scholarly journals A mutation-selection model of protein evolution under persistent positive selection

2021 ◽  
Author(s):  
Asif U Tamuri ◽  
Mario dos Reis
Keyword(s):  
Positive Selection ◽  
Protein Evolution ◽  
First Principles ◽  
Synonymous Codon ◽  
Selection Model ◽  
Inference Procedure ◽  
Codon Substitution ◽  
Adaptive Radiations ◽  
Surrogate Measure ◽  
Evolution Of Proteins

We use first principles of population genetics to model the evolution of proteins under persistent positive selection (PPS). PPS may occur when organisms are subjected to persistent environmental change, during adaptive radiations, or in host-pathogen interactions. Our mutation-selection model indicates protein evolution under PPS is an irreversible Markov process, and thus proteins under PPS show a strongly asymmetrical distribution of selection coefficients among amino acid substitutions. Our model shows the criteria ω > 1 (where ω is the ratio of non-synonymous over synonymous codon substitution rates) to detect positive selection is conservative and indeed arbitrary, because in real proteins many mutations are highly deleterious and are removed by selection even at positively-selected sites. We use a penalized-likelihood implementation of our model to successfully detect PPS in plant RuBisCO and influenza HA proteins. By directly estimating selection coefficients at protein sites, our inference procedure bypasses the need for using ω as a surrogate measure of selection and improves our ability to detect molecular adaptation in proteins.

A codon model of nucleotide substitution with selection on synonymous codon usage

2014 ◽  
Author(s):  
Laura Kubatko ◽  
Premal Shah ◽  
Radu Herbei ◽  
Michael Gilchrist
Keyword(s):  
Protein Production ◽  
Synonymous Codon ◽  
Error Rates ◽  
Selection Model ◽  
Substitution Model ◽  
Protein Coding ◽  
New Model ◽  
Protein Coding Genes ◽  
Codon Substitution ◽  
Yeast Genes

The quality of phylogenetic inference made from protein-coding genes depends, in part, on the realism with which the codon substitution process is modeled. Here we propose a new mechanistic model that combines the standard M0 substitution model of Yang (1997) with a simplified model from Gilchrist (2007) that includes selection on synonymous substitutions as a function of codon-specific nonsense error rates. We tested the newly proposed model by applying it to 104 protein-coding genes in brewer's yeast, and compared the fit of the new model to the standard M0 model and to the mutation-selection model of Yang and Nielsen (2008) using the AIC. Our new model provided significantly better fit in approximately 85% of the cases considered for the basic M0 model and in approximately 25% of the cases for the M0 model with estimated codon frequencies, but only in a few cases when the mutation-selection model was considered. However, our model includes a parameter that can be interpreted as a measure of the rate of protein production, and the estimates of this parameter were highly correlated with an independent measure of protein production for the yeast genes considered here. Finally, we found that in some cases the new model led to the preference of a different phylogeny for a subset of the genes considered, indicating that substitution model choice may have an impact on the estimated phylogeny.

scholarly journals Codon-Substitution Models for Heterogeneous Selection Pressure at Amino Acid Sites

Genetics ◽  
2000 ◽  
Vol 155 (1) ◽  
pp. 431-449 ◽  
Author(s):  
Ziheng Yang ◽  
Rasmus Nielsen ◽  
Nick Goldman ◽  
Anne-Mette Krabbe Pedersen
Keyword(s):  
Amino Acid ◽  
Positive Selection ◽  
Selective Pressure ◽  
Acid Sites ◽  
Data Sets ◽  
Protein Coding ◽  
Important Indicator ◽  
Diversifying Selection ◽  
Codon Substitution ◽  
Neutral Mutations

AbstractComparison of relative fixation rates of synonymous (silent) and nonsynonymous (amino acid-altering) mutations provides a means for understanding the mechanisms of molecular sequence evolution. The nonsynonymous/synonymous rate ratio (ω = dN/dS) is an important indicator of selective pressure at the protein level, with ω = 1 meaning neutral mutations, ω < 1 purifying selection, and ω > 1 diversifying positive selection. Amino acid sites in a protein are expected to be under different selective pressures and have different underlying ω ratios. We develop models that account for heterogeneous ω ratios among amino acid sites and apply them to phylogenetic analyses of protein-coding DNA sequences. These models are useful for testing for adaptive molecular evolution and identifying amino acid sites under diversifying selection. Ten data sets of genes from nuclear, mitochondrial, and viral genomes are analyzed to estimate the distributions of ω among sites. In all data sets analyzed, the selective pressure indicated by the ω ratio is found to be highly heterogeneous among sites. Previously unsuspected Darwinian selection is detected in several genes in which the average ω ratio across sites is <1, but in which some sites are clearly under diversifying selection with ω > 1. Genes undergoing positive selection include the β-globin gene from vertebrates, mitochondrial protein-coding genes from hominoids, the hemagglutinin (HA) gene from human influenza virus A, and HIV-1 env, vif, and pol genes. Tests for the presence of positively selected sites and their subsequent identification appear quite robust to the specific distributional form assumed for ω and can be achieved using any of several models we implement. However, we encountered difficulties in estimating the precise distribution of ω among sites from real data sets.

The Role of Behavioral Frictions in Health Insurance Marketplace Enrollment and Risk: Evidence from a Field Experiment

2021 ◽  
Vol 111 (5) ◽  
pp. 1549-1574
Author(s):  
Richard Domurat ◽  
Isaac Menashe ◽  
Wesley Yin
Keyword(s):  
Health Insurance ◽  
Field Experiment ◽  
Positive Selection ◽  
Adverse Selection ◽  
Low Income ◽  
Market Risk ◽  
Selection Model ◽  
Heterogeneous Effects ◽  
Low Income Consumers

We experimentally varied information mailed to 87,000 households in California’s health insurance marketplace to study the role of frictions in insurance take-up. Reminders about the enrollment deadline raised enrollment by 1.3 pp (16 percent) in this typically low take-up population. Heterogeneous effects of personalized subsidy information indicate misperceptions about program benefits. Consistent with an adverse selection model with frictional enrollment costs, the intervention lowered average spending risk by 5.1 percent, implying that marginal respondents were 37 percent less costly than inframarginal consumers. We observe the largest positive selection among low income consumers, who exhibit the largest frictions in enrollment. Finally, we estimate the implied value of the letter intervention to be $25 to $53 per month in subsidy dollars. These results suggest that frictions may partially explain low take-up for marketplace insurance, and that interventions reducing them can improve enrollment and market risk in exchanges. (JEL C93, G22, G52, H75, I13)

scholarly journals Laboratory-Directed Protein Evolution

2005 ◽  
Vol 69 (3) ◽  
pp. 373-392 ◽  
Author(s):  
Ling Yuan ◽  
Itzhak Kurek ◽  
James English ◽  
Robert Keenan
Keyword(s):  
Protein Evolution ◽  
Selective Pressure ◽  
Evolutionary Potential ◽  
Effective Strategies ◽  
Scientific Disciplines ◽  
Wide Range ◽  
Protein Functions ◽  
Evolution Of Proteins ◽  
Efficient Screening ◽  
New Protein

SUMMARY Systematic approaches to directed evolution of proteins have been documented since the 1970s. The ability to recruit new protein functions arises from the considerable substrate ambiguity of many proteins. The substrate ambiguity of a protein can be interpreted as the evolutionary potential that allows a protein to acquire new specificities through mutation or to regain function via mutations that differ from the original protein sequence. All organisms have evolutionarily exploited this substrate ambiguity. When exploited in a laboratory under controlled mutagenesis and selection, it enables a protein to “evolve” in desired directions. One of the most effective strategies in directed protein evolution is to gradually accumulate mutations, either sequentially or by recombination, while applying selective pressure. This is typically achieved by the generation of libraries of mutants followed by efficient screening of these libraries for targeted functions and subsequent repetition of the process using improved mutants from the previous screening. Here we review some of the successful strategies in creating protein diversity and the more recent progress in directed protein evolution in a wide range of scientific disciplines and its impacts in chemical, pharmaceutical, and agricultural sciences.

The Synonymous V107V Mutation In Factor IX Is Not So Silent and May Cause Hemophilia B In Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2197-2197 ◽  
Author(s):  
Chava Kimchi-Sarfaty ◽  
Vijaya L Simhadri ◽  
David Kopelman ◽  
Adam Friedman ◽  
Nathan Edwards ◽  
...  
Keyword(s):  
Codon Usage ◽  
In Silico ◽  
Synonymous Codon ◽  
Protein Translation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Structure Stability ◽  
Synonymous Mutation ◽  
Codon Substitution ◽  
In Silico Analyses

Abstract Abstract 2197 Hemophilia B is characterized by structural and functional defects in coagulation factor IX (FIX) caused by mutations in the F9 gene. Various mutations (nonsense, missense, etc.) are known to be associated with the disease, including a synonymous V107V mutation reported recently by Knobe and colleagues (Knobe et al., Hemophilia, 2008). However the mechanism by which this synonymous mutation contributes to the disease has not yet been elucidated. Earlier we have shown that synonymous codon substitutions in the mRNA of the multidrug resistance protein (MDR1) may change the conformation of the protein and result in altered functionality (Kimchi-Sarfaty et al., Science, 2008). Here we have performed in silico analyses of the synonymous codon substitution (GTGàGTA) leading to the V107V polymorphism and found that it may change the mRNA structure, stability, codon usage, and 3D structure of the encoded protein. We hypothesize that changes in codon usage might affect the rhythm of protein translation and thus result in slightly altered FIX conformation. In vitro analyses of FIX mRNA and protein expression supported our in silico analyses. The GTGàGTA (V107V) synonymous mutation results in reduced expression levels as well as an encoded protein with a slightly different conformation compared to wild-type FIX. These results show that the V107V polymorphism is not silent and might cause mild hemophilia B. This work sheds further light on ways in which synonymous mutations impact disease. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination policy Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cross-genotype characterization of genetic diversity and molecular adaptation in hepatitis C virus envelope glycoprotein genes

2007 ◽  
Vol 88 (2) ◽  
pp. 458-469 ◽  
Author(s):  
Richard J. P. Brown ◽  
Alexander W. Tarr ◽  
C. Patrick McClure ◽  
Vicky S. Juttla ◽  
Nader Tagiuri ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Positive Selection ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibody ◽  
Full Length ◽  
Envelope Gene ◽  
Adaptive Mutations ◽  
Codon Substitution ◽  
Sequence Databases

Investigation of the mechanisms underlying hepatitis C virus (HCV) envelope glycoprotein gene evolution will greatly assist rational development of broadly neutralizing antibody-based vaccines or vaccine components. Previously, comprehensive cross-genotype evolutionary studies of E1E2 have not been possible due to the paucity of full-length envelope gene sequences representative of all major HCV genotypes (1–6) deposited in international sequence databases. To address this shortfall, a full-length E1E2 clone panel, corresponding to genotypes of HCV that were previously under-represented, was generated. This panel, coupled with divergent isolates available via international sequence databases, was subjected to high-resolution methods for determining codon-substitution patterns, enabling a fine-scale dissection of the selective pressures operating on HCV E1E2. Whilst no evidence for positive selection was observed in E1, the E2 protein contained a number of sites under strong positive selection. A high proportion of these sites were located within the first hypervariable region (HVR1), and statistical analysis revealed that cross-genotype adaptive mutations were restricted to a subset of homologous positions within this region. Importantly, downstream of HVR1, a differential genotype-specific distribution of adaptive mutations was observed, suggesting that subtly different evolutionary pressures shape present-day genotype diversity in E2 outside HVR1. Despite these observations, it is demonstrated that purifying selection due to functional constraint is the major evolutionary force acting on HCV E1E2. These findings are important in the context of neutralizing-antibody vaccine targeting, as well as in contributing to our understanding of E1E2 function.

scholarly journals Protein Evolution Depends on Multiple Distinct Population Size Parameters

2017 ◽  
Author(s):  
Alexander Platt ◽  
Claudia C Weber ◽  
David A Liberles
Keyword(s):  
Population Size ◽  
Protein Evolution ◽  
Functional Constraints ◽  
Effective Population ◽  
Coding Sequences ◽  
The Many ◽  
Definition Of ◽  
Evolution Of Proteins ◽  
The Relationship ◽  
New Mutations

AbstractThat population size affects the fate of new mutations arising in genomes, modulating both how frequently they arise and how efficiently natural selection is able to filter them, is well established. It is therefore clear that these distinct roles for population size that characterize different processes should affect the evolution of proteins and need to be carefully defined. Empirical evidence is consistent with a role for demography in influencing protein evolution, supporting the idea that functional constraints alone do not determine the composition of coding sequences.Given that the relationship between population size, mutant fitness and fixation probability has been well characterized, estimating fitness from observed substitutions is well within reach with well-formulated models. Molecular evolution research has, therefore, increasingly begun to leverage concepts from population genetics to quantify the selective effects associated with different classes of mutation. However, in order for this type of analysis to provide meaningful information about the intra- and inter-specific evolution of coding sequences, a clear definition of concepts of population size, what they influence, and how they are best parameterized is essential.Here, we present an overview of the many distinct concepts that “population size” and “effective population size” may refer to, what they represent for studying proteins, and how this knowledge can be harnessed to produce better specified models of protein evolution.

scholarly journals TRIAD: a transposition-based approach for gene mutagenesis by random short in-frame insertions and deletions for directed protein evolution

2021 ◽  
Author(s):  
Stephane Emond ◽  
Florian Hollfelder
Keyword(s):  
Directed Evolution ◽  
Protein Evolution ◽  
Transposon Mutagenesis ◽  
Scfv Antibody ◽  
Standard Protocol ◽  
Insertions And Deletions ◽  
Natural Protein ◽  
Nucleotide Insertions ◽  
Evolution Of Proteins

Abstract Insertions and deletions (InDels) are among the most frequent changes observed in natural protein evolution, yet their potential has hardly been harnessed in directed evolution experiments. Here we describe the standard protocol for TRIAD (Transposition-based Random Insertion And Deletion mutagenesis), a simple and efficient Mu transposon mutagenesis approach for generating libraries of single InDel variants with one, two or three triplet nucleotide insertions or deletions. This method has recently been employed in three published examples of InDel-based directed evolution of proteins, including a phosphotriesterase, a scFv antibody and an ancestral luciferase.

scholarly journals Most cancers carry a substantial deleterious load due to Hill-Robertson interference

2019 ◽  
Author(s):  
Susanne Tilk ◽  
Christina Curtis ◽  
Dmitri A Petrov ◽  
Christopher D McFarland
Keyword(s):  
Positive Selection ◽  
Negative Selection ◽  
Selection Model ◽  
Fitness Cost ◽  
Deleterious Mutations ◽  
Weak Selection ◽  
Selective Pressures ◽  
Mutational Burden ◽  
Genome Wide ◽  
Average Fitness

AbstractCancer genomes exhibit surprisingly weak signatures of negative selection1,2. This may be because tumors evolve under weak selective pressures (‘weak selection’) or because genome-wide linkage in cancer prevents most deleterious mutations from being removed due to Hill-Robertson interference3 (‘inefficient selection’). The weak selection model argues that most genes are only important for multicellular function and that selection acts only on a subset of essential genes. In contrast, the inefficient selection model predicts that only cancers with low mutational burdens, where linkage effects are minimal, will exhibit strong signals of negative selection against deleterious passengers and positive selection for beneficial drivers. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, are present in clonal and subclonal mutations, and persist in Copy Number Alterations. A consequence of this inability to remove deleterious passengers is that tumors with elevated mutational burdens, which are expected to harbor substantial protein folding stress, upregulate heat shock pathways. Finally, using evolutionary modeling, we find that Hill-Robertson interference alone can reproduce the patterns of attenuated selection observed in both drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost). Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage.

scholarly journals Synonymous Codon Substitution Matrices

2006 ◽  
pp. 630-637 ◽  
Author(s):  
Adrian Schneider ◽  
Gaston H. Gonnet ◽  
Gina M. Cannarozzi
Keyword(s):  
Synonymous Codon ◽  
Codon Substitution ◽  
Substitution Matrices
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