scholarly journals Large-scale in silico mutagenesis experiments reveal optimization of genetic code and codon usage for protein mutational robustness

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Martin Schwersensky ◽  
Marianne Rooman ◽  
Fabrizio Pucci
Keyword(s):  
Codon Usage ◽  
Genetic Code ◽  
Large Scale ◽  
Amino Acid Level ◽  
Protein Structures ◽  
Mutational Robustness ◽  
The Core ◽  
Small Proteins ◽  
Neutral Mutations ◽  
The Impact

Abstract Background How, and the extent to which, evolution acts on DNA and protein sequences to ensure mutational robustness and evolvability is a long-standing open question in the field of molecular evolution. We addressed this issue through the first structurome-scale computational investigation, in which we estimated the change in folding free energy upon all possible single-site mutations introduced in more than 20,000 protein structures, as well as through available experimental stability and fitness data. Results At the amino acid level, we found the protein surface to be more robust against random mutations than the core, this difference being stronger for small proteins. The destabilizing and neutral mutations are more numerous in the core and on the surface, respectively, whereas the stabilizing mutations are about 4% in both regions. At the genetic code level, we observed smallest destabilization for mutations that are due to substitutions of base III in the codon, followed by base I, bases I+III, base II, and other multiple base substitutions. This ranking highly anticorrelates with the codon-anticodon mispairing frequency in the translation process. This suggests that the standard genetic code is optimized to limit the impact of random mutations, but even more so to limit translation errors. At the codon level, both the codon usage and the usage bias appear to optimize mutational robustness and translation accuracy, especially for surface residues. Conclusion Our results highlight the non-universality of mutational robustness and its multiscale dependence on protein features, the structure of the genetic code, and the codon usage. Our analyses and approach are strongly supported by available experimental mutagenesis data.

scholarly journals Large-scale in silico mutagenesis experiments reveal optimization of genetic code and codon usage for protein mutational robustness

2020 ◽  
Author(s):  
Martin Schwersensky ◽  
Marianne Rooman ◽  
Fabrizio Pucci
Keyword(s):  
Amino Acid ◽  
Codon Usage ◽  
Genetic Code ◽  
Amino Acid Level ◽  
Protein Structures ◽  
Dependent Manner ◽  
Mutational Robustness ◽  
The Core ◽  
Base Substitutions ◽  
The Impact

AbstractThe question of how natural evolution acts on DNA and protein sequences to ensure mutational robustness and evolvability has been asked for decades without definitive answer. We tackled this issue through a structurome-scale computational investigation, in which we estimated the change in folding free energy upon all possible single-site mutations introduced in more than 20,000 protein structures. The validity of our results are supported by a very good agreement with experimental mutagenesis data. At the amino acid level, we found the protein surface to be more robust to mutations than the core, in a protein length-dependent manner. About 4% of all mutations were shown to be stabilizing, and a majority of mutations on the surface and in the core to be neutral and destabilizing, respectively. At the nucleobase level, single base substitutions were shown to yield on average less destabilizing amino acid mutations than multiple base substitutions. More precisely, the smallest average destabilization occurs for substitutions of base III in the codon, followed by base I, bases I+III, and base II. This ranking highly anticorrelates with the frequency of codon-anticodon mispairing, and suggests that the standard genetic code is optimized more to limit translation errors than the impact of random mutations. Moreover, the codon usage also appears to be optimized for minimizing the errors at the protein level, especially for surface residues that evolve faster and have therefore been under stronger selection, and for biased codons, suggesting that the codon usage bias also partly aims to optimize protein mutational robustness.

scholarly journals Audio Mining: The Role of Vocal Tone in Persuasion

2021 ◽  
Author(s):  
Xin (Shane) Wang ◽  
Shijie Lu ◽  
X I Li ◽  
Mansur Khamitov ◽  
Neil Bendle
Keyword(s):  
Empirical Study ◽  
Large Scale ◽  
Controlled Experiments ◽  
The Core ◽  
Content Model ◽  
Stereotype Content ◽  
Key Indicators ◽  
The Impact ◽  
Insight Into

Abstract Persuasion success is often related to hard-to-measure characteristics, such as the way the persuader speaks. To examine how vocal tones impact persuasion in an online appeal, this research measures persuaders’ vocal tones in Kickstarter video pitches using novel audio mining technology. Connecting vocal tone dimensions with real-world funding outcomes offers insight into the impact of vocal tones on receivers’ actions. The core hypothesis of this paper is that a successful persuasion attempt is associated with vocal tones denoting (1) focus, (2) low stress, and (3) stable emotions. These three vocal tone dimensions—which are in line with the stereotype content model—matter because they allow receivers to make inferences about a persuader’s competence. The hypotheses are tested with a large-scale empirical study using Kickstarter data, which is then replicated in a different category. In addition, two controlled experiments provide evidence that perceptions of competence mediate the impact of the three vocal tones on persuasion attempt success. The results identify key indicators of persuasion attempt success and suggest a greater role for audio mining in academic consumer research.

scholarly journals Evaluating the Impact of Name Resolution Dependence on the DNS

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Haiyan Xu ◽  
Zhaoxin Zhang ◽  
Jianen Yan ◽  
Xin Ma
Keyword(s):  
Large Scale ◽  
Scale Free Network ◽  
Security Measures ◽  
Scale Free ◽  
Domain Names ◽  
The Core ◽  
Complex Dependence ◽  
Random Failure ◽  
Free Network ◽  
The Impact

In the process of resolving domain names to IP addresses, there exist complex dependence relationships between domains and name servers. This paper studies the impact of the resolution dependence on the DNS through constructing a domain name resolution network based on large-scale actual data. The core nodes of the resolution network are mined from different perspectives by means of four methods. Then, both core attacks and random attacks on the network are simulated for further vulnerability analysis. The experimental results show that when the top 1% of the core nodes in the network are attacked, 46.19% of the domain names become unresolved, and the load of the residual network increases by nearly 195%, while only 0.01% of domain names fail to be resolved and the load increases with 18% in the same attack scale of the random mode. For these key nodes, we need to take effective security measures to prevent them from being attacked. The simulation experiment also proves that the resolution network is a scale-free network, which exhibits robustness against random failure and vulnerability against intentional attacks. These findings provide new references for the configuration of the DNS.

scholarly journals Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants

2020 ◽  
Vol 117 (45) ◽  
pp. 28201-28211
Author(s):  
Sumaiya Iqbal ◽  
Eduardo Pérez-Palma ◽  
Jakob B. Jespersen ◽  
Patrick May ◽  
David Hoksza ◽  
...  
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Molecular Mechanisms ◽  
Amino Acid Level ◽  
Protein Structures ◽  
Point Mutations ◽  
Independent Set ◽  
Clinical Genetics ◽  
Missense Variants ◽  
The Impact

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variations on protein structure and function being especially challenging. Here we characterize the three-dimensional (3D) amino acid positions affected in pathogenic and population variants from 1,330 disease-associated genes using over 14,000 experimentally solved human protein structures. By measuring the statistical burden of variations (i.e., point mutations) from all genes on 40 3D protein features, accounting for the structural, chemical, and functional context of the variations’ positions, we identify features that are generally associated with pathogenic and population missense variants. We then perform the same amino acid-level analysis individually for 24 protein functional classes, which reveals unique characteristics of the positions of the altered amino acids: We observe up to 46% divergence of the class-specific features from the general characteristics obtained by the analysis on all genes, which is consistent with the structural diversity of essential regions across different protein classes. We demonstrate that the function-specific 3D features of the variants match the readouts of mutagenesis experiments for BRCA1 and PTEN, and positively correlate with an independent set of clinically interpreted pathogenic and benign missense variants. Finally, we make our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step toward translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the variants’ pathogenicity in terms of the perturbed molecular mechanisms.

scholarly journals A code within the genetic code: codon usage regulates co-translational protein folding

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Yi Liu
Keyword(s):  
Protein Folding ◽  
Codon Usage ◽  
Genetic Code ◽  
Synonymous Codon ◽  
Protein Structures ◽  
Translation Efficiency ◽  
Intrinsically Disordered ◽  
Synonymous Codons ◽  
Eukaryotic Organisms ◽  
And Function

Abstract The genetic code is degenerate, and most amino acids are encoded by two to six synonymous codons. Codon usage bias, the preference for certain synonymous codons, is a universal feature of all genomes examined. Synonymous codon mutations were previously thought to be silent; however, a growing body evidence now shows that codon usage regulates protein structure and gene expression through effects on co-translational protein folding, translation efficiency and accuracy, mRNA stability, and transcription. Codon usage regulates the speed of translation elongation, resulting in non-uniform ribosome decoding rates on mRNAs during translation that is adapted to co-translational protein folding process. Biochemical and genetic evidence demonstrate that codon usage plays an important role in regulating protein folding and function in both prokaryotic and eukaryotic organisms. Certain protein structural types are more sensitive than others to the effects of codon usage on protein folding, and predicted intrinsically disordered domains are more prone to misfolding caused by codon usage changes than other domain types. Bioinformatic analyses revealed that gene codon usage correlates with different protein structures in diverse organisms, indicating the existence of a codon usage code for co-translational protein folding. This review focuses on recent literature on the role and mechanism of codon usage in regulating translation kinetics and co-translational protein folding.

scholarly journals Phylogenetic analysis of mutational robustness based on codon usage supports that the standard genetic code does not prefer extreme environments

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ádám Radványi ◽  
Ádám Kun
Keyword(s):  
Physicochemical Properties ◽  
Codon Usage ◽  
Genetic Code ◽  
Biological Diversity ◽  
Phylogenetic Analyses ◽  
Extreme Environments ◽  
Gc Content ◽  
Standard Genetic Code ◽  
Mutational Robustness ◽  
Synonymous Mutations

AbstractThe mutational robustness of the genetic code is rarely discussed in the context of biological diversity, such as codon usage and related factors, often considered as independent of the actual organism’s proteome. Here we put the living beings back to picture and use distortion as a metric of mutational robustness. Distortion estimates the expected severities of non-synonymous mutations measuring it by amino acid physicochemical properties and weighting for codon usage. Using the biological variance of codon frequencies, we interpret the mutational robustness of the standard genetic code with regards to their corresponding environments and genomic compositions (GC-content). Employing phylogenetic analyses, we show that coding fidelity in physicochemical properties can deteriorate with codon usages adapted to extreme environments and these putative effects are not the artefacts of phylogenetic bias. High temperature environments select for codon usages with decreased mutational robustness of hydrophobic, volumetric, and isoelectric properties. Selection at high saline concentrations also leads to reduced fidelity in polar and isoelectric patterns. These show that the genetic code performs best with mesophilic codon usages, strengthening the view that LUCA or its ancestors preferred lower temperature environments. Taxonomic implications, such as rooting the tree of life, are also discussed.

CHIRONOMIDAE (DIPTERA) RESPONSES TO 2800 YEARS OF CULTURAL INFLUENCE; A PALAEOLIMNOLOGICAL STUDY WITH SPECIAL REFERENCE TO SEDIMENTATION, EUTROPHICATION, AND CONTAMINATION PROCESSES

1980 ◽  
Vol 112 (11) ◽  
pp. 1193-1238 ◽  
Author(s):  
W. F. Warwick
Keyword(s):  
Large Scale ◽  
Sediment Cores ◽  
Sediment Accumulation ◽  
Cultural Development ◽  
Relative Importance ◽  
Fine Sediments ◽  
The Core ◽  
Impact Processes ◽  
European Colonization ◽  
The Impact

AbstractChironomid fossil assemblages in sediment cores collected from the Bay of Quinte, Lake Ontario, were examined to assess the impact of cultural development on the aquatic environment and to estimate, semi-quantitatively, the relative importance of the various impact processes influencing the chironomid communities. The impact of the six cultures defined in the core—the British–Modern, French, Iroquois, Algonkian, Hopewell, and pre-Hopewell periods—was exerted through eutrophication, sedimentation, and contamination processes. Although the chironomid communities in general followed the accepted theories of faunal response to eutrophication, the impact of sedimentation compounded and at times overshadowed the impact of eutrophication. The chironomid community, which responded to initial European colonization by developing a more eutrophic fauna parallel with increased productivity in the bay, reverted to a more oligotrophic fauna when large scale deforestation of the watershed introduced massive amounts of clay sediments into the bay. The resulting unstable bottom conditions and dilution and/or burial of food materials led to an imbalanced oligotrophic fauna characterized by Micropsectra. This fauna was maintained until the high rates of mineral sediment accumulation declined and the effects of eutrophication became manifest. The transition from the imbalanced oligotrophic fauna to the depleted Chironomus/Procladius fauna tolerant of the present-day eutrophic conditions was so rapid that the intervening mesotrophic Phaenopsectra community was unable to develop fully. The recent increased incidence of deformed larvae implicates industrial and/or agricultural contamination in the continued degradation of the Bay of Quinte fauna.Primitive cultures similarly had measurable effects on the chironomid communities. The “more eutrophic” fauna engendered by the Hopewell culture was not inhibited by the accompanying accumulation of fine sediments as in the European periods and only reverted to a more oligotrophic fauna when reduced populations brought decreased productivity during the Algonkian and early Iroquois stages.

Learning Important Mathematics From Contextualization and Networked Collaboration—A Review of The SimCalc Vision and Contributions: Democratizing Access to Important Mathematics

2015 ◽  
Vol 46 (1) ◽  
pp. 125-129
Author(s):  
M. Kathleen Heid
Keyword(s):  
Large Scale ◽  
Educational Software ◽  
Mathematical Thinking ◽  
Leading Edge ◽  
Small Scale ◽  
Mathematical Concepts ◽  
Fundamental Theorem Of Calculus ◽  
The Core ◽  
The Impact ◽  
The Relationship

SimCalc is an educational software and curriculum program designed to introduce students as young as middle school age to fundamental mathematical concepts—change and variation—that underpin the transition from algebra to calculus. The core underlying mathematical idea is the Fundamental Theorem of Calculus, and through activities involving change and variation, SimCalc students acquire contextualized, networked, and collaborative experience with the relationship between derivatives and antiderivatives. The program had been guided from its birth by the late James J. Kaput, a mathematics education leader who thrived by working on the leading edge of the field. This book reports not only on the theory on which SimCalc is based but also on more than 15 years of small-scale and large-scale research on the impact of SimCalc. It also includes thoughtprovoking discussions of the ways in which the SimCalc approach relates to other work on engaging students in mathematical thinking.

Codon usage bias in prokaryotic genomes and environmental adaptation

2020 ◽  
Author(s):  
Davide Arella ◽  
Maddalena Dilucca ◽  
Andrea Giansanti
Keyword(s):  
Codon Usage ◽  
Codon Usage Bias ◽  
Pathogenic Bacteria ◽  
Large Scale ◽  
Synonymous Codon ◽  
Environmental Adaptation ◽  
Gene Copy ◽  
Phenotypic Traits ◽  
Translational Efficiency ◽  
The Impact

AbstractIn each genome synonymous codons are used with different frequencies; this phenomenon is known as codon usage bias. The preferred codons tend to correspond to the most highly expressed tRNAs. It had been known that codon usage bias can influence the cellular fitness and that might be associated with the lifestyle of the organism. To test the impact of environments on genome evolution we studied the relationship between codon usage bias and the phenotypic traits of 615 prokaryotic organisms. Principal component analysis revealed that prokaryotes with a specific phenotypic characteristic and living in similar environmental conditions have similar codon preferences, accessed by the Relative Synonymous Codon Usage (RSCU), and a similar tRNA availability gauged by the tRNA gene copy number (tGCN). In addition, by measuring the average tRNA adaptation index (tAI) for each genome, we discovered that organisms able to live in multiple habitats, including facultative organisms, mesophiles and pathogenic bacteria, exhibit lower extents of translational efficiency, consistent with their need to adapt to different environments.This is the first large-scale study that examines the role of translational efficiency in the environmental adaptation of prokaryotes. Our results show that synonymous codon choices might be under strong translational selection, adapting the codons to the tRNA pool to different extents depending on the organism’s lifestyle needs.

scholarly journals Computational Ways to Enhance Protein Inhibitor Design

2021 ◽  
Vol 7 ◽  
Author(s):  
Robert L. Jernigan ◽  
Kannan Sankar ◽  
Kejue Jia ◽  
Eshel Faraggi ◽  
Andrzej Kloczkowski
Keyword(s):  
Design Process ◽  
Large Scale ◽  
Protein Structures ◽  
Disordered Proteins ◽  
Large Set ◽  
Protein Inhibitor ◽  
Contact Potential ◽  
Computational Approaches ◽  
Conformational Variability ◽  
Small Proteins

Two new computational approaches are described to aid in the design of new peptide-based drugs by evaluating ensembles of protein structures from their dynamics and through the assessing of structures using empirical contact potential. These approaches build on the concept that conformational variability can aid in the binding process and, for disordered proteins, can even facilitate the binding of more diverse ligands. This latter consideration indicates that such a design process should be less restrictive so that multiple inhibitors might be effective. The example chosen here focuses on proteins/peptides that bind to hemagglutinin (HA) to block the large-scale conformational change for activation. Variability in the conformations is considered from sets of experimental structures, or as an alternative, from their simple computed dynamics; the set of designe peptides/small proteins from the David Baker lab designed to bind to hemagglutinin, is the large set considered and is assessed with the new empirical contact potentials.

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