scholarly journals Context-dependent and -independent selection on synonymous mutations revealed by 1,135 genomes of Arabidopsis thaliana

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Duan Chu ◽  
Lai Wei
Keyword(s):  
Selection Pressure ◽  
Translation Process ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Snp Data ◽  
Codon Context ◽  
Long Time ◽  
Functional Consequences ◽  
Context Dependent ◽  
Adaptation Index

Abstract Background Synonymous mutations do not alter the amino acids and therefore are regarded as neutral for a long time. However, they do change the tRNA adaptation index (tAI) of a particular codon (independent of its context), affecting the tRNA availability during translation. They could also change the isoaccepting relationship with its neighboring synonymous codons in particular context, which again affects the local translation process. Evidence of selection pressure on synonymous mutations has emerged. Results The proposed selection patterns on synonymous mutations are never formally and systematically tested in plant species. We fully take advantage of the SNP data from 1,135 A. thaliana lines, and found that the synonymous mutations that increase tAI or the isoaccepting mutations in isoaccepting codon context tend to have higher derived allele frequencies (DAF) compared to other synonymous mutations of the opposite effects. Conclusions Synonymous mutations are not strictly neutral. The synonymous mutations that increase tAI or the isoaccepting mutations in isoaccepting codon context are likely to be positively selected. We propose the concept of context-dependent and -independent selection on synonymous mutations. These concepts broaden our knowledge of the functional consequences of synonymous mutations, and should be appealing to phytologists and evolutionary biologists.

Highly conserved gsc1 gene of Pneumocystis jirovecii in patients with or without prior exposure to Echinocandins

2021 ◽  
Author(s):  
Pierre L. Bonnet ◽  
Solène Le Gal ◽  
Claire V. Hoffmann ◽  
Florent Morio ◽  
Fouleymata Diabira ◽  
...  
Keyword(s):  
Hot Spots ◽  
Selection Pressure ◽  
Gene Diversity ◽  
Prior Exposure ◽  
Cell Wall Component ◽  
Synonymous Mutations ◽  
Significant Difference ◽  
A Cell ◽  
Patient Groups ◽  
Noncompetitive Inhibitors

Echinocandins are noncompetitive inhibitors of the GSC1 subunit of the enzymatic complex involved in synthesis of 1,3-beta-D-glucan, a cell wall component of most fungi, including Pneumocystis spp. Echinocandins are widely used for treating systemic candidiasis and rarely used for treating Pneumocystis pneumonia. Consequently, data on P. jirovecii gsc1 gene diversity are still scarce, compared to the homologous fks1 gene of Candida spp. In this study, we analyzed P. jirovecii gsc1 gene diversity and the putative selection pressure of echinocandins on P. jirovecii. Gsc1 gene sequences of P. jirovecii specimens from two patient groups were compared. One group of 27 patients had prior exposure to echinocandins whereas the second group of 24 patients did not, at the time of P. jirovecii infection diagnoses. Two portions of P. jirovecii gsc1 gene, HS1 and HS2, homologous to hot spots described in Candida spp., were sequenced. Three SNPs at positions 2204, 2243, and 2303 close to the HS1 region and another SNP at position 4540 more distant from the HS2 region were identified. These SNPs represent synonymous mutations. Three gsc1 HS1 alleles, A, B, and C, and two gsc1 HS2 alleles, a and b, and four haplotypes, Ca, Cb, Aa, and Ba, were defined, without significant difference in haplotype distribution in both patient groups ( p = 0.57). Considering the identical diversity of P. jirovecii gsc1 gene and the detection of synonymous mutations in both patient groups, no selection pressure of echinocandins among P. jirovecii microorganisms can be pointed out so far.

Are synonymous codons indeed synonymous?

2012 ◽  
Vol 3 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Pál Venetianer
Keyword(s):  
Protein Synthesis ◽  
Synonymous Codon ◽  
Synonymous Mutations ◽  
Synonymous Codons ◽  
Two Factors ◽  
Trna Species ◽  
Frequency Of Occurence

AbstractIt has long been known that the distribution and frequency of occurence of synonymous codons can vary greatly among different species, and that the abundance of isoaccepting tRNA species could also be very different. The interaction of these two factors may influence the rate and efficiency of protein synthesis and therefore synonymous mutations might influence the fitness of the organism and cannot be treated generally as ‘neutral’ in an evolutionary sense. These general effects of synonymous mutations, and their possible role in evolution, have been discussed in several recent papers. This review, however, will only deal with the influence of synonymous codon replacements on the expression of individual genes. It will describe the possible mechanisms of such effects and will present examples demonstrating the existence and effects of each of these mechanisms.

scholarly journals GAS doesn't “turn the engine” when states are sequential or context-dependent

2004 ◽  
Vol 27 (6) ◽  
pp. 901-902
Author(s):  
Liane Gabora
Keyword(s):  
Probability Distribution ◽  
Selection Pressure ◽  
Cognitive Change ◽  
Selection Theory ◽  
Classical Formalism ◽  
Context Dependent

Selection theory requires multiple, simultaneously-actualized states. In cognition, each thought changes the “selection pressure” against which the next is evaluated; they are not simultaneously selected amongst. Cognitive change occurs not through selection among discrete “neural configurations,” but through interaction between conceptual web and context. This introduces a non-Kolmogorovian probability distribution, hence a classical formalism (e.g., selection theory) cannot be used.

scholarly journals Comparisons of Coding and Noncoding Sequences to infer the Origin of Codon usage Bias

2017 ◽  
Author(s):  
Prashant Mainali ◽  
Sobita Pathak
Keyword(s):  
Codon Usage ◽  
Codon Usage Bias ◽  
Gc Content ◽  
Mutation Bias ◽  
Translation Process ◽  
Noncoding Regions ◽  
Coding Regions ◽  
Synonymous Codons ◽  
Shed Light

ABSTRACTCodon usage bias is the preferential use of the subset of synonymous codons during translation. In this paper, the comparisons of normalized entropy and GC content between the sequence of coding regions of Escherichia coli k12 and noncoding regions (ncRNA, rRNA) of various organisms were done to shed light on the origin of the codon usage bias.The normalized entropy of the coding regions was found significantly higher than the noncoding regions, suggesting the role of the translation process in shaping codon usage bias. Further, when the position specific GC content of both coding and noncoding regions was analyzed, the GC2 content in coding regions was lower than GC1 and GC2 while in noncoding regions, the GC1, GC2, GC3 contents were approximately equal. This discrepancy is explained by the biased mutation coupled with the presence and absence of selection pressure. The accumulation of CG content occurs in the sequences due to mutation bias in DNA repair and recombination process. In noncoding regions, the mutation is harmful and thus, selected against while due to the degeneracy of codons in coding regions, a mutation in GC3 is neutral and hence, not selected. Thus, the accumulation of GC content occurs in coding regions, and thus codon usage bias occurs.

scholarly journals Individual copy number variation and extensive diversity between major MHC-DAB1 allelic lineages in the European bitterling

2022 ◽  
Author(s):  
Lorenzo Talarico ◽  
Anna Bryjová ◽  
Dagmar Čížková ◽  
Karel Douda ◽  
Martin Reichard
Keyword(s):  
Balancing Selection ◽  
Amplicon Sequencing ◽  
Synonymous Mutations ◽  
Allelic Lineages ◽  
Histocompatibility Complex ◽  
Number Variation ◽  
Long Time ◽  
Host Parasite ◽  
First Time

AbstractPolymorphism of the major histocompatibility complex (MHC), DAB1 gene was characterized for the first time in the European bitterling (Rhodeus amarus), a freshwater fish employed in studies of host-parasite coevolution and mate choice, taking advantage of newly designed primers coupled with high-throughput amplicon sequencing. Across 221 genotyped individuals, we detected 1–4 variants per fish, with 28% individuals possessing 3–4 variants. We identified 36 DAB1 variants, and they showed high sequence diversity mostly located within predicted antigen-binding sites, and both global and codon-specific excess of non-synonymous mutations. Despite deep divergence between two major allelic lineages, functional diversity was surprisingly low (3 supertypes). Overall, these findings suggest the role of positive and balancing selection in promotion and long-time maintenance of DAB1 polymorphism. Further investigations will clarify the role of pathogen-mediated selection to drive the evolution of DAB1 variation.

scholarly journals How synonymous mutations alter enzyme structure and function over long time scales

2021 ◽  
Author(s):  
Yang Jiang ◽  
Syam Sundar Neti ◽  
Priya Pradhan ◽  
Squire J. Booker ◽  
Edward P. O'Brien
Keyword(s):  
Time Scales ◽  
Active Sites ◽  
Specific Activity ◽  
Hydrophobic Surface ◽  
Coarse Grained ◽  
Phenotypic Traits ◽  
Native State ◽  
Synonymous Mutations ◽  
Long Time ◽  
Specific Activities

The specific activity of enzymes can be altered over long time scales in cells by synonymous mutations, which change an mRNA molecule's sequence but not the encoded protein's primary structure. How this happens at the molecular level is unknown. Here, we resolve this issue by applying multiscale modeling to three E. coli enzymes - type III chloramphenicol acetyltransferase, D-alanine-D-alanine ligase B, and dihydrofolate reductase. This modeling involves coarse-grained simulations of protein synthesis and post-translational behavior, all-atom simulations as a test of robustness, and QM/MM calculations to characterize function. We first demonstrate that our model accurately predicts experimentally measured changes in specific activity due to synonymous mutations. Then, we show that changes in codon translation rates induced by synonymous mutations cause shifts in co-translational and post-translational folding pathways that kinetically partition molecules into subpopulations that very slowly interconvert to the native, functional state. These long-lived states exhibit reduced catalytic activity, as demonstrated by their increased activation energies for the reactions they carry out. Structurally, these states resemble the native state, with localized misfolding near the active sites of the enzymes. The localized misfolding involves noncovalent lasso entanglements - a topology in which the protein backbone forms a loop closed by noncovalent native contacts which is then threaded by another portion of the protein. Such entanglements are often kinetic traps, as they can require a large proportion of the protein to unfold, which is energetically unfavorable, before they disentangle and attain the native state. The near-native-like structures of these misfolded states allow them to bypass the proteostasis machinery and remain soluble, as they exhibit similar hydrophobic surface areas as the native state. These entangled structures persist in all-atom simulations as well, indicating that these conclusions are independent of model resolution. Thus, synonymous mutations cause shifts in the co- and post-translational structural ensemble of proteins, whose altered subpopulations lead to long-term changes in the specific activities of some enzymes. The formation of entangled subpopulations is therefore a mechanism through which changes in translation elongation rate alter ensemble-averaged specific activities, which can ultimately affect the efficiency of biochemical pathways and phenotypic traits.

scholarly journals Genetic Codes with No Dedicated Stop Codon: Context-Dependent Translation Termination

Cell ◽  
2016 ◽  
Vol 166 (3) ◽  
pp. 691-702 ◽  
Author(s):  
Estienne Carl Swart ◽  
Valentina Serra ◽  
Giulio Petroni ◽  
Mariusz Nowacki
Keyword(s):  
Stop Codon ◽  
Translation Termination ◽  
Genetic Codes ◽  
Codon Context ◽  
Context Dependent

CREBBP Mutations In Relapsed Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 413-413
Author(s):  
Charles Mullighan ◽  
Jinghui Zhang ◽  
Lawryn H. Kasper ◽  
Stephanie Lerach ◽  
Debbie Payne-Turner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Lymphoblastic Leukemia ◽  
Selective Advantage ◽  
Genetic Alterations ◽  
Creb Binding Protein ◽  
Transcriptional Coactivator ◽  
Synonymous Mutations ◽  
Functional Consequences

Abstract Abstract 413 Relapsed acute lymphoblastic leukemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. To identify novel sequence mutations contributing to relapsed in ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. The cohort included B-progenitor ALL with high hyperdiploidy (N=3), TCF3-PBX1 (N=1), ETV6-RUNX1 (N=3), rearrangement of MLL (N=3), BCR-ABL1 (N=3), and low hyperdiploid, pseudodiploid, or miscellaneous karyotypes (N=10). This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including mutations in the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 63 diagnosis-relapse cases and 200 acute leukaemia cases that did not relapse found that 19% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP). The mutations were either present at diagnosis, acquired at relapse, or duplicated to homozygosity at the time of relapse. Moreover, several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations confer a selective advantage and promote resistance to therapy. The mutations either resulted in truncated alleles or deleterious substitutions in highly conserved residues of the HAT domain. To examine the functional consequences of the mutations, we introduced wild type or mutant Crebbp alleles into Cbp/Ep300flox/flox murine embryonic fibroblasts, (dKO MEFs), and examined histone acetylation, expression of CREBBP target genes, and cellular proliferation. The HAT domain mutations resulted in impaired acetylation of the key Crebbp substrate, H3K18, and resulted in impaired transcriptional regulation of multiple CREBBP targets and pathways, including cAMP, dsRNA and dexamethasone responsive genes. The latter observation suggests that CREBBP mutations may directly result in resistance to corticosteroid therapy, which is a hallmark of high risk ALL. Together, these data these results extend the landscape of genetic alterations in leukemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL. Disclosures: Pui: EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria.

scholarly journals Frequent Retroviral Gene Co-option during the Evolution of Vertebrates

2020 ◽  
Vol 37 (11) ◽  
pp. 3232-3242 ◽  
Author(s):  
Jianhua Wang ◽  
Guan-Zhu Han
Keyword(s):  
Temporal Pattern ◽  
Selection Pressure ◽  
Endogenous Retroviruses ◽  
Biological Functions ◽  
Comprehensive Picture ◽  
Long Time ◽  
Time Periods

Abstract Endogenous retroviruses are ubiquitous in the vertebrate genomes. On occasion, hosts recruited retroviral genes to mediate their own biological functions, a process formally known as co-option or exaptation. Much remains unknown about the extent of retroviral gene co-option in vertebrates, although more than ten retroviral gene co-option events have been documented. Here, we use a phylogenomic approach to analyze more than 700 vertebrate genomes to uncover retroviral gene co-option taking place during the evolution of vertebrates. We identify a total of 177 independent retroviral gene co-option events in vertebrates, a majority of which have not been reported previously. Among these retroviral gene co-option events, 93 and 84 involve gag and env genes, respectively. More than 78.0% (138 out of 177) of retroviral gene co-option occurred within mammals. The gag and env co-option events share a generally similar temporal pattern with less frequent retroviral gene co-option identified in the deep branches, suggesting that retroviral gene co-option might have not been maintained for very long time periods. Moreover, we find co-opted retroviral genes are subject to different selection pressure, implying potentially diverse cellular functionality. Our study provides a comprehensive picture of co-opted retroviral genes during the evolution of vertebrates and has implications in understanding the ancient evolution of vertebrate–retrovirus interaction.

scholarly journals Selection On synonymous Mutations Revealed by 1135 Genomes of Arabidopsis thaliana

2020 ◽  
Vol 16 ◽  
pp. 117693432091679 ◽  
Author(s):  
Lai Wei
Keyword(s):  
Arabidopsis Thaliana ◽  
Synonymous Codon ◽  
Natural Populations ◽  
Gc Content ◽  
Synonymous Codon Usage ◽  
Genome Project ◽  
Allele Frequencies ◽  
Coding Region ◽  
Synonymous Mutations ◽  
Snp Data

Synonymous mutations do not change the amino acid but do change the synonymous codon usage. In genomes of different organisms, the gene conversion process is biased toward GC, which is irrespective of mutation bias. In the coding region, this trend is especially obvious and it is possibly caused by the preference on G/C-ending codons over the A/T-ending ones. If the G/C-ending codons are advantageous, then the synonymous mutations that change A/T to G/C would be “optimal” compared to the opposite ones. In theory, one should observe signals of positive selection on these optimal synonymous mutations. The recently released single-nucleotide polymorphism (SNP) data from the 1001 genome project of Arabidopsis thaliana provided researchers with an unprecedented opportunity to verify this assumption. I fully take advantage of the SNP data from 1,135 A thaliana lines and came to the conclusion that synonymous mutations in natural populations are not strictly neutral: the synonymous mutations that increase GC content (from A/T to G/C) tend to have higher derived allele frequencies (DAFs) and, therefore, are likely to be positively selected. My current study broadens our knowledge of the selection patterns of synonymous mutations and should be appealing to evolutionary biologists. One sentence summary: In 1135 genomes of Arabidopsis thaliana, the synonymous mutations that increase the GC content tend to have higher derived allele frequencies (DAFs) and are likely to be positively selected.

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