scholarly journals De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton-related protein coding regions

2016 ◽  
Vol 6 (2) ◽  
pp. 211-216
Author(s):  
Rebecca J. Stoll ◽  
Grace R. Thompson ◽  
Mohammad D. Samy ◽  
George Blanck
Keyword(s):  
Amino Acid ◽  
De Novo ◽  
Amino Acid Substitutions ◽  
Related Protein ◽  
Protein Coding ◽  
Coding Regions

scholarly journals GeneSV – an Approach to Help Characterize Possible Variations in Genomic and Protein Sequences

2014 ◽  
Vol 8 ◽  
pp. BBI.S13076 ◽  
Author(s):  
Adam Zemla ◽  
Tanya Kostova ◽  
Rodion Gorchakov ◽  
Evgeniya Volkova ◽  
David W. C. Beasley ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Genetics ◽  
Genomic Sequence ◽  
Rna Virus ◽  
Protein Sequences ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Protein Coding ◽  
Nucleotide Variability ◽  
Coding Regions

A computational approach for identification and assessment of genomic sequence variability (GeneSV) is described. For a given nucleotide sequence, GeneSV collects information about the permissible nucleotide variability (changes that potentially preserve function) observed in corresponding regions in genomic sequences, and combines it with conservation/variability results from protein sequence and structure-based analyses of evaluated protein coding regions. GeneSV was used to predict effects (functional vs. non-functional) of 37 amino acid substitutions on the NS5 polymerase (RdRp) of dengue virus type 2 (DENV-2), 36 of which are not observed in any publicly available DENV-2 sequence. 32 novel mutants with single amino acid substitutions in the RdRp were generated using a DENV-2 reverse genetics system. In 81% (26 of 32) of predictions tested, GeneSV correctly predicted viability of introduced mutations. In 4 of 5 (80%) mutants with double amino acid substitutions proximal in structure to one another GeneSV was also correct in its predictions. Predictive capabilities of the developed system were illustrated on dengue RNA virus, but described in the manuscript a general approach to characterize real or theoretically possible variations in genomic and protein sequences can be applied to any organism.

scholarly journals Insertions and deletions trigger adaptive walks in Drosophila proteins

2012 ◽  
Vol 279 (1740) ◽  
pp. 3075-3082 ◽  
Author(s):  
Evgeny V. Leushkin ◽  
Georgii A. Bazykin ◽  
Alexey S. Kondrashov
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequences ◽  
Molecular Adaptation ◽  
Amino Acid Substitutions ◽  
Protein Coding ◽  
Evolution Of Life ◽  
High Fraction ◽  
Adaptive Walks ◽  
The Difference ◽  
Almost All

Maps that relate all possible genotypes or phenotypes to fitness—fitness landscapes—are central to the evolution of life, but remain poorly known. An insertion or a deletion (indel) of one or several amino acids constitutes a substantial leap of a protein within the space of amino acid sequences, and it is unlikely that after such a leap the new sequence corresponds precisely to a fitness peak. Thus, one can expect an indel in the protein-coding sequence that gets fixed in a population to be followed by some number of adaptive amino acid substitutions, which move the new sequence towards a nearby fitness peak. Here, we study substitutions that occur after a frame-preserving indel in evolving proteins of Drosophila . An insertion triggers 1.03 ± 0.75 amino acid substitutions within the protein region centred at the site of insertion, and a deletion triggers 4.77 ± 1.03 substitutions within such a region. The difference between these values is probably owing to a higher fraction of effectively neutral insertions. Almost all of the triggered amino acid substitutions can be attributed to positive selection, and most of them occur relatively soon after the triggering indel and take place upstream of its site. A high fraction of substitutions that follow an indel occur at previously conserved sites, suggesting that an indel substantially changes selection that shapes the protein region around it. Thus, an indel is often followed by an adaptive walk of length that is in agreement with the theory of molecular adaptation.

scholarly journals Engineering Responses to Amino Acid Substitutions in the VP0- and VP3-Coding Regions of PanAsia-1 Strains of Foot-and-Mouth Disease Virus Serotype O

2019 ◽  
Vol 93 (7) ◽  
Author(s):  
Xing-Wen Bai ◽  
Hui-Fang Bao ◽  
Ping-Hua Li ◽  
Xue-Qing Ma ◽  
Pu Sun ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Amino Acid ◽  
Heparan Sulfate ◽  
Foot And Mouth Disease ◽  
Amino Acid Substitutions ◽  
Plaque Size ◽  
Phenotypic Properties ◽  
Acid Sensitivity ◽  
Coding Regions ◽  
Mouth Disease Virus

ABSTRACTThe presence of sequence divergence through adaptive mutations in the major capsid protein VP1, and also in VP0 (VP4 and VP2) and VP3, of foot-and-mouth disease virus (FMDV) is relevant to a broad range of viral characteristics. To explore the potential role of isolate-specific residues in the VP0 and VP3 coding regions of PanAsia-1 strains in genetic and phenotypic properties of FMDV, a series of recombinant full-length genomic clones were constructed using Cathay topotype infectious cDNA as the original backbone. The deleterious and compensatory effects of individual amino acid substitutions at positions 4008 and 3060 and in several different domains of VP2 illustrated that the chain-based spatial interaction patterns of VP1, VP2, and VP3 (VP1-3), as well as between the internal VP4 and the three external capsid proteins of FMDV, might contribute to the assembly of eventually viable viruses. The Y2079H site-directed mutants dramatically induced a decrease in plaque size on BHK-21 cells and viral pathogenicity in suckling mice. Remarkably, the 2079H-encoding viruses displayed a moderate increase in acid sensitivity correlated with NH4Cl resistance compared to the Y2079-encoding viruses. Interestingly, none of all the 16 rescued viruses were able to infect heparan sulfate-expressing CHO-K1 cells. However, viral infection in BHK-21 cells was facilitated by utilizing non-integrin-dependent, heparin-sensitive receptor(s) and replacements of four uncharged amino acids at position 3174 in VP3 of FMDV had no apparent influence on heparin affinity. These results provide particular insights into the correlation of evolutionary biology with genetic diversity in adapting populations of FMDV.IMPORTANCEThe sequence variation within the capsid proteins occurs frequently in the infection of susceptible tissue cultures, reflecting the high levels of genetic diversity of FMDV. A systematic study for the functional significance of isolate-specific residues in VP0 and VP3 of FMDV PanAsia-1 strains suggested that the interaction of amino acid side chains between the N terminus of VP4 and several potential domains of VP1-3 had cascading effects on the viability and developmental characteristics of progeny viruses. Y2079H in VP0 of the indicated FMDVs could affect plaque size and pathogenicity, as well as acid sensitivity correlated with NH4Cl resistance, whereas there was no inevitable correlation in viral plaque and acid-sensitive phenotypes. The high affinity of non-integrin-dependent FMDVs for heparin might be explained by the differences in structures of heparan sulfate proteoglycans on the surfaces of different cell lines. These results may contribute to our understanding of the distinct phenotypic properties of FMDVin vitroandin vivo.

scholarly journals Human to yeast pathway transplantation: cross-species dissection of the adenine de novo pathway regulatory node

2017 ◽  
Author(s):  
Neta Agmon ◽  
Jasmine Temple ◽  
Zuojian Tang ◽  
Tobias Schraink ◽  
Maayan Baron ◽  
...  
Keyword(s):  
Yeast Strain ◽  
Transcriptional Control ◽  
De Novo ◽  
Enzyme Level ◽  
Yeast Cells ◽  
Protein Coding ◽  
Coding Regions ◽  
Human Proteins ◽  
Human Ortholog ◽  
Yeast Genes

AbstractPathway transplantation from one organism to another represents a means to a more complete understanding of a biochemical or regulatory process. The purine biosynthesis pathway, a core metabolic function, was transplanted from human to yeast. We replaced the entireSaccharomyces cerevisiaeadenine de novo pathway with the cognate human pathway components. A yeast strain was “humanized” for the full pathway by deleting all relevant yeast genes completely and then providing the human pathway in trans using a neochromosome expressing the human protein coding regions under the transcriptional control of their cognate yeast promoters and terminators. The “humanized” yeast strain grows in the absence of adenine, indicating complementation of the yeast pathway by the full set of human proteins. While the strain with the neochromosome is indeed prototrophic, it grows slowly in the absence of adenine. Dissection of the phenotype revealed that the human ortholog ofADE4, PPAT, shows only partial complementation. We have used several strategies to understand this phenotype, that point toPPAT/ADE4as the central regulatory node. Pathway metabolites are responsible for regulatingPPAT’sprotein abundance through transcription and proteolysis as well as its enzymatic activity by allosteric regulation in these yeast cells. Extensive phylogenetic analysis of PPATs from diverse organisms hints at adaptations of the enzyme-level regulation to the metabolite levels in the organism. Finally, we isolated specific mutations in PPAT as well as in other genes involved in the purine metabolic network that alleviate incomplete complementation byPPATand provide further insight into the complex regulation of this critical metabolic pathway.

scholarly journals Pandoravirus celtis illustrates the microevolution processes at work in the giant Pandoraviridae genomes

2018 ◽  
Author(s):  
Matthieu Legendre ◽  
Jean-Marie Alempic ◽  
Nadège Philippe ◽  
Audrey Lartigue ◽  
Sandra Jeudy ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Repertoire ◽  
Protein Coding ◽  
Genomic Changes ◽  
Coding Regions ◽  
Protein Coding Genes ◽  
Intergenic Regions ◽  
Mere Existence ◽  
Increasing Functions ◽  
Similar Gene

AbstractWith genomes of up to 2.7 Mb propagated in µm-long oblong particles and initially predicted to encode more than 2000 proteins, members of the Pandoraviridae family display the most extreme features of the known viral world. The mere existence of such giant viruses raises fundamental questions about their origin and the processes governing their evolution. A previous analysis of six newly available isolates, independently confirmed by a study including 3 others, established that the Pandoraviridae pan-genome is open, meaning that each new strain exhibits protein-coding genes not previously identified in other family members. With an average increment of about 60 proteins, the gene repertoire shows no sign of reaching a limit and remains largely coding for proteins without recognizable homologs in other viruses or cells (ORFans). To explain these results, we proposed that most new protein-coding genes were created de novo, from pre-existing non-coding regions of the G+C rich pandoravirus genomes. The comparison of the gene content of a new isolate, P. celtis, closely related (96% identical genome) to the previously described P. quercus is now used to test this hypothesis by studying genomic changes in a microevolution range. Our results confirm that the differences between these two similar gene contents mostly consist of protein-coding genes without known homologs (ORFans), with statistical signatures close to that of intergenic regions. These newborn proteins are under slight negative selection, perhaps to maintain stable folds and prevent protein aggregation pending the eventual emergence of fitness-increasing functions. Our study also unraveled several insertion events mediated by a transposase of the hAT family, 3 copies of which are found in P. celtis and are presumably active. Members of the Pandoraviridae are presently the first viruses known to encode this type of transposase.

scholarly journals Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110170
Author(s):  
Ruo-hao Wu ◽  
Wen-ting Tang ◽  
Kun-yin Qiu ◽  
Xiao-juan Li ◽  
Dan-xia Tang ◽  
...  
Keyword(s):  
De Novo ◽  
Facial Dysmorphism ◽  
Comprehensive Overview ◽  
Protein Coding ◽  
Coding Regions ◽  
Gtp Binding ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
First Time ◽  
Binding Loop

De novo germline variants of the casein kinase 2α subunit (CK2α) gene ( CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur–Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype–phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype–phenotype relationship in OCNS.

scholarly journals Characterization of the Complete Mitochondrial Genome of Ostertagia trifurcata of Small Ruminants and its Phylogenetic Associations for the Trichostrongyloidea Superfamily

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 107 ◽  
Author(s):  
Awais Ahmad ◽  
Xin Yang ◽  
Ting Zhang ◽  
Chunqun Wang ◽  
Caixian Zhou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Complete Mitochondrial Genome ◽  
Small Ruminants ◽  
Complete Characterization ◽  
Amino Acid Sequences ◽  
Trna Genes ◽  
Protein Coding ◽  
Coding Regions ◽  
Mtdna Sequence ◽  
Mt Genome

The complete mitochondrial (mt) genome of Ostertagia trifurcata, a parasitic nematode of small ruminants, has been sequenced and its phylogenetic relationship with selected members from the superfamily Trichostrongyloidea was investigated on the basis of deduced datasets of mt amino acid sequences. The entire mt genome of Ostertagia trifurcata is circular and 14,151 bp in length. It consists of a total of 36 genes comprising 12 genes coding for proteins (PCGs), 2 genes for ribosomal RNA (rRNA), 22 transfer RNA (tRNA) genes and 2 non-coding regions, since all genes are transcribed in the same direction. The phylogenetic analysis based on the concatenated datasets of predicted amino acid sequences of the 12 protein coding genes supported monophylies of the Haemonchidae, Dictyocaulidae and Molineidae families, but rejected monophylies of the Trichostrongylidae family. The complete characterization and provision of the mtDNA sequence of Ostertagia trifurcata provides novel genetic markers for molecular epidemiological investigations, systematics, diagnostics and population genetics of Ostertagia trifurcata and its correspondents.

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