Loss of Epitopes from SARS-Cov-2 Proteins for Non-synonymous Mutations: A Potential Global Threat

Mapping Intimacies ◽

10.31219/osf.io/45xnt ◽

2020 ◽

Author(s):

Aayatti Mallick Gupta ◽

Sukhendu Mandal

Keyword(s):

Amino Acid ◽

Positive Selection ◽

Important Determinant ◽

Surface Glycoprotein ◽

Spike Glycoprotein ◽

North Central ◽

Synonymous Mutations ◽

Indian Isolates ◽

Global Threat ◽

Selection Of

The non-synonymous mutations of SARS-Cov-2 have been identified, isolated, and sequenced across several COVID-19 infected countries from Asia, Africa, Europe, North, Central, and South Americas, and Oceania during the last few months since its emergence in Dec 2019 to April 2020. The surface glycoprotein spike of SARS-Cov-2 forms the most important hotspot for amino acid alterations followed by the ORF1a/ORF1ab poly-proteins. It is evident that the D614G mutation in spike glycoprotein and P4715L in RdRp showed co-existence among the various samples and are the important determinant of SARS-Cov-2 evolution from its emergence in China to the present epicenter. Both these mutations are increasing in number from March 2020 to become the most dominant subtype of SARS-Cov-2. It is important to notice that mutation P4715L in RdRp, G251V in ORF3a, and S1498F in the PL2 domain of NSP3 is associated with the epitope loss that may influence pathogenesis caused by antibody escape variants. Phylogenomics showed two distinct clades, (i) green clade with ancestral viral samples from China and most of Asia isolated between Dec 2019 to Feb 2020, and (ii) red with the evolved variants isolated from Europe and Americas from Mar 2020 to April 2020. The evolved variants have been found to show the loss in epitopes from its different proteins. SARS-Cov-2 from the Indian isolates distributed under both clades. The positive selection of mutations among the red clade is becoming predominant globally. These findings have important implications for SARS-Cov-2 transmission, pathogenesis, and immune interventions.

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Non-synonymous Mutations of SARS-Cov-2 Leads Epitope Loss and Segregates its Varaints

10.21203/rs.3.rs-29581/v1 ◽

2020 ◽

Author(s):

Aayatti Mallick Gupta ◽

Sukhendu Mandal

Keyword(s):

Amino Acid ◽

Important Determinant ◽

Surface Glycoprotein ◽

Spike Glycoprotein ◽

Synonymous Mutations ◽

The World

Abstract The non-synonymous mutations of SARS-Cov-2 isolated from across the world have been identified during the last few months. The surface glycoprotein spike of SARS-Cov-2 forms the most important hotspot for amino acid alterations followed by the ORF1a/ORF1ab poly-proteins. It is evident that the D614G mutation in spike glycoprotein and P4715L in RdRp is the important determinant of SARS-Cov-2 evolution since its emergence. P4715L in RdRp, G251V in ORF3a and S1498F of Nsp3 is associated with the epitope loss that may influence pathogenesis caused by antibody escape variants. Phylogenomics distinguished the ancestral viral samples from China and most part of Asia, isolated between Dec, 2019 to Feb, 2020 and the evolved variants isolated from Europe and Americas from Mar, 2020 to April, 2020. The evolved variants have been found to predominant globally with the loss of epitopes from its proteins. These have implications for SARS-Cov-2 transmission, pathogenesis and immune interventions.

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Genetic Diversity and Natural Selection of Plasmodium vivax Duffy Binding Protein-II From China-Myanmar Border of Yunnan Province, China

Frontiers in Microbiology ◽

10.3389/fmicb.2021.758061 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tian-Qi Shi ◽

Hai-Mo Shen ◽

Shen-Bo Chen ◽

Kokouvi Kassegne ◽

Yan-Bing Cui ◽

...

Keyword(s):

Genetic Diversity ◽

Population Structure ◽

Natural Selection ◽

Genetic Differentiation ◽

Positive Selection ◽

Plasmodium Vivax ◽

Yunnan Province ◽

Duffy Binding Protein ◽

Synonymous Mutations ◽

Selection Of

Malaria incidence has declined dramatically over the past decade and China was certified malaria-free in 2021. However, the presence of malaria in border areas and the importation of cases of malaria parasites are major challenges for the consolidation of the achievements made by China. Plasmodium vivax Duffy binding protein (PvDBP) performs a significant role in erythrocyte invasion, and is considered a promising P. vivax vaccine. However, the highly polymorphic region of PvDBP (PvDBP-II) impedes the development of blood-stage vaccine against P. vivax. In this study, we investigated the genetic diversity and natural selection of PvDBP-II among 124 P. vivax isolates collected from the China-Myanmar border (CMB) in Yunnan Province, China, during 2009–2011. To compare genetic diversity, natural selection, and population structure with CMB isolates, 85 pvdbp-II sequences of eastern Myanmar isolates were obtained from GenBank. In addition, global sequences of pvdbp-II were retrieved from GenBank to establish genetic differentiation relationships and networks with the CMB isolates. In total, 22 single nucleotide polymorphisms reflected in 20 non-synonymous and two synonymous mutations were identified. The overall nucleotide diversity of PvDBP-II from the 124 CMB isolates was 0.0059 with 21 haplotypes identified (Hd = 0.91). The high ratio of non-synonymous to synonymous mutations suggests that PvDBP-II had evolved under positive selection. Population structure analysis of the CMB and eastern Myanmar isolates were optimally grouped into five sub-populations (K = 5). Polymorphisms of PvDBP-II display that CMB isolates were genetically diverse. Mutation, recombination, and positive selection promote polymorphism of PvDBP-II of P. vivax population. Although low-level genetic differentiation in eastern Myanmar was identified along with the more effective malaria control measures, the complexity of population structure in malaria parasites has maintained. In conclusion, findings from this study advance knowledge of the understanding of the dynamic of P. vivax population, which will contribute to guiding the rational design of a PvDBP-II based vaccine.

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Positive selection of general amino acid permease mutants in Saccharomyces cerevisiae.

Journal of Bacteriology ◽

10.1128/jb.121.2.562-570.1975 ◽

1975 ◽

Vol 121 (2) ◽

pp. 562-570 ◽

Cited By ~ 51

Author(s):

J Rytka

Keyword(s):

Saccharomyces Cerevisiae ◽

Amino Acid ◽

Positive Selection ◽

Amino Acid Permease ◽

General Amino Acid Permease ◽

Selection Of

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Spike protein modeling and single amino acid variant analysis might suggest reduced transmitability of SARS-CoV-2 in Jordan, Middle East

10.21203/rs.3.rs-33156/v1 ◽

2020 ◽

Author(s):

Walid Al-Zyoud ◽

Hazem Haddad

Keyword(s):

Crystal Structure ◽

Amino Acid ◽

Middle East ◽

Active Sites ◽

Trna Synthetase ◽

Surface Glycoprotein ◽

Spike Protein ◽

Single Amino Acid ◽

Spike Glycoprotein ◽

Amino Acid Variants

Abstract Spike protein (approx. 180 kDa) is the surface glycoprotein of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) necessary for the interaction of the virus with human endothelial cell receptors on the cell membrane to be engulfed causing COVID-19 disease after binding with the angiotensin-converting enzyme 2 (ACE2) with an evident activation by type II transmembrane protease TMPRSS2 . Therefore, mutations and amino acid variants analysis are essential in characterizing the mechanism of binding of spike protein with its receptor, which totally gives insights on possibilities to design a peptide or nucleotide-based vaccine for COVID-19. Here, we employed Iterative Threading Assembly Refinement (I-TASSER) and Multiple Alignment using Fast Fourier Transform (MAFFT) to predict the three-dimensional structure and to analyze the amino acid variants for spike protein sequences of SARS-CoV-2 from GISAID database of samples collected from Jordan to try to find a justification for low number of confirmed COVID-19 in Jordan, Middle East. Our findings showed the molecules structurally close to the spike glycoprotein from the Enzyme Commission (EC) numbers and active sites included Isoleucyl-tRNA synthetase, Crystal structure of the tricorn protease (hydrolase); Crystal structure of the T. Thermophilus RNA polymerase holoenzyme (transferase); Crystal structure of the complex between pyruvate-ferredoxin oxidoreductase from Desulfovibrio africanus and pyruvate (oxidoreductase); and Reovirus core (virus). Our MAFFT findings showed that Four Amino Acid Variants (SAV) founded in 20 samples of SARS-CoV-2 were not conserved residues in spike glycoprotein. What is equal to 5% of samples showed tyrosine (polar) deletion at Y144 , 62% of samples showed aspartate (polar, acidic) substitution to glycine (nonpolar) at D614G, 5% of samples showed aspartate (polar, acidic) substitution to tyrosine (polar) at D1139Y and 5% of samples showed glycine (nonpolar) substitution to serine (polar) at G1167S respectively. By using Phyre2, our findings have shown lower sensitive mutational that cannot affect the pocket region or alpha and beta-sheet in all mutations except for D614G, which has the highest mutational sensitivity score (5 out of 9) indicating a bigger effect on the function of spike protein. This might suggest, in general, a reduced transmitability of SARS-CoV-2 in Jordan, Middle East. As the crystal structure of spike protein is not revealed yet, it was not possible to compare the predicted modes versus each other.

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Identification of positive selection in genes is greatly improved by using experimentally informed site-specific models

10.1101/037689 ◽

2016 ◽

Cited By ~ 7

Author(s):

Jesse D. Bloom

Keyword(s):

Amino Acid ◽

Positive Selection ◽

Null Model ◽

Biological Data ◽

Evolutionary Patterns ◽

Protein Coding ◽

Site Specific ◽

Synonymous Mutations ◽

Influenza Hemagglutinin ◽

Selection For

AbstractSites of positive selection are identified by comparing observed evolutionary patterns to those expected under a null model for evolution in the absence of such selection. For protein-coding genes, the most common null model is that nonsynonymous and synonymous mutations fix at equal rates; this unrealistic model has limited power to detect many interesting forms of selection. I describe a new approach that uses a null model based on high-throughput lab measurements of a gene's site-specific amino-acid preferences. This null model makes it possible to identify diversifying selection for amino-acid change and differential selection for mutations to amino acids that are unexpected given the measurements made in the lab. I show that this approach identifies sites of adaptive substitutions in four genes (lactamase, Gal4, influenza nucleoprotein, and influenza hemagglutinin) far better than a comparable method that simply compares the rates of nonsynonymous and synonymous substitutions. As rapid increases in biological data enable increasingly nuanced descriptions of the constraints on individual sites, approaches like the one here can improve our ability to identify many interesting forms of selection.

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Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0500267102 ◽

2005 ◽

Vol 102 (17) ◽

pp. 6051-6056 ◽

Cited By ~ 102

Author(s):

A. Goriely ◽

G. A. T. McVean ◽

A. M. M. van Pelt ◽

A. W. O'Rourke ◽

S. A. Wall ◽

...

Keyword(s):

Amino Acid ◽

Positive Selection ◽

Amino Acid Substitutions ◽

Gain Of Function ◽

Selection Of

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Mutations of Pneumocystis jirovecii Dihydrofolate Reductase Associated with Failure of Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.11.4301-4305.2004 ◽

2004 ◽

Vol 48 (11) ◽

pp. 4301-4305 ◽

Cited By ~ 64

Author(s):

Aimable Nahimana ◽

Meja Rabodonirina ◽

Jacques Bille ◽

Patrick Francioli ◽

Philippe M. Hauser

Keyword(s):

Drug Resistance ◽

Amino Acid ◽

Dihydrofolate Reductase ◽

Active Sites ◽

Pneumocystis Jirovecii ◽

Dihydropteroate Synthase ◽

Synonymous Mutations ◽

Dhfr Inhibitors ◽

Type Sequence ◽

Selection Of

ABSTRACT Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.

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