Non-synonymous Single Nucleotide Polymorphisms Research Articles

Comprehensive in silico analysis of prolactin receptor (PRLR) gene nonsynonymous single nucleotide polymorphisms (nsSNPs) reveals multifaceted impact on protein structure, function, and interactions

This study delves into the functional and structural implications of non-synonymous single nucleotide polymorphisms (nsSNPs) within the Prolactin Receptor (PRLR) gene. Thirteen deleterious nsSNPs were identified through bioinformatics tools, with SIFT predicting 168 out of 395 nsSNPs as detrimental, exhibiting tolerance index (TI) scores ranging from 0 to 0.05. Polyphen2 assigned likelihood scores >0.99 to all 13 nsSNPs, indicating high probability of harm, while Panther scores classified most nsSNPs as ‘probably damaging’, with specific mutations like W218R scoring 0.74, suggesting a higher impact. Stability analysis using DDG I-Mutant and DDG Mupro consistently predicted decreased stability for all mutations, with CUPSAT indicating mutations like V125G and W218R significantly decreasing stability. Structural analysis through DynaMut predicted destabilization for all mutations except L196I and L292H. MutPred2 highlighted structural alterations for all nsSNPs except L196I, L293V, R315W, and S353N. Domain analysis revealed key mutations within essential functional domains, with five nsSNPs located within Fibronectin type-III domains. Bayesian analysis through ConSurf identified 9 critical residues, with 11 nsSNPs exhibiting notably high conservation. STRING analysis unveiled a complex interaction network, indicating involvement in vital biological processes like lactation. Molecular dynamics (MD) simulations, spanning 100 nanoseconds, elucidated structural dynamics induced by detrimental missense SNPs. Post-translational modification (PTM) analysis identified specific mutations, such as R351, involved in methylation, while S353 was implicated in phosphorylation and glycosylation. These findings offer comprehensive insights into the molecular and phenotypic effects of deleterious nsSNPs in the PRLR gene, crucial for selective breeding. Communicated by Ramaswamy H. Sarma

A Comprehensive <i>in Silico</i> Analysis of the Functional and Structural Consequences of the Deleterious Missense Nonsynonymous SNPs in Human <i>GABRA6</i> Gene

Epilepsy, a prevalent neurological disorder, affects more than 50 million individuals worldwide and is characterized by recurring seizures. Nonsynonymous single nucleotide polymorphisms (nsSNPs) found within coding regions of epilepsy-related genes are believed to have significant impacts on protein function. This is due to their tendency to cause mutations in the encoded amino acids, which can subsequently lead to pathogenic alterations in protein structure and function. Consequently, nsSNPs have the potential to serve as diagnostic markers for epilepsy and other neuropsychiatric conditions. The primary objective of this study is to evaluate the harmful effects of missense nsSNP mutations on the <em>GABRA6</em> gene. The <em>GABRA6</em> gene encodes the alpha-6 subunit of the GABA<sub>A</sub> receptor, and previous research showed one case substitution mutation in the GABRA6 gene is associated with childhood absence epilepsy (CAE) and atonic seizures. To achieve this, we employed various computational tools, including SIFT, PolyPhen-2, PROVEAN, Condel, SNPs & GO, PMut, SNAP2, MutPred2, and SNPeffect4.0, for predicting missense nsSNPs. Additionally, we used I-Mutant3.0 and MUpro to analyze protein stability, ConSurf to assess evolutionary conservation, FTSite and COACH to predict ligand binding sites, SOPMA and PSIPRED to analyze protein secondary structures, project HOPE to predict structural changes, and I-TASSER to model the 3D structure. Furthermore, structural validation was conducted using the PROCHECK and ERRAT servers. At the same time, molecular dynamics simulations were performed using GROMACS to gain a better understanding of the effects of mutations on protein structure. Among the 451 missense nsSNPs identified within the <em>GABRA6</em> gene, three were found to have pathogenic effects on the structure and function of the protein, potentially, there may be a contribution to the development of seizures or other neuropsychiatric disorders. Notably, two of these missense nsSNPs (<em>W87S</em> and <em>W112R</em>) were located within the ligand-binding domain, while the third (<em>C310R</em>) was situated in the transmembrane domain. It is crucial to acknowledge that despite their predicted pathogenicity, these variants are currently classified as of uncertain significance in clinical and genomic databases worldwide due to the lack of correlation with epilepsy in empirical studies. Without experimental data to validate these predictions, caution is warranted in interpreting the findings.

A gain-of-function mutation in zinc cluster transcription factor Rob1 drives Candida albicans adaptive growth in the cystic fibrosis lung environment.

Candida albicans chronically colonizes the respiratory tract of patients with Cystic Fibrosis (CF). It competes with CF-associated pathogens (e.g. Pseudomonas aeruginosa) and contributes to disease severity. We hypothesize that C. albicans undergoes specific adaptation mechanisms that explain its persistence in the CF lung environment. To identify the underlying genetic and phenotypic determinants, we serially recovered 146 C. albicans clinical isolates over a period of 30 months from the sputum of 25 antifungal-naive CF patients. Multilocus sequence typing analyses revealed that most patients were individually colonized with genetically close strains, facilitating comparative analyses between serial isolates. We strikingly observed differential ability to filament and form monospecies and dual-species biofilms with P. aeruginosa among 18 serial isolates sharing the same diploid sequence type, recovered within one year from a pediatric patient. Whole genome sequencing revealed that their genomes were highly heterozygous and similar to each other, displaying a highly clonal subpopulation structure. Data mining identified 34 non-synonymous heterozygous SNPs in 19 open reading frames differentiating the hyperfilamentous and strong biofilm-former strains from the remaining isolates. Among these, we detected a glycine-to-glutamate substitution at position 299 (G299E) in the deduced amino acid sequence of the zinc cluster transcription factor ROB1 (ROB1G299E), encoding a major regulator of filamentous growth and biofilm formation. Introduction of the G299E heterozygous mutation in a co-isolated weak biofilm-former CF strain was sufficient to confer hyperfilamentous growth, increased expression of hyphal-specific genes, increased monospecies biofilm formation and increased survival in dual-species biofilms formed with P. aeruginosa, indicating that ROB1G299E is a gain-of-function mutation. Disruption of ROB1 in a hyperfilamentous isolate carrying the ROB1G299E allele abolished hyperfilamentation and biofilm formation. Our study links a single heterozygous mutation to the ability of C. albicans to better survive during the interaction with other CF-associated microbes and illuminates how adaptive traits emerge in microbial pathogens to persistently colonize and/or infect the CF-patient airways.

Allele mining for Granule Bound Starch Synthase1 (GBSS1) gene governing amylose content in aromatic rice (Oryza sativa L.) germplasm

The current research investigated sequence polymorphism and allelic variation in the GBSS1 gene responsible for determining the apparent amylose content (AAC) in an aromatic rice germplasm panel. Analysis of 271 germplasm accessions from India revealed a wide range of variation in AAC, from 4.81% (Manipur Black Rice) to 35.88% (IGSR -3-1-5). Re-sequencing and sequence analysis of a representative subset of 28 accessions unveiled a nucleotide diversity (π) of 0.00374, identifying 72 sequence variants. Two novel non-synonymous SNPs were identified: a G/A transition in exon 2, resulting in the substitution of glutamic acid at the 91st position with lysine, and a C/T transition in exon 11, substituting alanine at the 468thposition with valine. Additionally, two previously reported SNPs were validated: A/C in exon 6 (Tyr224Ser) and C/T in exon 10 (Pro415Ser). Furthermore, a 23 bp exon 2 duplication was found in Manipur Black Rice (4.81%), Bhogali Bora (6.20%), and NJ-72 (7.36%), indicating the prevalence of this allele in the very low AAC category (3–9%) in addition to the glutinous or waxy rice category with 0–2% AAC. These findings are significant for manipulating starch content in aromatic rice germplasm.

Prediction of deleterious non-synonymous SNPs of TMPRSS2 protein combined with Molecular Dynamics Simulations and free energy analysis to identify the potential peptide substrates against SARS-CoV-2.

Globally the SARS-CoV-2 viral infection demands for the new drugs, the TMPRSS2 target plays a vital role in facilitating the virus entry. The aim of the present study is to identify the potential peptide substrate from the Anti-viral database against TMPRSS2 of SARS-CoV-2. The compound screening and variation analysis were performed using molecular docking analysis and online tools such as PROVEAN and SNAP2 server, respectively. The re-docked crystal structure peptide substrate exhibits -128.151 kcal/mol whereas the RRKK peptide substrate shows -134.158 kcal/mol. Further, the selected compounds were proceeded with Molecular Dynamics Simulation, it explores the stability of the complex by revealing the hotspot residues (His296 and Ser441) were active for nucleophilic attack against TMPRSS2. The average Binding Free Energy values computed through MM/GBSA for RRKK, Camostat, and Crystal Structure were shown -69.9278 kcal/mol, -64.5983 kcal/mol, and -63.9755 kcal/mol, respectively against TMPRSS2. The 'rate of acylation' emerges as an indicator for RRKK's efficacy, it maintains the distance of 3.2 Å with Ser441 resembles, whilst its -NH backbone stabilizes at 2.5 Å 'Michaelis Complex' which leads to prevent the entry of SARS-CoV-2 to human cells. The sequence variation analysis explores that the V160 and G6 substitutions are essential to emphasize the uncover possibilities for the ongoing drug discovery research. Therefore, the identified peptide substrate found to be potent against SARS-CoV-2 and these results will be valuable for ongoing drug discovery research.Communicated by Ramaswamy H. Sarma.

In Silico Analysis of Non-Synonymous Snps in the Human WWOX Gene

Aim: To analyse the nsSNPs associated with the human WWOX gene using bioinformatics tools. Background: WW domain-containing oxidoreductase (WWOX) is a protein-coding gene that controls several biological processes, including RNA splicing, transcription, and protein degradation. The modification in the WWOX gene is associated with osteopenia, metabolic syndrome, gestational diabetes, tumour progression, and disruption in lipid metabolism. Objective: The study focused on understanding the structural and functional distribution of high-risk nsSNPs of the WWOX gene using several bioinformatics tools. Methods: Retrieval of nsSNPs of WWOX gene from NCBI and Uniprot database. Identification of deleterious missense SNPs using the tools SIFT, Polyphen v2, PROVEAN, FATHMM, PhD-SNP, and SNPs & GO. The gene-gene and protein-protein interactions were investigated using GeneMANIA and STRING, respectively. The structural and functional characterisation of the gene was predicted using I-Mutant, MUPro, SOPMA, Alpha Fold, and NetPhos 3.1. Results: The study identified 7 out of 646 nsSNPs (rs193001955, rs200371768, rs370792938, rs2303192, rs371364838, rs372362643, rs374343152) as deleterious. The identified nsSNPs were destabilizing the WWOX protein. The secondary structure prediction indicated that the majority of the nsSNPs were random coil and alpha-helix. Meanwhile, phosphorylation was observed in several positions in threonine and serine residues, and the least phosphorylation was observed for tyrosine in the WWOX gene. Phosphorylation of high-risk variants of this gene may lead to alteration in the regulation of posttranslational modification. Conclusion: Our study predicted 7 functional nsSNPs that had detrimental effects on the structure and function of the WWOX gene. This will aid in the identification of candidate deleterious nsSNPs markers as a potential therapeutic target for disease diagnosis.

Insights from the SNP analysis of TYMP gene linking MNGIE.

TYMP gene, which codes for thymidine phosphorylase (TP) is also known as platelet-derived endothelial cell growth factor (PD-ECGF). TP plays crucial roles in nucleotide metabolism and angiogenesis. Mutations in the TYMP gene can lead to Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) syndrome, a rare genetic disorder. Our main objective was to evaluate the impact of detrimental non-synonymous single nucleotide polymorphisms (nsSNPs) on TP protein structure and predict harmful variants in untranslated regions (UTR). We employed a combination of predictive algorithms to identify nsSNPs with potential deleterious effects, followed by molecular modeling analysis to understand their effects on protein structure and function. Using 13 algorithms, we identified 119 potentially deleterious nsSNPs, with 82 located in highly conserved regions. Of these, 53 nsSNPs were functional and exposed, while 79 nsSNPs reduced TP protein stability. Further analysis of 18 nsSNPs through 3D protein structure analysis revealed alterations in amino acid interactions, indicating their potential impact on protein function. This will help in the development of faster and more efficient genetic tests for detecting TYMP gene mutations.

Identification of Damaging and Deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in the Orang Asli, Jakun

The study of genetics and its relation to different disorders has recently been getting remarkable attention worldwide. Non-synonymous single-nucleotide polymorphisms (nsSNPs) are coding variants that introduce amino acid alterations to proteins. Since nsSNPs have various effects on protein structure and function, these changes can significantly impact human health. The primary purpose of this research is to examine the relationship between diseases and Jakun nsSNP mutations. A total of 10 samples with 24,604 nsSNPs were used in the study. Several in silico bioinformatics tools were used to classify the high-risk nsSNPs that might affect the structure and function of proteins in the Jakun tribe. The in silico tools PROVEAN, SIFT and PolyPhen2 identified 1395 high-risk nsSNPs. Further analysis with the DAVID annotation tool revealed that these related genes are associated with cardiovascular diseases, myocardial infarction, Alzheimer's and obesity. Other bioinformatics tools were then used to infer the protein structures of these high-risk nsSNPs. From SNP&GO and PhD-SNPs, the results conclude that there are four damaging nsSNPs in the Jakun tribe. The damaging nsSNPs and the mutation positions are MTHFR (A222V), ESR2 (G445S), ACSM3 (G460R) and UGT3A1 with two mutation sites, C121G and C67G. This study using in silico tools can be the basis for increasing medical discoveries, reducing lab costs and helping with clinical trials for further studies by providing genetically related information.

Investigating the Influence of ANTXR2 Gene Mutations on Protective Antigen Binding for Heightened Anthrax Resistance.

Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans.

Insights into the structure–function relationship of missense mutations in the human TOP2A protein in ovarian cancer

Topoisomerase 2-alpha (TOP2A) is a nuclear protein that is responsible for the maintenance of the topological state of DNA. TOP2A is highly upregulated in ovarian cancer, and its copy number is an important prognosis factor. A large number of single-nucleotide polymorphism (SNP), insertion, and deletion mutations have been reported in TOP2A. Thus, a structural and functional study of missense SNPs was carried out to screen potentially damaging mutations. The 193 non-synonymous SNPs in the coding region of TOP2A in the dbSNP database were selected for in silico analysis. The deleterious SNPs were screened using sorting intolerant from tolerant (SIFT), PolyPhen-2, SNAP2, and SNPs&Go, and we obtained four possibly damaging SNPs at the end (Y481C, N7741, E922K, and R1514W). Mutants Y481C and E922K were predicted to be highly deleterious and showed decreased protein stability compared with native proteins, as predicted by I-Mutant 3. We used the SWISS-MODEL to model the structure of these two mutants, and the structural attributes of modeled mutants were studied using Hope Project, solvent accessibility-based protein–protein interface identification and recognition (SPPIDER), SRide, and HBAT, which predicted small variations from the native protein. Molecular dynamics simulation demonstrated a decrease in root mean square deviation (RMSD) and the radius of gyration of two mutants, which is relative to the native protein. The molecular docking of TOP2A with etoposide suggests that mutations may lead to resistance to TOP2A-targeted chemotherapy. In addition, the relative expression analysis performed by qRT-PCR also reveals that there is a three-fold increase in the expression levels of the TOP2A protein in ovarian adenoma cancer cell lines. Our analysis reveals that Y481C and E922K are highly damaging variants of TOP2A, which alter the protein dynamics and may be implicated in causing ovarian cancer.

The role of silver nanoparticles alone and combined with imipenem on carbapenem-resistant Klebsiella pneumoniae.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections poses a significant threat to human health, necessitating urgent development of new antimicrobial agents. Silver nanoparticles (AgNPs), which are among the most widely used engineered nanomaterials, have been extensively studied. However, the impact of AgNPs on CRKP and the potential for drug resistance development remain inadequately explored. In this study, broth dilution method was used to determine the minimum inhibitory concentration (MIC) was determined using the broth dilution method. Results indicated MIC values of 93.1±193.3µg ml-1 for AgNPs, 2.3±5.1µg ml-1 for AgNO3, and 25.1±48.3µg ml-1 for imipenem (IMI). The combined inhibitory effect of AgNPs and IMI on CRKP was assessed using the checkerboard method. Moreover, after 6-20 generations of continuous culture, the MIC value of AgNPs increased 2-fold. Compared to IMI, resistance of Kl. pneumoniae to AgNPs developed more slowly, with a higher fold increase in MIC observed after 20 generations. Whole-genome sequencing revealed four nonsynonymous single nucleotide polymorphism mutations in CRKP after 20 generations of AgNP treatment. We have demonstrated that AgNPs significantly inhibit CRKP isolates and enhance the antibacterial activity of imipenem against Kl. pneumoniae. Although the development of AgNP resistance is gradual, continued efforts are necessary for monitoring and studying the mechanisms of AgNP resistance.

Unveiling the population genetic structure of Iranian horses breeds by whole-genome resequencing analysis.

Preserving genetic diversity is pivotal for enhancing genetic improvement and facilitating adaptive responses to selection. This study focuses on identifying key genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs), while exploring the genomic evolutionary connectedness among seven Iranian horses representing five indigenous breeds: Caspian, Turkemen, DareShuri, Kurdish, and Asil. Using whole-genome resequencing, we generated 2.7Gb of sequence data, with raw reads ranging from 1.2Gb for Caspian horses to 0.38Gb for Turkoman horses. Post-filtering, approximately 1.9Gb of reads remained, with ~ 1.5Gb successfully mapped to the horse reference genome (EquCab3.0), achieving mapping rates between 76.4% (Caspian) and 98.35% (Turkoman). We identified 2,909,816 SNPs in Caspian horses, constituting around 0.1% of the genome. Notably, 71% of these SNPs were situated in intergenic regions, while 8.5 and 6.8% were located upstream and downstream, respectively. A comparative analysis of SNPs between Iranian and non-Iranian horse breeds showed that Caspian horses had the lowest number of shared SNPs with Turkoman horses. Instead, they showed a closer genetic relationship with DareShuri, Quarter, Arabian, Standardbred, and Asil breeds. Hierarchical clustering highlighted Caspian horses as a distinct cluster, underscoring their distinctive genomic signature. Caspian horses exhibit a unique genetic profile marked by an enrichment of private mutations in neurological genes, influencing sensory perception and awareness. This distinct genetic makeup shapes mating preferences and signifies a separate evolutionary trajectory. Additionally, significant non-synonymous single nucleotide polymorphisms (nsSNPs) in reproductive genes offer intervention opportunities for managing Caspian horses. These findings reveal the population genetic structure of Iranian horse breeds, contributing to the advancement of knowledge in areas such as conservation, performance traits, climate adaptation, reproduction, and resistance to diseases in equine science.

Computational Analysis of Single Nucleotide Polymorphisms in Human HIC1 Gene.

Background A putative tumor suppressor gene called HIC1 (hypermethylated in cancer) is situated at 17p13.3, a locus where the allelic loss occurs often in human malignancies, including breast cancer. Hypermethylated in cancer 1 protein is a protein that in humans is encoded by the HIC1 gene and it's aHomo sapiens(Human). This gene functions as a growth regulatory and tumor repressor gene. The molecular function of HIC1 gene includes DNA-binding transcription factor activity, sequence-specific DNA binding, DNA binding, histone deacetylase binding, protein binding, metal ion binding, nucleic acid binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, RNA polymerase II-specific. The biological process of HIC1 gene includes multicellular organism development, negative regulation of Wnt signaling pathway, positive regulation of DNA damage response, signal transduction by p53 class mediator regulation of transcription, DNA-templated, negative regulation of transcription by RNA polymerase II, Wnt signaling pathway, transcription, DNA-templated, intrinsic apoptotic signaling pathway in response to DNA damage, cellular response to DNA damage stimulus. The study aimed to predict the stability and structure of the protein that will arise from single nucleotide polymorphisms (SNPs) in the human HIC1 gene. Methodology To investigate the possible negative effects associated with these SNPs, bioinformatic analysis is typically essential. The following tools were employed for forecasting harmful SNPs: scale-invariant feature transform (SIFT), Protein Analysis Through Evolutionary Relationships (PANTHER), nonsynonymous SNP by Protein Variation Effect Analyzer (PROVEAN), and nonsynonymous SNP by Single Nucleotide Polymorphism Annotation Platform (SNAP). Results The present study identified a total of 36 SNPs using the SIFT approach, which were shown to have functional significance. Twenty-six were determined to be tolerable, whereas 10 were shown to be detrimental. Out of 20 SNPs, seven (P370A, P646S, R654P, A476T, S400S, D666N, D7V) SNPs were predicted as "Possibly damaging" and seven (L9F, G468R, G490R, L482R, S12W, G489D, S12P) were identified as "probably benign", and six (R725G, G620S, A56V, E463D, D394N, L338V) were identified as "probably damaging" according to the predictions made by PANTHER tools. The majority of the pixels on the strip were red, indicating that the gene changes may have dangerous consequences. These results highlight the need for more research to fully comprehend how these mutations affect the hic1 protein's function, which is essential for the emergence of different types of cancer. Conclusion The current research has provided us with essential information about how SNPs might be used as a diagnostic marker for cancer, given that SNPs may be candidates for cellular changes caused by mutations linked to cancer.

Variación molecular de genes asociados a lipoxigenasas en grano de variedades de soya comercial mexicana

Lipoxygenase enzymes encoded by the Lox1, Lox2 and Lox3 genes play a crucial role in soybean grain, particularly in the development of off-flavors. Understanding molecular variation within Lox genes is essential for the improvement of soybean organoleptic traits. This study investigated the genetic variation in the internal regions of the Lox1, Lox2, and Lox3 genes in mature grain of commercially grown soybean cultivars in Mexico. Genomic DNA from a diverse panel of Mexican soybean cultivars was analyzed using resequencing techniques and in-silico analysis. Single nucleotide polymorphisms (SNP) within the Lox1, Lox2, and Lox3 genes were identified and characterized. The findings indicated that Lox3 gene displayed lower genetic variability compared to Lox1 and Lox2 genes, specifically, was identified a total of 26 SNPs in the Lox1 gene, 11 SNPs in the Lox2 gene, and 5 SNPs in the Lox3 gene among the examined cultivars. A non-synonymous SNP variant of the C/C genotype located in exon 6 of the Lox2 gene was associated with a destabilizing effect on the lipoxygenase 2 enzyme in the Guayparime S-10 and Huasteca 300 cultivars. These findings provide insights into the molecular variation of lipoxygenase-associated genes in Mexican soybean cultivars.

Computational Analysis of Non-synonymous SNPs in ATM Kinase: Structural Insights, Functional Implications, and Inhibitor Discovery.

Ataxia telangiectasia-mutated (ATM) protein kinase, a key player in cellular integrity regulation, is known for its role in DNA damage response. This study investigates the broader impact of ATM on cellular processes and potential clinical manifestations arising from mutations, aiming to expand our understanding of ATM's diverse functions beyond conventional roles. The research employs a comprehensive set of computational techniques for a thorough analysis of ATM mutations. The mutation data are curated from dbSNP and HuVarBase databases. A meticulous assessment is conducted, considering factors such as deleterious effects, protein stability, oncogenic potential, and biophysical characteristics of the identified mutations. Conservation analysis, utilizing diverse computational tools, provides insights into the evolutionary significance of these mutations. Molecular docking and dynamic simulation analyses are carried out for selected mutations, investigating their interactions with Y2080D, AZD0156, and quercetin inhibitors to gauge potential therapeutic implications. Among the 419 mutations scrutinized, five (V1913C, Y2080D, L2656P, C2770G, and C2930G) are identified as both disease causing and protein destabilizing. The study reveals the oncogenic potential of these mutations, supported by findings from the COSMIC database. Notably, Y2080D is associated with haematopoietic and lymphoid cancers, while C2770G shows a correlation with squamous cell carcinomas. Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options. In summary, this computational analysis provides a comprehensive understanding of ATM mutations, revealing their potential implications in cellular integrity and cancer development. The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function.

Polymorphism in the leucine-rich repeats of TLR7 in different breeds of chicken and in silico analysis of its effect on TLR7 structure and function

Chicken toll-like receptor 7 (chTLR7) is a viral sensing pattern recognition receptor and detects ssRNA. The ligand binding site comprises leucine-rich repeats (LRRs) located in the ectodomain of chTLR7. Hence, any polymorphism in the binding site would modify its functional interaction with the ligand, resulting in varied strength of immune response. This study first aimed to compare the single nucleotide polymorphisms (SNPs) associated with the ligand binding site of TLR7 in three indigenous chicken breeds namely Aseel, Kadaknath, Nicobari along with an exotic breed White Leghorn. Four synonymous SNPs (P123P, I171I, N339N and L421L) and four non-synonymous SNPs (I121V, S135T, F356S and S447G) were identified among various breeds. We employed in silico tools to screen the pathogenic nsSNPs and one nsSNP was identified as having potential impact on chTLR7 protein. Moreover, sequence and structure-based methods were used to determine the effect of nsSNPs on protein stability. It revealed I121V, F356S, and S447G as decreasing the stability while S135T increasing the stability of chTLR7. Additionally, docking analysis confirmed that I121V and F356S reduced the binding affinity of ligands (R-848 and polyU) to chTLR7 protein. The results suggest that the nsSNPs found in this study could alter the ligand binding of chTLR7 and modify the immune response between different breeds further contributing to disease susceptibility or resistance. Further, in vitro and in vivo studies are needed to analyze the effect of these SNPs on susceptibility or resistance against various viral diseases in poultry.

Identification of single nucleotide polymorphisms (SNPs) in selected rice phosphate transporter (OsPHT) genes

Phosphorus (P) is one of the fundamental elements for plant growth and development. Due to the scarcity of viable P in the soil for plants, P deficiency was often the culprit that restrained plant’s wellbeing. Plasma membrane phosphate transporters (PHT) are a group of proteins responsible for phosphate (Pi) uptake from soil and further allocation to plant organs and tissues. The PHT can be further categorized into constitutively expressed low-affinity Pi transporter or high-affinity Pi transporter that are induced upon Pi starvation. Significant variability in P use efficiency has been observed among different rice varieties. Genotypic differences such as single nucleotide polymorphisms (SNPs) could be responsible for the variation observed aside from the well-studied phenotypic responses. Nevertheless, the occurrence of the SNPs in OsPHT genes remain unexplored. Therefore, the objective of this study was to analyse and profile the SNPs in five selected high affinity OsPHT genes which are responsible for P uptake under P deficiency. The SNPs mining was conducted using Rice SNP-Seek Database against 3024 rice varieties with Oryza sativa japonica cultivar Nipponbare as the reference sequence. Results showed that a total of zero, seven, three, one and ten non-synonymous SNPs was identified in OsPHT1;2, OsPHT1;3, OsPHT1;6, OsPHT1;9 and OsPHT1;10, respectively. A base substitution of C to A at position 16028497 of chromosome 10 of OsPHT1;3 was found to change tyrosine to a stop codon. This could result in a truncated protein which has only 213 amino acids as compared 526 amino acids in the complete protein. The large number of non-synonymous SNPs in OsPHT1;10 could explain the redundant function of this gene in the translocation and uptake of P in rice. In short, the identified SNPs especially the non-synonymous SNPs could potentially disrupt the biosynthesis of phosphate in rice which requires further investigation.

Identification of molecular markers and candidate regions associated with grain number per spike in Pubing3228 using SLAF-BSA.

Grain number per spike, a pivotal agronomic trait dictating wheat yield, lacks a comprehensive understanding of its underlying mechanism in Pubing3228, despite the identification of certain pertinent genes. Thus, our investigation sought to ascertain molecular markers and candidate regions associated with grain number per spike through a high-density genetic mapping approach that amalgamates site-specific amplified fragment sequencing (SLAF-seq) and bulked segregation analysis (BSA). To facilitate this, we conducted a comparative analysis of two wheat germplasms, Pubing3228 and Jing4839, known to exhibit marked discrepancies in spike shape. By leveraging this methodology, we successfully procured 2,810,474 SLAF tags, subsequently resulting in the identification of 187,489 single nucleotide polymorphisms (SNPs) between the parental strains. We subsequently employed the SNP-index association algorithm alongside the extended distribution (ED) association algorithm to detect regions associated with the trait. The former algorithm identified 24 trait-associated regions, whereas the latter yielded 70. Remarkably, the intersection of these two algorithms led to the identification of 25 trait-associated regions. Amongst these regions, we identified 399 annotated genes, including three genes harboring non-synonymous mutant SNP loci. Notably, the APETALA2 (AP2) transcription factor families, which exhibited a strong correlation with spike type, were also annotated. Given these findings, it is plausible to hypothesize that these genes play a critical role in determining spike shape. In summation, our study contributes significant insights into the genetic foundation of grain number per spike. The molecular markers and candidate regions we have identified can be readily employed for marker-assisted breeding endeavors, ultimately leading to the development of novel wheat cultivars possessing enhanced yield potential. Furthermore, conducting further functional analyses on the identified genes will undoubtedly facilitate a comprehensive elucidation of the underlying mechanisms governing spike development in wheat.

Genetic Basis and Evolutionary Forces of Sexually Dimorphic Color Variation in a Toad-Headed Agamid Lizard.

In the animal kingdom, sexually dimorphic color variation is a widespread phenomenon that significantly influences survival and reproductive success. However, the genetic underpinnings of this variation remain inadequately understood. Our investigation into sexually dimorphic color variation in the desert-dwelling Guinan population of the toad-headed agamid lizard (Phrynocephalus putjatai) utilized a multidisciplinary approach, encompassing phenotypic, ultrastructural, biochemical, genomic analyses, and behavioral experiments. Our findings unveil the association between distinct skin colorations and varying levels of carotenoid and pteridine pigments. The red coloration in males is determined by a genomic region on chromosome 14, housing four pigmentation genes: BCO2 and three 6-pyruvoyltetrahydropterin synthases. A Guinan population-specific nonsynonymous single nucleotide polymorphism in BCO2 is predicted to alter the electrostatic potential within the binding domain of the BCO2-β-carotene complex, influencing their interaction. Additionally, the gene MAP7 on chromosome 2 emerges as a potential contributor to the blue coloration in subadults and adult females. Sex-specific expression patterns point to steroid hormone-associated genes (SULT2B1 and SRD5A2) as potential upstream regulators influencing sexually dimorphic coloration. Visual modeling and field experiments support the potential selective advantages of vibrant coloration in desert environments. This implies that natural selection, potentially coupled with assortative mating, might have played a role in fixing color alleles, contributing to prevalence in the local desert habitat. This study provides novel insights into the genetic basis of carotenoid and pteridine-based color variation, shedding light on the evolution of sexually dimorphic coloration in animals. Moreover, it advances our understanding of the driving forces behind such intricate coloration patterns.

In-silico investigation of porcine X-chromosome reveals deleterious non-synonymous SNPS

in-silico investigation of porcine X-chromosome reveals deleterious non-synonymous SNPS