scholarly journals Crossing fitness valleys via double substitutions within codons

2019 ◽  
Author(s):  
Frida Belinky ◽  
Itamar Sela ◽  
Igor B. Rogozin ◽  
Eugene V. Koonin
Keyword(s):  
Amino Acid ◽  
Positive Selection ◽  
Deleterious Effect ◽  
Fitness Landscape ◽  
Purifying Selection ◽  
Nucleotide Substitutions ◽  
Fitness Effect ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Ancestral States

AbstractSingle nucleotide substitutions in protein-coding genes can be divided into synonymous (S), with little fitness effect, and non-synonymous (N) ones that alter amino acids and thus generally have a greater effect. Most of the N substitutions are affected by purifying selection that eliminates them from evolving populations. However, additional mutations of nearby bases can modulate the deleterious effect of single substitutions and thus might be subject to positive selection. To elucidate the effects of selection on double substitutions in all codons, it is critical to differentiate selection from mutational biases. We approached this problem by comparing the fractions of double substitutions within codons to those of the equivalent double S substitutions in adjacent codons. Under the assumption that substitutions occur one at a time, all within-codon double substitutions can be represented as “ancestral-intermediate-final” sequences and can be partitioned into 4 classes: 1) SS: S intermediate – S final, 2) SN: S intermediate – N final, 3) NS: N intermediate – S final, 4) NN: N intermediate – N final. We found that the selective pressure on the second substitution markedly differs among these classes of double substitutions. Analogous to single S substitutions, SS evolve neutrally whereas, analogous to single N substitutions, SN are subject to purifying selection. In contrast, NS show positive selection on the second step because the original amino acid is recovered. The NN double substitutions are heterogeneous and can be subject to either purifying or positive selection, or evolve neutrally, depending on the amino acid similarity between the final or intermediate and the ancestral states. The general trend is that the second mutation compensates for the deleterious effect of the first one, resulting in frequent crossing of valleys on the fitness landscape.

scholarly journals Crossing fitness valleys via double substitutions within codons

BMC Biology ◽  
2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Frida Belinky ◽  
Itamar Sela ◽  
Igor B. Rogozin ◽  
Eugene V. Koonin
Keyword(s):  
Amino Acid ◽  
Positive Selection ◽  
Fitness Landscape ◽  
Purifying Selection ◽  
Second Step ◽  
Nucleotide Substitutions ◽  
Protein Coding ◽  
Synonymous Substitutions ◽  
Ancestral States ◽  
Double Substitution

Abstract Background Single nucleotide substitutions in protein-coding genes can be divided into synonymous (S), with little fitness effect, and non-synonymous (N) ones that alter amino acids and thus generally have a greater effect. Most of the N substitutions are affected by purifying selection that eliminates them from evolving populations. However, additional mutations of nearby bases potentially could alleviate the deleterious effect of single substitutions, making them subject to positive selection. To elucidate the effects of selection on double substitutions in all codons, it is critical to differentiate selection from mutational biases. Results We addressed the evolutionary regimes of within-codon double substitutions in 37 groups of closely related prokaryotic genomes from diverse phyla by comparing the fractions of double substitutions within codons to those of the equivalent double S substitutions in adjacent codons. Under the assumption that substitutions occur one at a time, all within-codon double substitutions can be represented as “ancestral-intermediate-final” sequences (where “intermediate” refers to the first single substitution and “final” refers to the second substitution) and can be partitioned into four classes: (1) SS, S intermediate–S final; (2) SN, S intermediate–N final; (3) NS, N intermediate–S final; and (4) NN, N intermediate–N final. We found that the selective pressure on the second substitution markedly differs among these classes of double substitutions. Analogous to single S (synonymous) substitutions, SS double substitutions evolve neutrally, whereas analogous to single N (non-synonymous) substitutions, SN double substitutions are subject to purifying selection. In contrast, NS show positive selection on the second step because the original amino acid is recovered. The NN double substitutions are heterogeneous and can be subject to either purifying or positive selection, or evolve neutrally, depending on the amino acid similarity between the final or intermediate and the ancestral states. Conclusions The results of the present, comprehensive analysis of the evolutionary landscape of within-codon double substitutions reaffirm the largely conservative regime of protein evolution. However, the second step of a double substitution can be subject to positive selection when the first step is deleterious. Such positive selection can result in frequent crossing of valleys on the fitness landscape.

scholarly journals Protein Coding Gene Nucleotide Substitution Pattern in the Apicomplexan ProtozoaCryptosporidium parvumandCryptosporidium hominis

2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Guangtao Ge ◽  
Lenore Cowen ◽  
Xiaochuan Feng ◽  
Giovanni Widmer
Keyword(s):  
Positive Selection ◽  
Purifying Selection ◽  
High Ratio ◽  
Genome Comparison ◽  
Nucleotide Substitutions ◽  
Substitution Pattern ◽  
Protein Coding ◽  
Genome Wide ◽  
The Impact ◽  
Selection Of

Cryptosporidium parvumandC. hominisare related protozoan pathogens which infect the intestinal epithelium of humans and other vertebrates. To explore the evolution of these parasites, and identify genes under positive selection, we performed a pairwise whole-genome comparison between all orthologous protein coding genes inC. parvumandC. hominis. Genome-wide calculation of the ratio of nonsynonymous versus synonymous nucleotide substitutions (dN/dS) was performed to detect the impact of positive and purifying selection. Of 2465 pairs of orthologous genes, a total of 27 (1.1%) showed a high ratio of nonsynonymous substitutions, consistent with positive selection. A majority of these genes were annotated as hypothetical proteins. In addition, proteins with transmembrane and signal peptide domains are significantly more frequent in the highdN/dSgroup.

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.

scholarly journals A Novel Distinct Genetic Variant of Tomato Torrado Virus with Substantially Shorter RNA1-Specific 3’untranslated Region (3’UTR)

Plants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2454
Author(s):  
Marta Budziszewska ◽  
Przemysław Wieczorek
Keyword(s):  
Amino Acid ◽  
Genetic Variability ◽  
Untranslated Region ◽  
Genetic Variant ◽  
Sequencing Data ◽  
Sequence Analyses ◽  
Nucleotide Substitutions ◽  
Systemic Necrosis ◽  
Single Nucleotide

Tomato torrado virus (ToTV) induces severe systemic necrosis in Solanum lycopersicum. This work aimed at describing the genetic variability of necrosis-inducing ToTV-Wal’17 collected in 2017, derived from the ToTV-Wal’03 after long-term passages in plants. Sequence analyses of the ToTV-Wal’17 indicated twenty-eight single nucleotide substitutions in coding sequence of both RNAs, twelve of which resulted in amino acid changes in viral polyproteins. Moreover the sequencing data revealed that the 3’UTR of ToTV-Wal’17 RNA1 was 394 nts shorter in comparison to Wal’03. The performed sequence analyses revealed that 3’UTR of RNA1 of ToTV-Wal’17 is the most divergent across all previously described European isolates.

scholarly journals Inferring the number and position of changes in selective regime in a non-equilibrium mutation-selection framework

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Andrew M. Ritchie ◽  
Tristan L. Stark ◽  
David A. Liberles
Keyword(s):  
Amino Acid ◽  
Evolutionary Biology ◽  
Fitness Landscape ◽  
Simulated Data ◽  
Time Reversibility ◽  
Data Set ◽  
Protein Coding ◽  
Fitness Parameters ◽  
Selection Framework ◽  
Non Equilibrium

Abstract Background Recovering the historical patterns of selection acting on a protein coding sequence is a major goal of evolutionary biology. Mutation-selection models address this problem by explicitly modelling fixation rates as a function of site-specific amino acid fitness values.However, they are restricted in their utility for investigating directional evolution because they require prior knowledge of the locations of fitness changes in the lineages of a phylogeny. Results We apply a modified mutation-selection methodology that relaxes assumptions of equlibrium and time-reversibility. Our implementation allows us to identify branches where adaptive or compensatory shifts in the fitness landscape have taken place, signalled by a change in amino acid fitness profiles. Through simulation and analysis of an empirical data set of $$\beta $$ β -lactamase genes, we test our ability to recover the position of adaptive events within the tree and successfully reconstruct initial codon frequencies and fitness profile parameters generated under the non-stationary model. Conclusion We demonstrate successful detection of selective shifts and identification of the affected branch on partitions of 300 codons or more. We successfully reconstruct fitness parameters and initial codon frequencies in simulated data and demonstrate that failing to account for non-equilibrium evolution can increase the error in fitness profile estimation. We also demonstrate reconstruction of plausible shifts in amino acid fitnesses in the bacterial $$\beta $$ β -lactamase family and discuss some caveats for interpretation.

scholarly journals Evolutionary switches between two serine codon sets are driven by selection

2016 ◽  
Vol 113 (46) ◽  
pp. 13109-13113 ◽  
Author(s):  
Igor B. Rogozin ◽  
Frida Belinky ◽  
Vladimir Pavlenko ◽  
Svetlana A. Shabalina ◽  
David M. Kristensen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Great Majority ◽  
Purifying Selection ◽  
Nucleotide Substitutions ◽  
Closely Related Species ◽  
Published Evidence ◽  
Genome Wide ◽  
A Genome ◽  
Evolutionarily Conserved ◽  
Frequent Reversal

Serine is the only amino acid that is encoded by two disjoint codon sets so that a tandem substitution of two nucleotides is required to switch between the two sets. Previously published evidence suggests that, for the most evolutionarily conserved serines, the codon set switch occurs by simultaneous substitution of two nucleotides. Here we report a genome-wide reconstruction of the evolution of serine codons in triplets of closely related species from diverse prokaryotes and eukaryotes. The results indicate that the great majority of codon set switches proceed by two consecutive nucleotide substitutions, via a threonine or cysteine intermediate, and are driven by selection. These findings imply a strong pressure of purifying selection in protein evolution, which in the case of serine codon set switches occurs via an initial deleterious substitution quickly followed by a second, compensatory substitution. The result is frequent reversal of amino acid replacements and, at short evolutionary distances, pervasive homoplasy.

scholarly journals Different Mutations in the Genome-Linked Protein VPg of Potato virus Y Confer Virulence on the pvr23 Resistance in Pepper

2006 ◽  
Vol 19 (5) ◽  
pp. 557-563 ◽  
Author(s):  
Valérie Ayme ◽  
Sylvie Souche ◽  
Carole Caranta ◽  
Mireille Jacquemond ◽  
Joël Chadœuf ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genetic Drift ◽  
Potato Virus ◽  
High Frequency ◽  
Potato Virus Y ◽  
Relative Fitness ◽  
Amino Acid Substitutions ◽  
Nucleotide Substitutions ◽  
Single Nucleotide ◽  
Pepper Plants

Five different amino acid substitutions in the VPg of Potato virus Y were shown to be independently responsible for virulence toward pvr23 resistance gene of pepper. A consequence of these multiple mutations toward virulence involving single nucleotide substitutions is a particularly high frequency of resistance breaking (37% of inoculated plants from the first inoculation) and suggests a potentially low durability of pvr23 resistance. These five mutants were observed with significantly different frequencies, one of them being overrepresented. Genetic drift alone could not explain the observed distribution of virulent mutants. More plausible scenarios were obtained by taking into account either the relative substitution rates, the relative fitness of the mutants in pvr23 pepper plants, or both.

scholarly journals Probability of change in life: Amino acid changes in single nucleotide substitutions

Biosystems ◽  
2020 ◽  
Vol 193-194 ◽  
pp. 104135 ◽  
Author(s):  
Kwok-Fong Chan ◽  
Stelios Koukouravas ◽  
Joshua Yi Yeo ◽  
Darius Wen-Shuo Koh ◽  
Samuel Ken-En Gan
Keyword(s):  
Amino Acid ◽  
Nucleotide Substitutions ◽  
Single Nucleotide

scholarly journals Tandem Substitutions in Somatic Hypermutation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 996-996
Author(s):  
Marvyn T. Koning ◽  
Julieta Haydee Sepulveda Yanez ◽  
Diego Alvarez-Saravia ◽  
Bas Pilzecker ◽  
Pauline Van Schouwenburg ◽  
...  
Keyword(s):  
Amino Acid ◽  
Somatic Hypermutation ◽  
Adaptive Immune Response ◽  
Affinity Maturation ◽  
Reference Sequence ◽  
Nucleotide Substitutions ◽  
Sequence Context ◽  
Single Nucleotide ◽  
Adaptive Immune ◽  
Amino Acid Codon

Abstract Upon antigen recognition, activation-induced cytosine deaminase initiates affinity maturation of the B-cell receptor by somatic hypermutation (SHM) through error-prone DNA repair pathways. SHM typically creates single nucleotide substitutions, but tandem substitutions may also occur. While tandem substitutions have been described in mice and other species, the incidence of this phenomenon and its underlying mechanism in humans is currently unknown. We investigated incidence and sequence context of tandem substitutions by massive parallel sequencing of V(D)J repertoires in healthy human donors generated by unbiased ARTISAN PCR. Selection of unique, clonally unrelated, antigen-experienced sequences carrying up to 5% mutations yielded 13.532 VDJ, 7.952 VJ-kappa and 7.598 VJ-lambda. Comparison to the closest germline allele allowed for identification of a total of 122.878 single nucleotide substitutions (SNS), 10.735 tandem dinucleotide substitutions (TDNS) and 2.615 longer contiguous substitutions. After correcting for expected clusters of adjacent SNS, tandem substitutions comprised 5,7% of all AID-induced mutations. The mutation of more than one nucleotide in a single event, was shown to overcome amino acid codon redundancy and may therefore enhance the adaptive immune response. Clustering of such mutations around AID hotspots and their overall distribution indicates that tandem substitutions are an integral part of the SHM spectrum. In the majority of tandem substitutions, the mutated sequence may be identified in the directly adjacent reference sequence context. Tandem substitutions in humans therefore represent single nucleotide juxtalocations. Such juxtalocations appear to be favored in polydipyramidine stretches. These observations could be confirmed in patients with MSH2/6 deficiency, but were absent in a VDJ library from an UNG-deficient patient, indicating a strict dependence on abasic sites as an instigating mechanism. Together, these findings delineate a model where tandem substitutions are predominantly generated by translesion synthesis across an apyramidinic site that is typically created by UNG. During replication, apyrimidinic sites transiently adapt an extruded configuration, causing skipping of the extruded base. Consequent strand decontraction leads to the juxtalocation, after which exonucleases repair the apyramidinic site and any directly adjacent mismatched base pairs. The mismatch repair pathway appears to account for the remainder of tandem substitutions. Our study shows that a significant portion of mutations acquired during SHM are caused by tandem substitutions, and that this mechanism may enhance affinity maturation and expedite the adaptive immune response by overcoming amino acid codon degeneracies or mutating two adjacent amino acid residues simultaneously. Figure legend. Corrected incidence of tandem dinucleotide substitutions in healthy donors. (A) Dinucleotide substitutions from unique IGHV, IGKV and IGLV sequences and corrected after in silico predictions of dinucleotide substitutions that did not occur in tandem. Burgundy cells represent sequence inversions, light and dark purple cells represent juxtalocations of the 5' and 3' base in the pair (as seen from the non-transcribed strand), respectively. For unshaded cells, juxtalocation could not be assessed due to one or more nucleotides in the reference sequence matching the mutated sequence. (B) Relative contribution of sequence inversions and juxtalocations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evolution of subgenomic RNA shapes dengue virus adaptation and epidemiological fitness

2018 ◽  
Author(s):  
Esteban Finol ◽  
Eng Eong Ooi
Keyword(s):  
Dengue Virus ◽  
Positive Selection ◽  
Protein Interactions ◽  
Untranslated Region ◽  
Sequence Divergence ◽  
Purifying Selection ◽  
Viral Fitness ◽  
List Type ◽  
Nucleotide Substitutions ◽  
Genetic Changes

AbstractGenetic changes in the dengue virus (DENV) genome affects viral fitness both clinically and epidemiologically. Even in the 3’ untranslated region (3’UTR), mutations could impact the formation of subgenomic flaviviral RNA (sfRNA) and the specificity of sfRNA in inhibiting host proteins necessary for successful viral replication. Indeed, we have recently shown that mutations in the 3’UTR of DENV2 affected its ability to inhibit TRIM25 E3 ligase activity to reduce interferon (IFN) expression, which potentially contributed to the emergence of a new viral clade during the 1994 dengue epidemic in Puerto Rico. However, whether differences in 3’UTRs shaped DENV evolution on a larger scale remains incompletely understood. Herein, we combined RNA phylogeny with phylogenetics to gain insights on sfRNA evolution. We found that sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Interestingly, only the second flaviviral Nuclease-resistant RNA (fNR2) structure of DENV-2 has undergone strong positive selection. Epidemiological reports also suggest that nucleotide substitutions in fNR2 may drive DENV-2 epidemiological fitness, possibly through sfRNA-protein interactions. Collectively, our findings indicate that 3’UTRs are important determinants of DENV fitness in human-mosquito cycles.HighlightsDengue viruses (DENV) preserve RNA elements in their 3’ untranslated region (UTR).Site-specific quantification of natural selection revealed positive selection on DENV2 sfRNA.Flaviviral nuclease-resistant RNA (fNR) structures in DENV 3’UTRs contribute to DENV speciation.A highly evolving fNR structure appears to increase DENV-2 epidemiological fitness.

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