scholarly journals InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Jun-ichi Takeda ◽  
Kentaro Nanatsue ◽  
Ryosuke Yamagishi ◽  
Mikako Ito ◽  
Nobuhiko Haga ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Operating Characteristic ◽  
Radical Change ◽  
Training Dataset ◽  
Single Nucleotide ◽  
Amino Acid Properties ◽  
Genome Wide ◽  
Mutation Database ◽  
Fold Cross Validation

Abstract In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

scholarly journals A single amino acid substitution (157 Gly----Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1582-1585
Author(s):  
H Fujii ◽  
H Kanno ◽  
A Hirono ◽  
T Shiomura ◽  
S Miwa
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Messenger Rna ◽  
Phosphoglycerate Kinase ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Kinetic Properties ◽  
Total Blood ◽  
Single Nucleotide ◽  
Chronic Hemolysis

We have determined a single amino acid substitution in a new phosphoglycerate kinase (PGK) variant, PGK Shizuoka, associated with chronic hemolysis and myoglobinuria. PGK Shizuoka had an extremely low enzyme activity with normal kinetic properties and normal electrophoretic mobility. Total blood cell RNA of the patient was reverse-transcribed and amplified by the polymerase chain reaction. A single nucleotide substitution from guanine to thymine at position 473 of PGK messenger RNA was found. This nucleotide change causes a single amino acid substitution from Gly to Val at the 157th position, which is located in the NH2-terminal domain of the enzyme. This mutation creates a new Bst XI cleavage site in exon 5, and we thus confirmed the mutation in the variant gene. The replacement of Gly by Val is considered to affect enzyme catalysis.

scholarly journals A Single Amino Acid Change in the Response Regulator PhoP, Acquired duringYersinia pestisEvolution, Affects PhoP Target Gene Transcription and Polymyxin B Susceptibility

2018 ◽  
Vol 200 (9) ◽  
pp. e00050-18 ◽  
Author(s):  
Hana S. Fukuto ◽  
Viveka Vadyvaloo ◽  
Joseph B. McPhee ◽  
Hendrik N. Poinar ◽  
Edward C. Holmes ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Target Gene ◽  
Response Regulator ◽  
Polymyxin B ◽  
Single Amino Acid ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Content Type ◽  
Virulent Strains

ABSTRACTYersinia pestis, the causative agent of plague, evolved from the closely related pathogenYersinia pseudotuberculosis. During its emergence,Y. pestisis believed to have acquired its unique pathogenic characteristics through numerous gene gains/losses, genomic rearrangements, and single nucleotide polymorphism (SNP) changes. One such SNP creates a single amino acid variation in the DNA binding domain of PhoP, the response regulator in the PhoP/PhoQ two-component system.Y. pseudotuberculosisand the basal human-avirulent strains ofY. pestisharbor glycines at position 215 of PhoP, whereas the modern human-virulent strains (e.g., KIM and CO92) harbor serines at this residue. Since PhoP plays multiple roles in the adaptation ofY. pestisto stressful host conditions, we tested whether this amino acid substitution affects PhoP activity or the ability ofY. pestisto survive in host environments. Compared to the parental KIM6+ strain carrying the modern allele ofphoP(phoP-S215), a derivative carrying the basal allele (phoP-G215) exhibited slightly defective growth under a low-Mg2+condition and decreased transcription of a PhoP target gene,ugd, as well as an ∼8-fold increase in the susceptibility to the antimicrobial peptide polymyxin B. ThephoP-G215strain showed no apparent defect in flea colonization, although aphoP-null mutant showed decreased flea infectivity in competition experiments. Our results suggest that the amino acid variation at position 215 of PhoP causes subtle changes in the PhoP activity and raise the possibility that the change in this residue have contributed to the evolution of increased virulence inY. pestis.IMPORTANCEY. pestisacquired a single nucleotide polymorphism (SNP) inphoPwhen the highly human-virulent strains diverged from less virulent basal strains, resulting in an amino acid substitution in the DNA binding domain of the PhoP response regulator. We show thatY. pestiscarrying the modernphoPallele has an increased ability to induce the PhoP-regulatedugdgene and resist antimicrobial peptides compared to an isogenic strain carrying the basal allele. Given the important roles PhoP plays in host adaptation, the results raise an intriguing possibility that this amino acid substitution contributed to the evolution of increased virulence inY. pestis. Additionally, we present the first evidence thatphoPconfers a survival fitness advantage toY. pestisinside the flea midgut.

scholarly journals 712. Identification of a Novel Tedizolid Resistance Mutation in rpoB of Methicillin-Resistant Staphylococcus aureus

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S256-S256
Author(s):  
Brian Werth ◽  
Kelsi Penewit ◽  
Stephen Salipante ◽  
Tianwei Shen ◽  
Libin Xu ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Novel Mutation ◽  
Resistance Mutation ◽  
Serial Passage ◽  
Single Nucleotide Variant ◽  
23S Rrna ◽  
Single Nucleotide ◽  
Chloramphenicol Resistance ◽  
Methicillin Resistant

Abstract Background Tedizolid (TDZ) is an oxazolidinone antimicrobial with broad-spectrum activity against Gram-positive bacteria including methicillin-resistant S. aureus (MRSA). Resistance to TDZ is uncommon but mutations in the 23S rRNA target as well as in the transferable rRNA methyltransferase gene cfr, which also mediate resistance to linezolid and chloramphenicol have been implicated. The objective of this study was to determine whether other TDZ resistance pathways exist in MRSA. Methods Using a well-characterized MRSA strain, N315, we selected for TDZ resistance by serial passage in escalating concentrations of TDZ in Mueller Hinton broth (MHB) starting with 0.5× the MIC. Once visible growth was achieved a sample of the broth was diluted 1:1,000 into fresh MHB with twice the previous concentration of TDZ until an isolate with an MIC of ≥4 mg/mL was recovered. This MIC was selected since it is 1 dilution above the breakpoint for resistance ≥2 mg/L). This isolate was subjected to whole genome sequencing (WGS) and MICs to other antimicrobials were assessed. Homology modeling was performed to evaluate the potential impact of the mutation on target protein function. Results After 10 days of serial passage we recovered a stable mutant with a TDZ MIC of 4 mg/L. WGS revealed a single nucleotide variant (A1345G) in the rpoB gene corresponding to an amino acid substitution at D449N. The following table and figure summarize the changes in drug susceptibility between the parent and evolved strain and reveals the location of the amino acid substitution relative to the TDZ binding site. Conclusion We have identified a novel mutation in the RNA polymerase gene, rpoB, that mediates oxazolidinone and chloramphenicol resistance. This variant lies outside of the rifampin resistance determinant clusters of rpoB that span from 1,384 to 1,464 and 1,543 to 1,590, and as expected did not affect rifampin susceptibility. The underlying molecular mechanism by which this single nucleotide variant confers TDZ resistance remains unclear but may involve transcriptional modulation by altered sigma factor binding. Disclosures All authors: No reported disclosures.

scholarly journals tbg - a new file format for genomic data

2021 ◽  
Author(s):  
Philipp Schönnenbeck ◽  
Tilman Schell ◽  
Susanne Gerber ◽  
Markus Pfenninger
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Genomic Data ◽  
Biological Research ◽  
File Format ◽  
Single Nucleotide ◽  
Protein Coding ◽  
Genome Wide ◽  
Nucleotide Data ◽  
User Friendly

AbstractMotivationThe question of determining whether a Single-Nucleotide Polymorphism (SNP) or a variant in general leads to a change in the amino acid sequence of a protein coding gene is often a laborious and time-consuming challenge. Here, we introduce the tbg file format for storing genomic data and tbg-tools, a user-friendly toolbox for the faster analysis of SNPs. The file format stores information for each nucleotide in each gene, allowing to predict which change in the amino acid sequence will be caused by a variant in the nucleotide sequence. Our new tool therefore has the potential to make biological sense of the unprecedented amount of genome-wide genetic variation that researchers currently face.ResultsThe new tab-separated file for storing the nucleotide data can be easily analyzed and used for a wide variety of biological research. It is also possible to automate some of these analyses using the additional analysis tools from tbg-toolsAvailabilitytbg-tools is written in Python and allows the installation from the command line. It can be found on https://github.com/Croxa/[email protected]

scholarly journals A single amino acid substitution (157 Gly----Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1582-1585 ◽  
Author(s):  
H Fujii ◽  
H Kanno ◽  
A Hirono ◽  
T Shiomura ◽  
S Miwa
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Messenger Rna ◽  
Phosphoglycerate Kinase ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Kinetic Properties ◽  
Total Blood ◽  
Single Nucleotide ◽  
Chronic Hemolysis

Abstract We have determined a single amino acid substitution in a new phosphoglycerate kinase (PGK) variant, PGK Shizuoka, associated with chronic hemolysis and myoglobinuria. PGK Shizuoka had an extremely low enzyme activity with normal kinetic properties and normal electrophoretic mobility. Total blood cell RNA of the patient was reverse-transcribed and amplified by the polymerase chain reaction. A single nucleotide substitution from guanine to thymine at position 473 of PGK messenger RNA was found. This nucleotide change causes a single amino acid substitution from Gly to Val at the 157th position, which is located in the NH2-terminal domain of the enzyme. This mutation creates a new Bst XI cleavage site in exon 5, and we thus confirmed the mutation in the variant gene. The replacement of Gly by Val is considered to affect enzyme catalysis.

scholarly journals The neutrophil alloantigen HNA-3a (5b) is located on choline transporter-like protein 2 and appears to be encoded by an R>Q154 amino acid substitution

Blood ◽  
2010 ◽  
Vol 115 (10) ◽  
pp. 2073-2076 ◽  
Author(s):  
Brian R. Curtis ◽  
Nancy J. Cox ◽  
Mia J. Sullivan ◽  
Anuar Konkashbaev ◽  
Krista Bowens ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Amino Acid ◽  
Lung Injury ◽  
Amino Acid Substitution ◽  
Large Scale ◽  
Spectrometric Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Choline Transporter ◽  
Specific Antibodies

Abstract The molecular basis of the HNA-3a/b (5b/a) leukocyte antigen system has not yet been defined despite evidence that HNA-3a–specific antibodies are particularly prone to cause severe, often fatal, transfusion-related lung injury. We used genome-wide single nucleotide polymorphism scanning and sequencing of DNA from persons of different HNA-3a/b phenotypes to identify a single single nucleotide polymorphism in exon 7 of the CLT2 gene (SLC44A2) that predicts an amino acid substitution in the first extracellular loop of choline transporter-like protein 2, a member of the choline transporter-like protein family of membrane glycoproteins, and correlates perfectly with HNA-3a/b phenotypes (R154 encodes HNA-3a; Q154 encodes HNA-3b). Mass spectrometric analysis of proteins immunoprecipitated from leukocytes by anti–HNA-3a provided direct evidence that anti–HNA-3a recognizes choline transporter-like protein 2. These findings will enable large-scale genotyping for HNA-3a/b to identify blood donors at risk to have HNA-3a–specific antibodies and should facilitate development of practical methods to detect such antibodies and prevent transfusion-related lung injury.

scholarly journals Predicting Amino Acid Substitution Probabilities Using Single Nucleotide Polymorphisms

Genetics ◽  
2017 ◽  
pp. genetics.300078.2017
Author(s):  
Francesca Rizzato ◽  
Alex Rodriguez ◽  
Xevi Biarnés ◽  
Alessandro Laio
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Amino Acid Substitution ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide
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