regimens consisting of tenofovir/emtricitabine, cobicistat and elvitegravir, atazanavir or darunavir. The cobicistat/elvitegravir-based regimen is well tolerated and patients achieved high rates of HIV RNA suppression in clinical trials. Cobicistat inhibits renal tubular secretion of creatinine, resulting in increased serum creatinine concentrations and reduced estimated glomerular filtration rate, with a new set point reached after 4 weeks. Treatment limiting renal toxicity with cobicistat/elvitegravir and tenofovir disoproxil fumarate is infrequent and may be further reduced when cobicistat is co-formulated with tenofovir alafenamide fumarate, a novel formation of tenofovir currently undergoing clinical trials.
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