Prediction of genes encoding toxin of Mycobacterium tuberculosis H37RV strain

Prediction of genes encoding toxin of Mycobacterium tuberculosis H37RV strain | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Prediction of genes encoding toxin of Mycobacterium tuberculosis H37RV strain Temam Gemeda Genemo, Hunduma Dinka This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5966480/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, primarily affects the lungs but can spread to other organs. It is a major global health issue, leading to nearly 2 million deaths annually. Early diagnosis is vital for effective treatment, yet traditional methods like culture and smear microscopy can take 6–8 weeks. This highlights the need for molecular diagnostics that can rapidly detect TB DNA. Therefore, the present study aims to predict genes encoding toxins in the M.tuberculosis strain H37Rv, widely used in tuberculosis research. For this purpose, a total of one whole genome sequence of M. tuberculosis strain H37Rv was retrieved from NCBI, and the 16s RNA, MGE, resistance genes, toxin-encoding genes, and proteins associated with the toxin genes were analyzed using; NCBI, ContEst16S, Rapid Annotation Search Tool (RAST), Rapid Annotation using Subsystem Technology (RAST) quality report and TubercuList website. This finding identified 47 16S rRNA genes and 59 toxin-encoding genes associated with various toxin proteins. We assessed genome similarities and Average Nucleotide Identity (ANI) among toxin genes. Notably, except for two toxin genes, all other sequences showed a 0.00% OrthoANI value. Additionally, antibiotic resistance genes identified include gidB, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG, and pncA, with the latter four being specific to M. tuberculosis. The results of this study also revealed homologs of VapC toxins in M.tuberculosis, linked to VapBC toxin-antitoxin systems. These findings lay the groundwork for future research on toxin-encoding genes and antibiotic resistance in M.tuberculosis H37Rv. Biological sciences/Computational biology and bioinformatics Biological sciences/Molecular biology katG gene M. tuberculosis H37Rv strain Toxin VapBC toxin-antitoxin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1. INTRODUCTION 1.1. Background and Justification of the Study Tuberculosis (TB) is a multisystem airborne infectious disease that causes high mortality rate worldwide. This infectious disease is caused by the bacterium called Mycobacterium tuberculosis ( M. tuberculosis ) [ 1 ]. Usually tuberculosis disease affects the lungs, and also it may affect brain, kidneys or spine. According to World Health Organisation (WHO), Tuberculosis is still a leading killer (nearly 2 million die annually) of young adults worldwide. TB remains a significant global health challenge; disproportionately affecting adolescents and young adults (AYAs) aged 10–24 years. Each year, an estimated 1.8 million AYAs contract TB, accounting for approximately 18% of the annual global TB incidence[ 2 ]. Despite being preventable and treatable, TB is a leading cause of death among this age group. In 2019, the WHO estimated that 71,000 adolescents (11,000 aged 10–14 years and 60,000 aged 15–19 years) and 90,000 young adults died from TB. The risk of Mycobacterium tuberculosis infection and progression to active TB disease increases during this phase of life [ 3 ]. The risk of TB progression is exacerbated by HIV infection, which is a substantial concern in this age group. In 2021, around 28% of new global HIV infections occurred in individuals aged 15–24 years, and AYAs with HIV experience poorer outcomes along the HIV care cascade compared to other age groups [ 4 ] Adolescents and young adults with TB who are living with HIV, in conditions of extreme poverty and/or violence, and/or have been previously treated for TB disease are at greater risk of poor adherence to TB treatment and loss to follow-up. During the critical developmental period of 10–24 years, individuals undergo rapid physical, cognitive, emotional, and social changes, as they acquire the resources needed for health and well-being in adulthood, and become more autonomous. The WHO and other institutions have emphasized the need for healthcare services and research to address the specific needs of Adolescents and young adults [ 5 ]. However, most national TB programs (NTPs) do not currently account for Adolescents and young adults -specific considerations and requirements in their policies and practices [ 3 ]. Tuberculosis severity and prevalence is very high in patients co-infected with the human immunodeficiency virus (HIV). Weakness, weight loss, fever, night sweats, coughing, difficulties for breathing, chest pain and coughing up of the blood were some of the most common symptoms of tuberculosis disease [ 1 ]. Cough, weight loss/anorexia, fever, night sweats, hemoptysis, chest pain (also can result from tuberculous and fatigue) is classic clinical features that are associated with active pulmonary TB[ 6 ]. Sometime these symptoms are not displayed typical in elderly individuals. The sign and symptoms of tuberculosis disease are dependent on body parts where the disease-causing bacteria are growing [ 7 ]. An early diagnosis is an essential point for the control of tuberculosis disease. Traditionally tuberculosis is diagnosed through microbiological infection culture and direct microscopic examination (smear microscopy). Culture and smear microscopy method of microbiological tuberculosis infection diagnose is requiring up to 6–8 weeks. Therefore, identification of M. tuberculosis by molecular method is very necessary [ 6 ]. M. tuberculosis is identified through molecular methods by amplification of nucleic acids, direct DNA sequencing analysis, automated molecular testing, microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays. Molecular based identification of M. tuberculosis sample from grown-up cultures for the identification of the species and detection of genetic mutations related with the resistance to main antibiotics [ 7 ]. Treatment of Tuberculosis needs several appropriate different antibiotic drugs that are given at least for 6 months to 12 months [ 6 ]. Partial or inconsistent treatment of tuberculosis leads to the development of drug resistant bacilli, known as multidrug-resistant TB (MDR-TB), which fails to respond to standard first-line drugs and becomes difficult and more expensive to treat [ 2 , 8 ]. Tuberculosis caused by M. tuberculosis is prevented by administration of BCG vaccine. Currently, M. tuberculosis develops resistant strain for BCG vaccine and millions of world population were hospitalized due to tuberculosis disease. To overcome this problems researcher were advising possibilities for TB vaccine improvement. The key possibilities for TB vaccine improvement are insertion of immunogenic gene into the genome of BCG to enhance immunogenicity (eg: RD1), attenuation of M. tuberculosis through the deletion of a virulent gene and subunit or recombinant vaccines development [ 9 ]. Key possibilities for these TB vaccine improvement methods highly depend on M. tuberculosis genome annotation and analysis of gene encoding virulent factors (toxin genes) and protein associated with this virulent factor’s gene[ 10 ]. The molecular analysis of identifying genes and proteins encoding virulence factors in M. tuberculosis typically involves a multi-step process combining genomic analysis, bioinformatics, and experimental validation. While 16S rRNA sequences are not directly used to identify virulence factors, the whole genome sequence of the bacterium can be analyzed to predict potential virulence factors [ 1 , 11 ]. Bacterial infections often involve virulence factors that play a crucial role in the pathogenicity of the bacteria. Virulence factors are gene molecules produced by pathogens that contribute to their ability to cause disease. Accurate detection and characterization of virulence factor genes (VFGs) is essential for precise treatment and prognostic management of hypervirulent bacterial infections. Identifying the specific virulence factors and their genetic basis allows clinicians to better understand the mechanisms by which a pathogen causes disease. This knowledge can inform the development of targeted therapies, vaccination strategies, and infection control measures. Early and reliable detection of VFGs is particularly important for severe or difficult-to-treat infections, as it enables clinicians to select the most appropriate antimicrobial interventions[ 12 , 13 ] Furthermore, analyzing the VFGs of a bacterial strain can provide insights into its evolutionary adaptations and potential for causing outbreaks or epidemics. By mapping the virulence gene profiles of different bacterial isolates, researchers can track the emergence and spread of hypervirulent strains, supporting public health efforts to monitor and contain infectious disease threats [ 11 , 14 ]. M. tuberculosis H37RV strain infection induces a more severe inflammatory immune response associated with tissue damage. For this study M. tuberculosis strain H37RV was selected as it has been used extensively worldwide in biomedical research. Unlike some clinical isolates, it retains full virulence in animal models of tuberculosis and is susceptible to drugs and receptive to genetic manipulation[ 15 ] [ 16 ]. M. tuberculosis employs a range of virulence factors to establish infection and evade the host immune system. One of the most notable virulence factors to establish by bacterium is toxins [ 17 ]. Therefore, the aim of this work was to predict genes encoding toxin for M. tuberculosis H37RV strain. 1.2. Objective General objective To predict genes encoding virulence factors for M. tuberculosis H37RV strain Specific objectives The specific objectives of the analysis are: - To predict 16sRNA and compare genomes of M. tuberculosis H37RV strains To identify M. tuberculosis H37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping To determine M. tuberculosis H37RV strain genes encoding toxin To determine protein sequence for the predicted respective virulence encoding gene for M. tuberculosis H37RV strain 2. METHODS 2.1. Prediction of16sRNA for M. tuberculosis H37Rv strains and comparative genomes Prediction of 16sRNA for M. tuberculosis H37Rv strain was done by obtaining the sequences of M. tuberculosis H37Rv strain from NCBI by using accession number NC_000962.3. The method named ContEst16S (Contamination Estimator by 16S), in which 16S rRNA gene fragments from the query genome assemblies was used to screen contaminated and the normal genome downloaded. The standard software tools are freely available at http://www.ezbiocloud.net/sw/oat [ 18 , 19 ]. The predicted functional gene of M. tuberculosis H37Rv strain 16sRNA with base length was analysed by the Rapid Annotation Search Tool (RAST) the SEED Viewer a read only browser of the curated SEED data [ 20 ] The Comparative genome study were analysed to determine genome sequence similarities between selected toxin encoding gene sequences of M. tuberculosis H37Rv strain. In addition, comparative genome studies were also analysed by Orthologous Average Nucleotide Identity Tool (OAT) and CLC Genome Workbenchs (QIAGEN CLC Genomics Workbench 24.0). OAT software used OrthoANI to measure the overall similarity between genome sequences. This software measure similarity between maximum of ten genome sequences [ 16 ].Comparative genome similarities and Average Nucleotide Identity were analysed by selection of 10 gene sequences encoding toxin of M. tuberculosis H37Rv strain. OAT software that uses OrthoANI to measure overall similarity between two genome sequences were used to analysis Comparative genome similarities and Average Nucleotide Identity. Comparative genome similarities of selected genome sequences were calculated using Ortho ANI [ 11 , 21 ]. M. tuberculosis H37Rv strain contains VapC Toxin 1 PIN domain, Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain. Comparative genome similarities and Average Nucleotide Identity were analysed by selection of 10% of VapC Toxin 1 PIN domain and one gene sequence form all other toxin encoding gene sequences (Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain) of M. tuberculosis H37Rv strain. The result was determined by Heatmap with values and un-weighted pair group method with arithmetic mean (UPGMA) trees. Comprehensive EzBioCloud bioinformatics platform, the software tools which freely available at http://www . ezbio cloud. net/ sw/ oat, was used to Calculating Average Nucleotide Identity. Average Nucleotide Identity calculation involves the fragmentation of genome sequences, followed by nucleotide sequence search, alignment and identity calculating software, OAT[ 22 , 23 ]. Sequence data that support the findings of this study have been deposited in the NCBI (European Nucleotide Archive) with the primary accession number NC_000962.3 2.2. Identifying of M. tuberculosis H37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping To identify specific genes from data, the computational tools; BLAST specialized genomic analysis software to compare sequences against databases of known genes or protein families was used [ 24 ]. The identification of Mycobacterium tuberculosis H37RV strain Mobile Genetic Elements was proceed by using of specialized genomic analysis softwareCGview.ca that available at http://stothard.afns.ualberta.ca/cgview_server/ [ 2 ]. This specialized genomic analysis software identifies Mobile Genetic Elements of Mycobacterium tuberculosis H37RV strain by comparing the sequences of Mycobacterium tuberculosis H37RV strain against databases of known genes or protein families[ 21 , 24 ]. Circular genome mapping for complete 16S rRNA of Mycobacterium tuberculosis H37RV strains was obtained using CGView server available at http://stothard.afns.ualberta.ca/ cgview. The prediction of genes was proceeded by the Velvet assembled contigs using Glimmer software[ 19 ]. This online software is freely available at https://ccb.jhu.edu/software/glimmer/ . The predicted genes were annotated using in-house pipeline RAST server available at http://rast.theseed.org/FIG/rast.cgi/.Circular genome mapping for complete 16S rRNA of M. tuberculosis H37RV strains was analysed by using CGView online serveravailable via http://stothard.afns.ualberta.ca/cgviewserver/ [ 17 ] [ 16 ]. The Mobile Genetic Elements and Sequence Composition of M. tuberculosis H37RVstrains complete genomes was analyzed by using CGView online server explored through Phigaro a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input[ 16 , 25 ]. The composition of GC Content and GC Skew was determined by Sequence Composition detection software available via http://stothard.afns.ualberta.ca/ cgview server and GC content plots generating formula [ 26 ]. The Comprehensive Antibiotic Resistance Database (CARD) Resistance Gene Identifier (RGI), CRISPR arrays and their associated Cas proteins finder and Open Reading Frames (ORFs) of M. tuberculosis H37RV strain Annotate by Prokka; the genome sequence annotate and identify coding sequences special bioinformatics tools available at CGView server package online software[ 11 ]. Antibiotic Resistance gene (CARD) of M. tuberculosis H37RV strains was retrieved from online CARD data base available at http://stothard.afns.ualberta.ca/ cgview server. The Mobile Genetic Elements View explored through Phigaro a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input [ 27 ]. The sequence composition determines GC Content and GC Skew of Mycobacterium tuberculosis H37RVstrains through CGview.ca that available at http://stothard.afns.ualberta.ca/ cgview_ server/ [ 26 ]. The GC content plots are generated by calculating the GC content for each sliding window using the formula: \(\:\text{G}\text{C}\:\text{c}\text{o}\text{n}\text{t}\text{e}\text{n}\text{t}\:=\:\:\frac{G+C}{Window\:Size}\) = values between 0 and 1 [ 26 ]. The window moves by the step size, and the calculation repeats Window size (bp) = Auto (1000) The GC skew is generated through the formula: \(\:\text{G}\text{C}\:\text{s}\text{k}\text{e}\text{w}\:=\:\:\frac{G-C}{\:G+C}\) = values between − 1 and 1 [ 26 ]). This size of the sliding window (number of nucleotides) used for each calculation Step size = Auto (1000). The number of nucleotides to move the window after each calculation = Auto (100) [ 26 ] 2.3. Determining M. tuberculosis H37RV strain genes encoding virulence factors The gene sequences for virulence factor encoding gene of M. tuberculosis H37RV strain was analysed by retrieving, on May 05/2024, of M. tuberculosis H37RV strain sequence from NCBI. The contamination in 16S rRNA gene fragments from the query genome assemblies was checked by method named ContEst16S available at http://www.ezbiocloud.net/ sw . The normal sequence fragment was downloaded on May 05 2024 and annotated by Rapid Annotation using Subsystem Technology (RAST) annotation ( https://rast.nmpdr.org/ ). The M. tuberculosis H37Rv strain toxin genes were retrieved by Re-annotation of the genome sequence of M. tuberculosis H37Rv strain complete genome sequence through search of respective toxin genes by using contig Id [ 28 ] from NCI data base from https://www.ncbi.nlm.nih.gov/prokaryotic genome annotation pipeline. The software is freely available at https://www.ncbi.nlm.nih.gov/NC . The Gene name, Gene length, Gene Identifier and chromosomal location of gene encoding toxin genes in M. tuberculosis H37Rv strain was retrieved from online website database called TubercuList website, NCBI database which Release 26, Dec 2012. This genome database is freely available at http://tuberculist.epfl.ch/ https://mycobrowser.epfl.ch/ . 2.4. Determination of protein for respective virulence factor encoding genes of Mycobacterium tuberculosis H37RV strain Determination of protein for respective virulence factor encoding genes of Mycobacterium tuberculosis H37RV strain was analysed through the approaches of genome Annotation and genome Assemble. The genome sequence was annotated by using rapid annotations subsystems technology [ 21 , 29 ]. The gene encoding virulence associated proteins was detected to determine virulence associated proteins and protein for respective virulence factor encoding genes was determination by RAST quality report [ 21 ]. 3. RESULTS 3.1 Prediction of 16sRNA for M. tuberculosis H37Rv strain complete genome sequence. The result of 16s rRNA predicted for M. tuberculosis H37Rv strain is presented in Table 1 . A total of 47 16s rRNA were predicted with variable number of contig features. Table 1 Predicted 16s rRNA of M. tuberculosis H37Rvstrain complete genome sequence Contig feature Splitting statistics Sequence size 4,411,532 Number of 16s RNAs 47 Number of contigs (with PEGs) 1 GC content (%) 65.6 Number of Subsystems 293 Number of Coding Sequences 4259 Length of the smallest contig (L50 value) 1 The complete genome of M. tuberculosis H37Rv strains analysed by CLC Genome Workbench (QIAGEN CLC Genomics Workbench 24.0) shows a total 15042 open reading frame (ORF) sequences of which 3,995 ORF are with TTG start codon, 4,428 ORF with ATG start codon and 6,619 ORF with CTG start codon. Further analysis of the predicted 16S rRNA of M. tuberculosis H37Rv strains for their genome annotation at subsytem and non-subsystem category distribution was conducted by RAST software server ( https://rast.nmpdr.org/seedviewer.cgi)an d depicted in Fig. 1 . As shown in Fig. 1 a, subsystem coverage (bar chart) and non-subsystem coverage were found to be 23 and77%, respectively. It was predicted that there is a total coverage of 955 subsystems and 3304 non-subsystems for M. tuberculosis H37Rv strain. In subsystem coverage, the hypothetical and non-hypothetical gene sizes are 83 and 82, respectively (Fig. 1 a). The percentage distribution of subsystem features was depicted in graphical representation (Fig. 1 b). The highest percentage of subsystem features was detected for amino acids and derivatives and followed by carbohydrate metabolic features. However, the lowest percentage was detected for Secondary Metabolism subsystem feature (Fig. 1 c) Comparative genome similarities and Average Nucleotide Identity of M. tuberculosis H37Rv strain toxin encoding gene sequences were analysed by selection of 10 toxin encoding gene sequences. M. tuberculosis H37Rv strain contains 59 genes sequences that encoding toxin. Out of these 44 (74%) genes sequences were encoding toxin VapC Toxin 1, PIN domain genes and the left 26% includes Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain. The results of Orthologous Average Nucleotide Identity analyses of 10 gene sequences encoding toxin of M. tuberculosis H37Rv strain(comparative genome analysis) showed that the gene sequences encoding YoeB toxin protein and Death on curing protein, Doc toxin show an OrthoANI value of 100% (Fig. 2 ). This shows that; the gene sequence encoding YoeB toxin protein and Death on curing protein Doc toxin encoding gene sequences of M. tuberculosis H37Rv strain have sequence with identical distribution. This implied that; the two toxin encoding genes sequences were highly convergent. The results also show that; except gene encoding YoeB toxin protein and Death on curing protein, Doc toxin, all toxin encoding genes show an OrthoANI value of 0.00% (Fig. 3 ). This indicates no detectable genetic similarity between any of the selected toxin encoding genes sequences of M. tuberculosis H37Rv strain. This absence of detectable similarity could imply that; VapC at Toxin 1 PIN domain, ParE toxin domain, HigB toxin domain, MazF toxin domain and YdcE toxin domains are highly divergent or evolved independently. Orthologous Average Nucleotide Identity (OrthoANI) is a method used to measure the genetic similarity between two genomic sequences. It is commonly used in genomics to determine the relatedness of bacterial strains. 3.2. Identifying of Mycobacterium tuberculosis H37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping The Comprehensive Antibiotic Resistance Database (CARD) Resistance Gene Identifier(RGI), CRISPR arrays and their associated Cas proteins finder and Open Reading Frames (ORFs) of M. tuberculosis H37RV strain Annotate by Prokka; the genome sequence annotate and identify coding sequences special bioinformatics tools available at CGView server package online software and determined as state in Fig. 4 . Antibiotic Resistance gene (CARD) of M. tuberculosis H37RV strains analysis results revealed that M. tuberculosis H37RV strains poses gidB , gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG and pncA antibiotic resistance genes of which inhA, embB, katG and pncA were specific to M. tuberculosis. The coding sequence(CDS), Transfer ribonucleic acid (tRNA), Ribosomal ribonucleic acid (rRNA), Transfer-messenger ribonucleic acid (tmRNA) a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties and repeat region of M.tuberculosis H37RV strains was determined and presented in Fig. 5 . The Mobile Genetic Elements and Sequence Composition of M. tuberculosis H37RV strains complete genomes was obtained using CG View online server and determined in Fig. 6 .The result show that; M. tuberculosis H37RV strains contains radA, recA, uvrA, uvrB, exoA_2 and mobC and int mobile genetic element with replication/recombination/repair (Fig. 6 olive colour), transfer (Fig. 6 navy blue colour) and integration/excision (Fig. 6 lime colour) function respectively. 3.3. Determination of M. tuberculosis H37RV strain genes encoding virulence factors Toxin encoding genes for M.tuberculosis H37RV strain; the Gene name, Gene length, Gene Identifier and chromosomal location were determined and the results were presented in table forms (Table 2 ). The result of this analysis revealed that M.tuberculosis H37RV strain possesses 59 toxin encoding genes sequence. From this 44 of them clustered under PIN domain protein families encoding gene which associated toxic components toxin–antitoxin systems. The gene clustered under PIN domain protein families encoding genes cover virulence association protein C (VapC) encoding functional gene of M. tuberculosis H37RV strain genome. They encode a toxic PilT N-terminus (PIN) domain and antitoxin VapB . The Mycobacterium tuberculosis H37RV strain also contains toxins genes such as relE toxn genes, higB toxin genes, and pares toxin genes. The virulent bacterial species contain the groups of toxin encoding genes including relE, higB, and parE which function as regulation of cellular protein translation under nutritional stress conditions, Controls Biofilm Formation and the Expression of Type III Secretion System Genes, and cell elongation and significantly increased recA and lexA gene expression respectively. Table 2 M. tuberculosis H37Rvstrain toxin encoding Gene annotation summary information Gene name Gene length Identifier Location Gene annotation Link vapC1 402 bp Rv0065 71821 bp https://mycobrowser.epfl.ch/genes/Rv0065 vapC26 408 bp Rv0582 677922 bp https://mycobrowser.epfl.ch/genes/Rv0582 vapC24 438 bp Rv0240 289345 bp https://mycobrowser.epfl.ch/genes/Rv0240 vapC25 429 bp Rv0277c 332708 bp https://mycobrowser.epfl.ch/genes/Rv0277c vapC2 426 bp Rv0301 364044 bp https://mycobrowser.epfl.ch/genes/Rv0301 mazF1 282 bp Rv0456A 547076 bp https://mycobrowser.epfl.ch/genes/Rv0456A vapC3 414 bp Rv0549c 640228 bp https://mycobrowser.epfl.ch/genes/Rv0549c vapC4 393 bp Rv0595c 694839 bp https://mycobrowser.epfl.ch/genes/Rv0595c vapC27 414 bp Rv0598c 697154 bp https://mycobrowser.epfl.ch/genes/Rv0598c vapC28 402 bp Rv0609 703486 bp https://mycobrowser.epfl.ch/genes/Rv0609 vapC29 402 bp Rv0617 711006 bp https://mycobrowser.epfl.ch/genes/Rv0617 vapC30 396 bp Rv0624 716664 bp https://mycobrowser.epfl.ch/genes/Rv0624 vapC5 408 bp Rv0627 718282 bp https://mycobrowser.epfl.ch/genes/Rv0627 vapC6 384 bp Rv0656c 752984 bp https://mycobrowser.epfl.ch/genes/Rv0656c mazF2 309 bp Rv0659c 754685 bp https://mycobrowser.epfl.ch/genes/Rv0659c vapC7 438 bp Rv0661c 755335 bp https://mycobrowser.epfl.ch/genes/Rv0661c vapC8 339 bp Rv0665 758801 bp https://mycobrowser.epfl.ch/genes/Rv0665 vapC31 429 bp Rv0749 841228 bp https://mycobrowser.epfl.ch/genes/Rv0749 mazF8 318 bp Rv2274c 2546488 bp https://mycobrowser.epfl.ch/genes/Rv2274c vapC35 408 bp Rv1962c 2204866 bp https://mycobrowser.epfl.ch/genes/Rv1962c vapC9 384 bp Rv0960 1073545 bp https://mycobrowser.epfl.ch/genes/Rv0960 vapC15 399 bp Rv2010 2258273 bp https://mycobrowser.epfl.ch/genes/Rv2010 mazF3 312 bp Rv1102c 1230660 bp https://mycobrowser.epfl.ch/genes/Rv1102c vapC32 375 bp Rv1114 1239610 bp https://mycobrowser.epfl.ch/genes/Rv1114 mazF4 318 bp Rv1495 1686570 bp https://mycobrowser.epfl.ch/genes/Rv1495 vapC33 432 bp Rv1242 1384535 bp https://mycobrowser.epfl.ch/genes/Rv1242 relE 294 bp Rv1246c 1388685 bp https://mycobrowser.epfl.ch/genes/Rv1246c vapC10 402 bp Rv1397c 1574112 bp https://mycobrowser.epfl.ch/genes/Rv1397c vapC11 405 bp Rv1561 1764979 bp https://mycobrowser.epfl.ch/genes/Rv1561 vapC12 390 bp Rv1720c 1947030 bp https://mycobrowser.epfl.ch/genes/Rv1720c vapC34 249 bp Rv1741 1967917 bp https://mycobrowser.epfl.ch/genes/Rv1741 vapC13 396 bp Rv1838c 2087257 bp https://mycobrowser.epfl.ch/genes/Rv1838c mazF5 330 bp Rv1942c 2194644 bp https://mycobrowser.epfl.ch/genes/Rv1942c vapC14 312 bp Rv1953 2200938 bp https://mycobrowser.epfl.ch/genes/Rv1953 higB 378 bp Rv1955 2201719 bp https://mycobrowser.epfl.ch/genes/Rv1955 parE1 297 bp Rv1959c 2203681 bp https://mycobrowser.epfl.ch/genes/Rv1959c vapC36 420 bp Rv1982c 2225413 bp https://mycobrowser.epfl.ch/genes/Rv1982c mazF6 345 bp Rv1991c 2234305 bp https://mycobrowser.epfl.ch/genes/Rv1991c mazF7 411 bp Rv2063A 2321057 bp https://mycobrowser.epfl.ch/genes/Rv2063A vapC37 435 bp Rv2103c 2364086 bp https://mycobrowser.epfl.ch/genes/Rv2103c parE2 318 bp Rv2142c 2402193 bp https://mycobrowser.epfl.ch/genes/Rv2142c vapC16 426 bp Rv2231A 2505736 bp https://mycobrowser.epfl.ch/genes/Rv2231A vapC18 414 bp Rv2546 2868154 bp https://mycobrowser.epfl.ch/genes/Rv2546 vapC38 426 bp Rv2494 2808310 bp https://mycobrowser.epfl.ch/genes/Rv2494 vapC39 420 bp Rv2530c 2854267 bp https://mycobrowser.epfl.ch/genes/Rv2530c vapC17 402 bp Rv2527 2851315 bp https://mycobrowser.epfl.ch/genes/Rv2527 vapC19 378 bp Rv2548 2868860 bp https://mycobrowser.epfl.ch/genes/Rv2548 vapC20 396 bp Rv2549c 2869727 bp https://mycobrowser.epfl.ch/genes/Rv2549c vapC40 405 bp Rv2596 2925734 bp https://mycobrowser.epfl.ch/genes/Rv2596 vapC41 441 bp Rv2602 2930344 bp https://mycobrowser.epfl.ch/genes/Rv2602 vapC21 417 bp Rv2757c 3070170 bp https://mycobrowser.epfl.ch/genes/Rv2757c vapC42 396 bp Rv2759c 3070875 bp https://mycobrowser.epfl.ch/genes/Rv2759c mazF9 357 bp Rv2801c 3110167 bp https://mycobrowser.epfl.ch/genes/Rv2801c vapC22 393 bp Rv2829c 3136620 bp https://mycobrowser.epfl.ch/genes/Rv2829c vapC23 381 bp Rv2863 3174992 bp https://mycobrowser.epfl.ch/genes/Rv2863 relG 264 bp Rv2866 3177822 bp https://mycobrowser.epfl.ch/genes/Rv2866 vapC43 444 bp Rv2872 3183382 bp https://mycobrowser.epfl.ch/genes/Rv2872 vapC44 429 bp Rv3320c 3707642 bp https://mycobrowser.epfl.ch/genes/Rv3320c relK 258 bp Rv3358 3771045 bp https://mycobrowser.epfl.ch/genes/Rv3358 vapC46 393 bp Rv3384c 3799243 bp https://mycobrowser.epfl.ch/genes/Rv3384c vapC47 411 bp Rv3408 3826548 bp https://mycobrowser.epfl.ch/genes/Rv3408 vapC48 438 bp Rv3697c 4139805 bp https://mycobrowser.epfl.ch/genes/Rv3697c 3.4. Determination of protein for respective virulence factor encoding genes of M. tuberculosis The RAST quality report genome annotation showed that; M.tuberculosis H37RV strain contains 59 virulence associated proteins. These were protein encoded by these virulent genes were clustered in to Toxin 1PIN domain families proteins encoding genes, Endoribonuclease toxin MazF proteins encoding genes, rel family toxin proteins encoding genes, higB families toxin proteins encoding genes and parE families toxin proteins encoding genes. The PIN (PilT N terminus) domain is a protein domain that is found in a variety of proteins, including those involved in virulence and toxin-antitoxin systems in bacteria and archaea. The PIN domain belongs to a large nuclease super family and has a characteristic active center consisting of three highly conserved catalytic residues that coordinate metal ions. Within M. tuberculosis CDC1551, the VapC-like PIN domain is found in proteins such as the Virulence associated protein C (VapC) and the hypothetical protein MT3492. These toxins are typically co-expressed with an antitoxin protein, which forms an inert complex and neutralizes the toxic effects of the PIN domain-containing toxin. The VapBC toxin-antitoxin, where VapB is inhibitor and VapC, is PIN-domain ribonuclease toxin operons encoded in M. tuberculosis H37RV strain genome. PIN-domain protein is a protein domain which functions as a toxin that can inhibit cell growth or viability by cleavage of the cellular RNA. They have ribonucleases biochemical properties. TheVapC PIN-domain Toxin 1 proteins of M. tuberculosis H37RV strain has 44 virulence associated proteins such as; VapC1protein, Toxin 1protein, toxin VapC24protein,toxin VapC25 protein, toxin vapC2 protein, toxin VapC3 protein, toxin VapC26 protein, toxin VapC27 protein, toxin VapC28 protein, toxin VapC29 protein, toxin VapC30 protein, toxin VapC7 protein, Toxin protein, toxin VapC31 protein, toxin VapC9 protein, Toxin VapC32 protein, toxin VapC10 protein, toxin VapC11 protein, toxin VapC12 protein, toxin VapC34 protein, toxin VapC13 protein, toxin VapC14 protein, Toxin HigB protein, toxin VapC35 protein, toxin VapC36 protein, toxin VapC15 protein, Toxin HigB protein, toxin VapC37 protein, toxin VapC38 protein, toxin VapC39 protein, toxin VapC18 protein, toxin VapC19 protein, toxin VapC20 protein, toxin VapC40 protein, toxin VapC41 protein, VapC21 antibacterial toxin protein, toxin VapC42 protein, toxin VapC22 protein, toxin VapC43 protein, Toxin HigB protein, toxin VapC44 protein, toxin VapC46 protein, toxin VapC47 protein and toxin VapC48 protein. These toxin proteins exist with equal antitoxin proteins. So that the VapC found in M. tuberculosis H37RV strains determined as VapBC operon possess toxin-antitoxin system. The sequence similarity of M. tuberculosis H37RV strain in Conserved Protein Domain PIN-domain proteins Family of most diverse 10 bacteria species were detected by online server https://www.ncbi.nlm.nih.gov/Structure/lexington/files/banner.pngconserved domain architecture retrieval tool and the sequence similarity were determined Fig. 7 . The result show that M. tuberculosis H37RV strain VapC proteins share sequence similarities at active center of structure-specific of Conserved Protein Domain PIN-domain Family proteins with all of the selected most diverse 10 bacteria species 4. DISCUSSION The 16s RNA M. tuberculosis H37Rv strain complete genome sequence was predicted. It was found that M. tuberculosis H37Rv strain complete genome sequence has 47 16s RNA molecules. Comparative genome similarities were calculated using Ortho ANI and similar closely related species show high comparative genome similarities percentage [ 13 , 21 ]. The ten toxin encoding genes sequence of Mycobacterium tuberculosis H37Rv strain were selected and the heatmap results show that; except gene encoding YoeB toxin protein and Death on curing protein, Doc toxin, all toxin encoding genes show an OrthoANI value of 0.00%. This indicates that; there are no detectable similarities between selected sequences of M.tuberculosis H37Rvstrain. This implies that; the toxin domains are highly divergent or evolved independently. Orthologous Average Nucleotide Identity (OAT) was used to analysis genome comparative to measure Average Nucleotide Identity and similarity between genomic sequences and calculate OrthoANI values between genomes of interest with the results from 0.00–100% [ 16 ].Comparative genome similarities and Average Nucleotide Identity possess less OrthoANI values were considered as highly divergent genome sequences [ 11 , 30 ].The gene encoding YoeB toxin protein and Death on curing protein, Doc toxins shows 100% OrthoANI values. According to [ 10 , 21 ] the same species demarcation cut-off at 95 ~ 96% and large comparison studies have demonstrated both algorithms produce near identical reciprocal similarities. The M. tuberculosis H37Rv strain possesses 59 toxin encoding genes. These genes were associated with toxic protein of PIN domain protein families, relE, higB, parE1and mazF proteins families. Predicting coding region of complete genome of M. tuberculosis H37Rv strain was proceeded through proker. A M. tuberculosis H37RV strain poses gidB , gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG and pncA antibiotic resistance genes. From this antibiotic resistance genes (inhA, embB, katG and pncA) were specific to M. tuberculosis. This agrees with the report of [ 31 ] where Antibiotic Resistance genes such as gidB , gyrA, gyrB, rpoB, rpsL and rrs were associated with not only with M. tuberculosis but also in ESKAPE and other bacterial pathogens. Toxin-antitoxin (TA) systems are widely distributed across prokaryotic organisms, and many species possess multiple copies of these systems within their genomes [ 2 , 25 ]. The present analysis result showed that the vapBCproteins of M. tuberculosis H37RV strain corporates as toxin- antitoxin sytem. The vapBC operon is a widely distributed toxin-antitoxin system found in many prokaryotic organisms. This operon often overlaps with open reading frames, indicating their close relationship and co-expression. Within the vapBC operon, the toxin component is typically a PIN domain-containing protein, such as the VapC found in Mycobacterium bovis [ 2 , 29 ]. These PIN domain toxins are co-expressed with an inhibitor protein, known as the antitoxin [ 32 ]. The gene clustered under PIN domain protein families encoding genes cover virulence association protein C (VapC) encoding functional gene of M. tuberculosis H37RV strain genome. They encode a toxic PilT N-terminus (PIN) domain and antitoxin VapB . The PIN domain protein families’ toxins genes cleave RNA which inhibited co-expression of the antitoxin [ 29 , 33 ]. Other toxin encoding genes of Mycobacterium tuberculosis H37RV strain are toxins genes which clustered under mazF which are Endoribonuclease MazF toxin. The mazF genetoxin functions as rapidly disruption ribosome biogenesis. They targeting both ribosomal protein transcripts and rRNA precursors, help to inhibit cell growth [ 29 , 34 ]. 5. CONCLUSION AND RECOMMENDATION Comparative genome similarities and Average Nucleotide Identity were analysed by selection of 10% of Toxin 1 PIN domain (VAPC) and one gene sequence form the left all of the M. tuberculosis H37Rv strain toxin encoding gene sequences. The result shows that except two toxins encoding gene sequences all of M. tuberculosis H37Rv strain toxin encoding gene sequence score 0.00%OrthoANI value. This implies that; M. tuberculosis H37Rv strain toxin encoding genes were evolved independently. M. tuberculosis H37Rv strain possessed antibiotic resistance genes such as gidB, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG, and pncA. The analysis revealed that the M. tuberculosis H37RV strain possesses 59 toxin-encoding genes. Of these, 44 are clustered under the PIN domain protein families, which are associated with toxin–antitoxin systems. Additionally, M. tuberculosis H37RV contains other toxin-encoding genes such as mazF, relE, higB, and parE. The mazF gene encodes an endoribonuclease that disrupts ribosome biogenesis. The relE, higB, and parE toxin genes regulate cellular protein translation under nutritional stress conditions, control biofilm formation and the expression of type III secretion system genes, and are involved in cell elongation and the significant increase of recA and lexA gene expression, respectively. Based on the result of this finding the following core point was recommended. Make further studies to investigate the potential of disrupting of M. tuberculosis H37Rv strain antibiotics resistance genes Conduct further genetic studies to understand the regulatory mechanisms controlling M. tuberculosis H37Rv strain bacteria toxin-encoding genes The genome comparison of M. tuberculosis H37Rv strain absence of detectable similarity. This result warrants further investigation to validate the findings. Declarations Author Contribution 1. Temam Gemeda Genemo" wrote the main manuscript text, prepared figures all the figures and Reviewed the manuscript2. Hunduma Dinka " Reviewed the manuscript and advise the main manuscript wroter Data Availability "Sequence data that support the findings of this study have been deposited in the NCBI (European Nucleotide Archive) with the primary accession number NC_000962.3" References Dar, H. A. et al. Pangenome analysis of Mycobacterium tuberculosis reveals core-drug targets and screening of promising lead compounds for drug discovery. Antibiotics 9 (11), 819 (2020). Lamanna, A. C. & Karbstein, K. Nob1 binds the single-stranded cleavage site D at the 3′-end of 18S rRNA with its PIN domain. Proceedings of the National Academy of Sciences, 106(34): pp. 14259–14264. (2009). Rodríguez-Bustamante, E. et al. New Alternatives in the Fight against Tuberculosis: Possible Targets for Resistant Mycobacteria. Processes 11 (9), 2793 (2023). Enane, L. A. et al. Traversing the cascade: urgent research priorities for implementing the ‘treat all’strategy for children and adolescents living with HIV in sub-Saharan Africa. J. virus eradication . 4 , 40–46 (2018). Chiang, S. S. et al. Caring for adolescents and young adults with tuberculosis or at risk of tuberculosis: consensus statement from an international expert panel. J. Adolesc. Health . 72 (3), 323–331 (2023). Ahmed, S. H. et al. Efficacy and safety of bedaquiline and delamanid in the treatment of drug-resistant tuberculosis in adults: A systematic review and meta-analysis. Indian J. Tuberculosis . 71 (1), 79–88 (2024). Nahid, P. et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am. J. Respir. Crit Care Med. 200 (10), e93–e142 (2019). Daley, C. L. The global fight against tuberculosis. Torac. Surg. Clin. 29 (1), 19–25 (2019). Veerapandian, R. et al. 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Lee, I. et al. OrthoANI: an improved algorithm and software for calculating average nucleotide identity. Int. J. Syst. Evol. MicroBiol. 66 (2), 1100–1103 (2016). Echeverria-Valencia, G., Flores-Villalva, S. & Espitia, C. I. Virulence factors and pathogenicity of Mycobacterium Vol. 4 (InTech Rijeka, 2018). Kd, P. NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res. 35 , D61–D65 (2007). Lee, I. et al. ContEst16S: an algorithm that identifies contaminated prokaryotic genomes using 16S RNA gene sequences. Int. J. Syst. Evol. MicroBiol. 67 (6), 2053–2057 (2017). Aziz, R. K. et al. The RAST Server: rapid annotations using subsystems technology. BMC Genom. 9 , 1–15 (2008). Maglott, D. et al. Entrez Gene: gene-centered information at NCBI. Nucleic Acids Res. 33 (suppl_1), D54–D58 (2005). Delcher, A. L. et al. Improved microbial gene identification with GLIMMER. Nucleic Acids Res. 27 (23), 4636–4641 (1999). Gu, Q. et al. Bioinformatics analysis of type II toxin-antitoxin systems and regulatory functional assessment of HigBA and SS-ATA in Streptococcus suis1 (Journal of Integrative Agriculture, 2024). Tatusova, T. et al. NCBI prokaryotic genome annotation pipeline. Nucleic Acids Res. 44 (14), 6614–6624 (2016). Wang, J. et al. The conserved domain database in 2023. Nucleic Acids Res. 51 (D1), D384–D388 (2023). Grant, J. R. et al. Proksee: in-depth characterization and visualization of bacterial genomes. Nucleic Acids Res. 51 (W1), W484–W492 (2023). Starikova, E. V. et al. Phigaro: high-throughput prophage sequence annotation. Bioinformatics 36 (12), 3882–3884 (2020). DeJesus, M. A. et al. Comprehensive essentiality analysis of the Mycobacterium tuberculosis genome via saturating transposon mutagenesis. MBio 8 (1), 02133–02116. p. 10.1128/mbio (2017). Sharrock, A. et al. VapC proteins from Mycobacterium tuberculosis share ribonuclease sequence specificity but differ in regulation and toxicity. PloS one . 13 (8), e0203412 (2018). Sillo, F. et al. Comparative genomics of sibling fungal pathogenic taxa identifies adaptive evolution without divergence in pathogenicity genes or genomic structure. Genome Biol. Evol. 7 (12), 3190–3206 (2015). Lagutkin, D. et al. Genome-Wide study of drug resistant Mycobacterium tuberculosis and its intra-host evolution during treatment. Microorganisms 10 (7), 1440 (2022). Kane, J. F. & Hartley, D. L. Formation of recombinant protein inclusion bodies in Escherichia coli. Trends Biotechnol. 6 (5), 95–101 (1988). Cooper, H. & Patall, E. A. The relative benefits of meta-analysis conducted with individual participant data versus aggregated data. Psychol. Methods . 14 (2), 165 (2009). Ardissone, S. & Greub, G. The Chlamydia-related Waddlia chondrophila encodes functional type II toxin-antitoxin systems. Appl. Environ. Microbiol. 90 (2), e00681–e00623 (2024). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5966480","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":414735445,"identity":"a56e3f59-681c-4b05-94bd-2dd6d60919ca","order_by":0,"name":"Temam Gemeda 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14:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5966480/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5966480/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":76294011,"identity":"3c5bd2c5-71f0-4034-93b0-e80414037737","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":171939,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eM. tuberculosis \u003c/em\u003eH37Rv strain 16S rRNA genome annotation based on RAST server.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/eb172a02d5b7cd66b9a4899e.png"},{"id":76295474,"identity":"4f6e66e2-9e11-472e-a289-99ce9e5d2975","added_by":"auto","created_at":"2025-02-14 13:08:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61190,"visible":true,"origin":"","legend":"\u003cp\u003eAverage Nucleotide Identity among gene sequences encoding YoeB toxin protein and Death on curing protein, Doc toxin \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/5b252c73c36249c990d5c28e.png"},{"id":76294014,"identity":"9e19dcef-e8d6-42e7-8e53-be58b1c5c4de","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83499,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap with values and unweighted pair group method with arithmetic mean (UPGMA) trees between ten gene sequences encoding toxin of \u003cem\u003eM. tuberculosis H37Rv strain\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/d546dcc920826a63ec94b2b8.png"},{"id":76294013,"identity":"3d6c3e81-b10c-400e-b345-889d02546c7a","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":317264,"visible":true,"origin":"","legend":"\u003cp\u003eGraphic circular genome mapping determination of open reading frame, clustered regularly interspaced short palindromic repeats (CRISPR)\u003cstrong\u003e-\u003c/strong\u003e\u003cem\u003eCas\u003c/em\u003e (CRISPR-associated proteins) and Comprehensive Antibiotic Resistance gene\u003cem\u003e M.tuberculosis\u003c/em\u003eH37RV strains (Mtb/Mbtb;- \u003cem\u003eM. tuberculosis)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/21e67cae3988fbecd39c0fac.png"},{"id":76294016,"identity":"c803525c-7c91-4cbc-a4c3-68158242e2c2","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":258416,"visible":true,"origin":"","legend":"\u003cp\u003eThe CDS, tRNA, rRNA, tmRNA and repeat region of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strains determined by graphic circular genome mapping gene annotation\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/99fdcab75137f2ef6be886e7.png"},{"id":76294021,"identity":"73662923-76bc-429d-8c0c-539861c955f8","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":141002,"visible":true,"origin":"","legend":"\u003cp\u003eGraphic circular genome mapping of \u003cem\u003eMycobacterium tuberculosis \u003c/em\u003eH37RV Mobile Genetic Elements and GC and GC Skew Content View explored through Phigaro and Sequence Composition determine using CGView online server.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/3137eee442722172c5174d0b.png"},{"id":76294020,"identity":"9ca8cf55-256b-4275-8b15-8507f808a267","added_by":"auto","created_at":"2025-02-14 12:52:33","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":96124,"visible":true,"origin":"","legend":"\u003cp\u003eConserved domain sequence similarities at active center of structure-specific VapC PIN-domain proteins families of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain with 10 selected most diverse bacterial species.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/82663ce14ac03e07c7de7a7f.png"},{"id":84949611,"identity":"747aac84-0b13-4ed4-a2b8-2a90f66c7bfa","added_by":"auto","created_at":"2025-06-19 06:53:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2246451,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5966480/v1/979f7e4c-3037-4737-9bf1-20e3ca67bc2a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prediction of genes encoding toxin of Mycobacterium tuberculosis H37RV strain","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1. Background and Justification of the Study\u003c/h2\u003e \u003cp\u003eTuberculosis (TB) is a multisystem airborne infectious disease that causes high mortality rate worldwide. This infectious disease is caused by the bacterium called \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (\u003cem\u003eM. tuberculosis\u003c/em\u003e) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Usually tuberculosis disease affects the lungs, and also it may affect brain, kidneys or spine. According to World Health Organisation (WHO), Tuberculosis is still a leading killer (nearly 2\u0026nbsp;million die annually) of young adults worldwide. TB remains a significant global health challenge; disproportionately affecting adolescents and young adults (AYAs) aged 10\u0026ndash;24 years. Each year, an estimated 1.8\u0026nbsp;million AYAs contract TB, accounting for approximately 18% of the annual global TB incidence[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite being preventable and treatable, TB is a leading cause of death among this age group. In 2019, the WHO estimated that 71,000 adolescents (11,000 aged 10\u0026ndash;14 years and 60,000 aged 15\u0026ndash;19 years) and 90,000 young adults died from TB. The risk of Mycobacterium tuberculosis infection and progression to active TB disease increases during this phase of life [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The risk of TB progression is exacerbated by HIV infection, which is a substantial concern in this age group. In 2021, around 28% of new global HIV infections occurred in individuals aged 15\u0026ndash;24 years, and AYAs with HIV experience poorer outcomes along the HIV care cascade compared to other age groups [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAdolescents and young adults with TB who are living with HIV, in conditions of extreme poverty and/or violence, and/or have been previously treated for TB disease are at greater risk of poor adherence to TB treatment and loss to follow-up. During the critical developmental period of 10\u0026ndash;24 years, individuals undergo rapid physical, cognitive, emotional, and social changes, as they acquire the resources needed for health and well-being in adulthood, and become more autonomous. The WHO and other institutions have emphasized the need for healthcare services and research to address the specific needs of Adolescents and young adults [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, most national TB programs (NTPs) do not currently account for Adolescents and young adults -specific considerations and requirements in their policies and practices [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTuberculosis severity and prevalence is very high in patients co-infected with the human immunodeficiency virus (HIV). Weakness, weight loss, fever, night sweats, coughing, difficulties for breathing, chest pain and coughing up of the blood were some of the most common symptoms of tuberculosis disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cough, weight loss/anorexia, fever, night sweats, hemoptysis, chest pain (also can result from tuberculous and fatigue) is classic clinical features that are associated with active pulmonary TB[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Sometime these symptoms are not displayed typical in elderly individuals. The sign and symptoms of tuberculosis disease are dependent on body parts where the disease-causing bacteria are growing [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAn early diagnosis is an essential point for the control of tuberculosis disease. Traditionally tuberculosis is diagnosed through microbiological infection culture and direct microscopic examination (smear microscopy). Culture and smear microscopy method of microbiological tuberculosis infection diagnose is requiring up to 6\u0026ndash;8 weeks. Therefore, identification of \u003cem\u003eM. tuberculosis\u003c/em\u003e by molecular method is very necessary [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. \u003cem\u003eM. tuberculosis\u003c/em\u003e is identified through molecular methods by amplification of nucleic acids, direct DNA sequencing analysis, automated molecular testing, microscopic-observation drug susceptibility (MODS) and thin-layer agar (TLA) assays. Molecular based identification of \u003cem\u003eM. tuberculosis\u003c/em\u003e sample from grown-up cultures for the identification of the species and detection of genetic mutations related with the resistance to main antibiotics [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment of Tuberculosis needs several appropriate different antibiotic drugs that are given at least for 6 months to 12 months [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Partial or inconsistent treatment of tuberculosis leads to the development of drug resistant bacilli, known as multidrug-resistant TB (MDR-TB), which fails to respond to standard first-line drugs and becomes difficult and more expensive to treat [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Tuberculosis caused by \u003cem\u003eM. tuberculosis\u003c/em\u003e is prevented by administration of BCG vaccine. Currently, \u003cem\u003eM. tuberculosis\u003c/em\u003e develops resistant strain for BCG vaccine and millions of world population were hospitalized due to tuberculosis disease. To overcome this problems researcher were advising possibilities for TB vaccine improvement. The key possibilities for TB vaccine improvement are insertion of immunogenic gene into the genome of BCG to enhance immunogenicity (eg: RD1), attenuation of \u003cem\u003eM. tuberculosis\u003c/em\u003e through the deletion of a virulent gene and subunit or recombinant vaccines development [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Key possibilities for these TB vaccine improvement methods highly depend on \u003cem\u003eM. tuberculosis\u003c/em\u003e genome annotation and analysis of gene encoding virulent factors (toxin genes) and protein associated with this virulent factor\u0026rsquo;s gene[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe molecular analysis of identifying genes and proteins encoding virulence factors in \u003cem\u003eM. tuberculosis\u003c/em\u003e typically involves a multi-step process combining genomic analysis, bioinformatics, and experimental validation. While 16S rRNA sequences are not directly used to identify virulence factors, the whole genome sequence of the bacterium can be analyzed to predict potential virulence factors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Bacterial infections often involve virulence factors that play a crucial role in the pathogenicity of the bacteria. Virulence factors are gene molecules produced by pathogens that contribute to their ability to cause disease. Accurate detection and characterization of virulence factor genes (VFGs) is essential for precise treatment and prognostic management of hypervirulent bacterial infections. Identifying the specific virulence factors and their genetic basis allows clinicians to better understand the mechanisms by which a pathogen causes disease. This knowledge can inform the development of targeted therapies, vaccination strategies, and infection control measures. Early and reliable detection of VFGs is particularly important for severe or difficult-to-treat infections, as it enables clinicians to select the most appropriate antimicrobial interventions[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eFurthermore, analyzing the VFGs of a bacterial strain can provide insights into its evolutionary adaptations and potential for causing outbreaks or epidemics. By mapping the virulence gene profiles of different bacterial isolates, researchers can track the emergence and spread of hypervirulent strains, supporting public health efforts to monitor and contain infectious disease threats [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain infection induces a more severe inflammatory immune response associated with tissue damage. For this study \u003cem\u003eM. tuberculosis\u003c/em\u003e strain H37RV was selected as it has been used extensively worldwide in biomedical research. Unlike some clinical isolates, it retains full virulence in animal models of tuberculosis and is susceptible to drugs and receptive to genetic manipulation[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. \u003cem\u003eM. tuberculosis\u003c/em\u003e employs a range of virulence factors to establish infection and evade the host immune system. One of the most notable virulence factors to establish by bacterium is toxins [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the aim of this work was to predict genes encoding toxin for \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Objective\u003c/h2\u003e \u003cp\u003e \u003cb\u003eGeneral objective\u003c/b\u003e \u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTo predict genes encoding virulence factors for \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e \u003cb\u003eSpecific objectives\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe specific objectives of the analysis are: -\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTo predict 16sRNA and compare genomes of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strains\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo identify \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo determine \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain genes encoding toxin\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo determine protein sequence for the predicted respective virulence encoding gene for \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"2. METHODS","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Prediction of16sRNA for \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strains and comparative genomes\u003c/h2\u003e \u003cp\u003ePrediction of 16sRNA for \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain was done by obtaining the sequences of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain from NCBI by using accession number NC_000962.3. The method named ContEst16S (Contamination Estimator by 16S), in which 16S rRNA gene fragments from the query genome assemblies was used to screen contaminated and the normal genome downloaded. The standard software tools are freely available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ezbiocloud.net/sw/oat\u003c/span\u003e\u003cspan address=\"http://www.ezbiocloud.net/sw/oat\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The predicted functional gene of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain 16sRNA with base length was analysed by the Rapid Annotation Search Tool (RAST) the SEED Viewer a read only browser of the curated SEED data [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe Comparative genome study were analysed to determine genome sequence similarities between selected toxin encoding gene sequences of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain. In addition, comparative genome studies were also analysed by Orthologous Average Nucleotide Identity Tool (OAT) and CLC Genome Workbenchs (QIAGEN CLC Genomics Workbench 24.0). OAT software used OrthoANI to measure the overall similarity between genome sequences. This software measure similarity between maximum of ten genome sequences [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].Comparative genome similarities and Average Nucleotide Identity were analysed by selection of 10 gene sequences encoding toxin of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain. OAT software that uses OrthoANI to measure overall similarity between two genome sequences were used to analysis Comparative genome similarities and Average Nucleotide Identity. Comparative genome similarities of selected genome sequences were calculated using Ortho ANI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain contains VapC Toxin 1 PIN domain, Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain. Comparative genome similarities and Average Nucleotide Identity were analysed by selection of 10% of VapC Toxin 1 PIN domain and one gene sequence form all other toxin encoding gene sequences (Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain) of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain. The result was determined by Heatmap with values and un-weighted pair group method with arithmetic mean (UPGMA) trees. Comprehensive EzBioCloud bioinformatics platform, the software tools which freely available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www\u003c/span\u003e\u003cspan address=\"http://www\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. ezbio cloud. net/ sw/ oat, was used to Calculating Average Nucleotide Identity. Average Nucleotide Identity calculation involves the fragmentation of genome sequences, followed by nucleotide sequence search, alignment and identity calculating software, OAT[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Sequence data that support the findings of this study have been deposited in the NCBI (European Nucleotide Archive) with the primary accession number NC_000962.3\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Identifying of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping\u003c/h2\u003e \u003cp\u003eTo identify specific genes from data, the computational tools; BLAST specialized genomic analysis software to compare sequences against databases of known genes or protein families was used [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The identification of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e H37RV strain Mobile Genetic Elements was proceed by using of specialized genomic analysis softwareCGview.ca that available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/cgview_server/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/cgview_server/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This specialized genomic analysis software identifies Mobile Genetic Elements of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RV strain by comparing the sequences of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RV strain against databases of known genes or protein families[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Circular genome mapping for complete 16S rRNA of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RV strains was obtained using CGView server available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e cgview. The prediction of genes was proceeded by the Velvet assembled contigs using Glimmer software[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This online software is freely available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ccb.jhu.edu/software/glimmer/\u003c/span\u003e\u003cspan address=\"https://ccb.jhu.edu/software/glimmer/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. The predicted genes were annotated using in-house pipeline RAST server available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://rast.theseed.org/FIG/rast.cgi/.Circular\u003c/span\u003e\u003cspan address=\"http://rast.theseed.org/FIG/rast.cgi/.Circular\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e genome mapping for complete 16S rRNA of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strains was analysed by using CGView online serveravailable via \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/cgviewserver/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/cgviewserver/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The Mobile Genetic Elements and Sequence Composition of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RVstrains complete genomes was analyzed by using CGView online server explored through Phigaro a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe composition of GC Content and GC Skew was determined by Sequence Composition detection software available via \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e cgview server and GC content plots generating formula [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The Comprehensive Antibiotic Resistance Database (CARD) Resistance Gene Identifier (RGI), CRISPR arrays and their associated Cas proteins finder and Open Reading Frames (ORFs) of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain Annotate by Prokka; the genome sequence annotate and identify coding sequences special bioinformatics tools available at CGView server package online software[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Antibiotic Resistance gene (CARD) of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strains was retrieved from online CARD data base available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e cgview server. The Mobile Genetic Elements View explored through Phigaro a standalone command-line application that is able to detect prophage regions taking raw genome and metagenome assemblies as an input [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The sequence composition determines GC Content and GC Skew of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RVstrains through CGview.ca that available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://stothard.afns.ualberta.ca/\u003c/span\u003e\u003cspan address=\"http://stothard.afns.ualberta.ca/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e cgview_ server/ [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The GC content plots are generated by calculating the GC content for each sliding window using the formula:\u003c/p\u003e \u003cp\u003e \u003cspan class=\"InlineEquation\"\u003e \u003cspan class=\"mathinline\"\u003e\\(\\:\\text{G}\\text{C}\\:\\text{c}\\text{o}\\text{n}\\text{t}\\text{e}\\text{n}\\text{t}\\:=\\:\\:\\frac{G+C}{Window\\:Size}\\)\u003c/span\u003e \u003c/span\u003e= values between 0 and 1 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe window moves by the step size, and the calculation repeats\u003c/p\u003e \u003cp\u003eWindow size (bp)\u0026thinsp;=\u0026thinsp;Auto (1000)\u003c/p\u003e \u003cp\u003eThe GC skew is generated through the formula:\u003c/p\u003e \u003cp\u003e \u003cspan class=\"InlineEquation\"\u003e \u003cspan class=\"mathinline\"\u003e\\(\\:\\text{G}\\text{C}\\:\\text{s}\\text{k}\\text{e}\\text{w}\\:=\\:\\:\\frac{G-C}{\\:G+C}\\)\u003c/span\u003e \u003c/span\u003e= values between \u0026minus;\u0026thinsp;1 and 1 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]).\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThis size of the sliding window (number of nucleotides) used for each calculation Step size\u0026thinsp;=\u0026thinsp;Auto (1000).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe number of nucleotides to move the window after each calculation\u0026thinsp;=\u0026thinsp;Auto (100) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Determining \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain genes encoding virulence factors\u003c/h2\u003e \u003cp\u003eThe gene sequences for virulence factor encoding gene of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain was analysed by retrieving, on May 05/2024, of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain sequence from NCBI. The contamination in 16S rRNA gene fragments from the query genome assemblies was checked by method named ContEst16S available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ezbiocloud.net/\u003c/span\u003e\u003cspan address=\"http://www.ezbiocloud.net/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003esw\u003c/span\u003e. The normal sequence fragment was downloaded on May 05 2024 and annotated by Rapid Annotation using Subsystem Technology (RAST) annotation (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://rast.nmpdr.org/\u003c/span\u003e\u003cspan address=\"https://rast.nmpdr.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain toxin genes were retrieved by Re-annotation of the genome sequence of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain complete genome sequence through search of respective toxin genes by using contig Id [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] from NCI data base from \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/prokaryotic\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/prokaryotic\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e genome annotation pipeline. The software is freely available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/NC\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/NC\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. The Gene name, Gene length, Gene Identifier and chromosomal location of gene encoding toxin genes in \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain was retrieved from online website database called TubercuList website, NCBI database which Release 26, Dec 2012. This genome database is freely available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://tuberculist.epfl.ch/\u003c/span\u003e\u003cspan address=\"http://tuberculist.epfl.ch/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Determination of protein for respective virulence factor encoding genes of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RV strain\u003c/h2\u003e \u003cp\u003eDetermination of protein for respective virulence factor encoding genes of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003eH37RV strain was analysed through the approaches of genome Annotation and genome Assemble. The genome sequence was annotated by using rapid annotations subsystems technology [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The gene encoding virulence associated proteins was detected to determine virulence associated proteins and protein for respective virulence factor encoding genes was determination by RAST quality report [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Prediction of 16sRNA for \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain complete genome sequence.\u003c/h2\u003e \u003cp\u003eThe result of 16s rRNA predicted for \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain is presented in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 47 16s rRNA were predicted with variable number of contig features.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredicted 16s rRNA of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rvstrain complete genome sequence\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContig feature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSplitting statistics\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequence size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,411,532\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of 16s RNAs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of contigs (with PEGs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGC content (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of Subsystems\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of Coding Sequences\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4259\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of the smallest contig (L50 value)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe complete genome of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strains analysed by CLC Genome Workbench (QIAGEN CLC Genomics Workbench 24.0) shows a total 15042 open reading frame (ORF) sequences of which 3,995 ORF are with TTG start codon, 4,428 ORF with ATG start codon and 6,619 ORF with CTG start codon.\u003c/p\u003e \u003cp\u003eFurther analysis of the predicted 16S rRNA of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strains for their genome annotation at subsytem and non-subsystem category distribution was conducted by RAST software server (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://rast.nmpdr.org/seedviewer.cgi)an\u003c/span\u003e\u003cspan address=\"https://rast.nmpdr.org/seedviewer.cgi)an\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ed depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, subsystem coverage (bar chart) and non-subsystem coverage were found to be 23 and77%, respectively. It was predicted that there is a total coverage of 955 subsystems and 3304 non-subsystems for \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain. In subsystem coverage, the hypothetical and non-hypothetical gene sizes are 83 and 82, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The percentage distribution of subsystem features was depicted in graphical representation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The highest percentage of subsystem features was detected for amino acids and derivatives and followed by carbohydrate metabolic features. However, the lowest percentage was detected for Secondary Metabolism subsystem feature (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec)\u003c/p\u003e \u003cp\u003eComparative genome similarities and Average Nucleotide Identity of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain toxin encoding gene sequences were analysed by selection of 10 toxin encoding gene sequences. \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain contains 59 genes sequences that encoding toxin. Out of these 44 (74%) genes sequences were encoding toxin VapC Toxin 1, PIN domain genes and the left 26% includes Doc toxin domain, ParE toxin domain, HigB toxin domain, MazF toxin domain, YdcE and YoeB toxin domain.\u003c/p\u003e \u003cp\u003eThe results of Orthologous Average Nucleotide Identity analyses of 10 gene sequences encoding toxin of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain(comparative genome analysis) showed that the gene sequences encoding YoeB toxin protein and Death on curing protein, Doc toxin show an OrthoANI value of 100% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This shows that; the gene sequence encoding YoeB toxin protein and Death on curing protein Doc toxin encoding gene sequences of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain have sequence with identical distribution. This implied that; the two toxin encoding genes sequences were highly convergent.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe results also show that; except gene encoding YoeB toxin protein and Death on curing protein, Doc toxin, all toxin encoding genes show an OrthoANI value of 0.00% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This indicates no detectable genetic similarity between any of the selected toxin encoding genes sequences of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain. This absence of detectable similarity could imply that; VapC at Toxin 1 PIN domain, ParE toxin domain, HigB toxin domain, MazF toxin domain and YdcE toxin domains are highly divergent or evolved independently. Orthologous Average Nucleotide Identity (OrthoANI) is a method used to measure the genetic similarity between two genomic sequences. It is commonly used in genomics to determine the relatedness of bacterial strains.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Identifying of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e H37RV strain Mobile Genetic Elements, Resistance genes and Genome mapping\u003c/h2\u003e \u003cp\u003eThe Comprehensive Antibiotic Resistance Database (CARD) Resistance Gene Identifier(RGI), CRISPR arrays and their associated Cas proteins finder and Open Reading Frames (ORFs) of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain Annotate by Prokka; the genome sequence annotate and identify coding sequences special bioinformatics tools available at CGView server package online software and determined as state in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Antibiotic Resistance gene (CARD) of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strains analysis results revealed that \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strains poses \u003cem\u003egidB\u003c/em\u003e, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG and pncA antibiotic resistance genes of which inhA, embB, katG and pncA were specific to \u003cem\u003eM. tuberculosis.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe coding sequence(CDS), Transfer ribonucleic acid (tRNA), Ribosomal ribonucleic acid (rRNA), Transfer-messenger ribonucleic acid (tmRNA) a bacterial RNA molecule with dual tRNA-like and messenger RNA-like properties and repeat region of \u003cem\u003eM.tuberculosis\u003c/em\u003eH37RV strains was determined and presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe Mobile Genetic Elements and Sequence Composition of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strains complete genomes was obtained using CG View online server and determined in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.The result show that; \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strains contains radA, recA, uvrA, uvrB, exoA_2 and mobC and int mobile genetic element with replication/recombination/repair (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e olive colour), transfer (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e navy blue colour) and integration/excision (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e lime colour) function respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Determination of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain genes encoding virulence factors\u003c/h2\u003e \u003cp\u003eToxin encoding genes for\u003cem\u003eM.tuberculosis\u003c/em\u003eH37RV strain; the Gene name, Gene length, Gene Identifier and chromosomal location were determined and the results were presented in table forms (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The result of this analysis revealed that \u003cem\u003eM.tuberculosis\u003c/em\u003eH37RV strain possesses 59 toxin encoding genes sequence. From this 44 of them clustered under PIN domain protein families encoding gene which associated toxic components toxin\u0026ndash;antitoxin systems. The gene clustered under PIN domain protein families encoding genes cover virulence association protein C (VapC) encoding functional gene of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain genome. They encode a toxic PilT N-terminus (PIN) domain and antitoxin \u003cem\u003eVapB\u003c/em\u003e. The \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e H37RV strain also contains toxins genes such as relE toxn genes, higB toxin genes, and pares toxin genes. The virulent bacterial species contain the groups of toxin encoding genes including relE, higB, and parE which function as regulation of cellular protein translation under nutritional stress conditions, Controls Biofilm Formation and the Expression of Type III Secretion System Genes, and cell elongation and significantly increased recA and lexA gene expression respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rvstrain toxin encoding Gene annotation summary information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGene length\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIdentifier\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGene annotation Link\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e402 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71821 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0065\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0065\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e408 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0582\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e677922 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0582\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0582\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e438 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e289345 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0240\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0240\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e429 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0277c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e332708 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0277c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0277c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e426 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e364044 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0301\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0301\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emazF1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e282 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0456A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e547076 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0456A\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0456A\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e414 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0549c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e640228 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0549c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0549c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e393 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0595c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e694839 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan 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align=\"left\" colname=\"c2\"\u003e \u003cp\u003e402 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0617\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e711006 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv0617\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv0617\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e396 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv0624\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" 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align=\"left\" colname=\"c2\"\u003e \u003cp\u003e432 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv1242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1384535 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv1242\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv1242\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erelE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e294 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv1246c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" 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colname=\"c4\"\u003e \u003cp\u003e2868860 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2548\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2548\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e396 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv2549c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2869727 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan 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colname=\"c4\"\u003e \u003cp\u003e3070875 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2759c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2759c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emazF9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e357 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv2801c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3110167 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2801c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2801c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e393 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv2829c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3136620 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2829c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2829c\" targettype=\"URL\" 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align=\"left\" colname=\"c2\"\u003e \u003cp\u003e264 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv2866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3177822 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2866\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2866\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e444 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv2872\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3183382 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv2872\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv2872\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e429 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv3320c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3707642 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv3320c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv3320c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erelK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e258 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv3358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3771045 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv3358\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv3358\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e393 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv3384c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3799243 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv3384c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv3384c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e411 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv3408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3826548 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv3408\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv3408\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003evapC48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e438 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRv3697c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4139805 bp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mycobrowser.epfl.ch/genes/Rv3697c\u003c/span\u003e\u003cspan address=\"https://mycobrowser.epfl.ch/genes/Rv3697c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Determination of protein for respective virulence factor encoding genes of \u003cem\u003eM. tuberculosis\u003c/em\u003e\u003c/h2\u003e \u003cp\u003eThe RAST quality report genome annotation showed that; \u003cem\u003eM.tuberculosis\u003c/em\u003eH37RV strain contains 59 virulence associated proteins. These were protein encoded by these virulent genes were clustered in to Toxin 1PIN domain families proteins encoding genes, Endoribonuclease toxin MazF proteins encoding genes, rel family toxin proteins encoding genes, higB families toxin proteins encoding genes and parE families toxin proteins encoding genes. The PIN (PilT N terminus) domain is a protein domain that is found in a variety of proteins, including those involved in virulence and toxin-antitoxin systems in bacteria and archaea. The PIN domain belongs to a large nuclease super family and has a characteristic active center consisting of three highly conserved catalytic residues that coordinate metal ions. Within \u003cem\u003eM. tuberculosis\u003c/em\u003e CDC1551, the VapC-like PIN domain is found in proteins such as the Virulence associated protein C (VapC) and the hypothetical protein MT3492. These toxins are typically co-expressed with an antitoxin protein, which forms an inert complex and neutralizes the toxic effects of the PIN domain-containing toxin.\u003c/p\u003e \u003cp\u003eThe VapBC toxin-antitoxin, where VapB is inhibitor and VapC, is PIN-domain ribonuclease toxin operons encoded in \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain genome. PIN-domain protein is a protein domain which functions as a toxin that can inhibit cell growth or viability by cleavage of the cellular RNA. They have ribonucleases biochemical properties. TheVapC PIN-domain Toxin 1 proteins of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain has 44 virulence associated proteins such as; VapC1protein, Toxin 1protein, toxin VapC24protein,toxin VapC25 protein, toxin vapC2 protein, toxin VapC3 protein, toxin VapC26 protein, toxin VapC27 protein, toxin VapC28 protein, toxin VapC29 protein, toxin VapC30 protein, toxin VapC7 protein, Toxin protein, toxin VapC31 protein, toxin VapC9 protein, Toxin VapC32 protein, toxin VapC10 protein, toxin VapC11 protein, toxin VapC12 protein, toxin VapC34 protein, toxin VapC13 protein, toxin VapC14 protein, Toxin HigB protein, toxin VapC35 protein, toxin VapC36 protein, toxin VapC15 protein, Toxin HigB protein, toxin VapC37 protein, toxin VapC38 protein, toxin VapC39 protein, toxin VapC18 protein, toxin VapC19 protein, toxin VapC20 protein, toxin VapC40 protein, toxin VapC41 protein, VapC21 antibacterial toxin protein, toxin VapC42 protein, toxin VapC22 protein, toxin VapC43 protein, Toxin HigB protein, toxin VapC44 protein, toxin VapC46 protein, toxin VapC47 protein and toxin VapC48 protein. These toxin proteins exist with equal antitoxin proteins. So that the VapC found in \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strains determined as VapBC operon possess toxin-antitoxin system.\u003c/p\u003e \u003cp\u003eThe sequence similarity of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain in Conserved Protein Domain PIN-domain proteins Family of most diverse 10 bacteria species were detected by online server \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/Structure/lexington/files/banner.pngconserved\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/Structure/lexington/files/banner.pngconserved\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e domain architecture retrieval tool and the sequence similarity were determined Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. The result show that \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain VapC proteins share sequence similarities at active center of structure-specific of Conserved Protein Domain PIN-domain Family proteins with all of the selected most diverse 10 bacteria species\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eThe 16s RNA \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain complete genome sequence was predicted. It was found that \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain complete genome sequence has 47 16s RNA molecules. Comparative genome similarities were calculated using Ortho ANI and similar closely related species show high comparative genome similarities percentage [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The ten toxin encoding genes sequence of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e H37Rv strain were selected and the heatmap results show that; except gene encoding YoeB toxin protein and Death on curing protein, Doc toxin, all toxin encoding genes show an OrthoANI value of 0.00%. This indicates that; there are no detectable similarities between selected sequences of \u003cem\u003eM.tuberculosis\u003c/em\u003e H37Rvstrain. This implies that; the toxin domains are highly divergent or evolved independently. Orthologous Average Nucleotide Identity (OAT) was used to analysis genome comparative to measure Average Nucleotide Identity and similarity between genomic sequences and calculate OrthoANI values between genomes of interest with the results from 0.00\u0026ndash;100% [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].Comparative genome similarities and Average Nucleotide Identity possess less OrthoANI values were considered as highly divergent genome sequences [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].The gene encoding YoeB toxin protein and Death on curing protein, Doc toxins shows 100% OrthoANI values. According to [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] the same species demarcation cut-off at 95\u0026thinsp;~\u0026thinsp;96% and large comparison studies have demonstrated both algorithms produce near identical reciprocal similarities.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain possesses 59 toxin encoding genes. These genes were associated with toxic protein of PIN domain protein families, relE, higB, parE1and mazF proteins families. Predicting coding region of complete genome of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain was proceeded through proker.\u003c/p\u003e \u003cp\u003eA \u003cem\u003eM. tuberculosis H37RV strain poses gidB\u003c/em\u003e, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG and pncA antibiotic resistance genes. From this antibiotic resistance genes (inhA, embB, katG and pncA) were specific to \u003cem\u003eM. tuberculosis.\u003c/em\u003e This agrees with the report of [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] where Antibiotic Resistance genes \u003cem\u003esuch as gidB\u003c/em\u003e, gyrA, gyrB, rpoB, rpsL and rrs were associated with not only with \u003cem\u003eM. tuberculosis\u003c/em\u003e but also in ESKAPE and other bacterial pathogens. Toxin-antitoxin (TA) systems are widely distributed across prokaryotic organisms, and many species possess multiple copies of these systems within their genomes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The present analysis result showed that the vapBCproteins of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain corporates as toxin- antitoxin sytem. The vapBC operon is a widely distributed toxin-antitoxin system found in many prokaryotic organisms. This operon often overlaps with open reading frames, indicating their close relationship and co-expression. Within the vapBC operon, the toxin component is typically a PIN domain-containing protein, such as the VapC found in \u003cem\u003eMycobacterium bovis\u003c/em\u003e [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. These PIN domain toxins are co-expressed with an inhibitor protein, known as the antitoxin [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The gene clustered under PIN domain protein families encoding genes cover virulence association protein C (VapC) encoding functional gene of \u003cem\u003eM. tuberculosis\u003c/em\u003eH37RV strain genome. They encode a toxic PilT N-terminus (PIN) domain and antitoxin \u003cem\u003eVapB\u003c/em\u003e. The PIN domain protein families\u0026rsquo; toxins genes cleave RNA which inhibited co-expression of the antitoxin [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Other toxin encoding genes of \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e H37RV strain are toxins genes which clustered under mazF which are Endoribonuclease \u003cem\u003eMazF\u003c/em\u003e toxin. The mazF genetoxin functions as rapidly disruption ribosome biogenesis. They targeting both ribosomal protein transcripts and rRNA precursors, help to inhibit cell growth [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e"},{"header":"5. CONCLUSION AND RECOMMENDATION","content":"\u003cp\u003eComparative genome similarities and Average Nucleotide Identity were analysed by selection of 10% of Toxin 1 PIN domain (VAPC) and one gene sequence form the left all of the \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain toxin encoding gene sequences. The result shows that except two toxins encoding gene sequences all of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain toxin encoding gene sequence score 0.00%OrthoANI value. This implies that; \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain toxin encoding genes were evolved independently. \u003cem\u003eM. tuberculosis\u003c/em\u003eH37Rv strain possessed antibiotic resistance genes such as gidB, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG, and pncA. The analysis revealed that the \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV strain possesses 59 toxin-encoding genes. Of these, 44 are clustered under the PIN domain protein families, which are associated with toxin\u0026ndash;antitoxin systems. Additionally, \u003cem\u003eM. tuberculosis\u003c/em\u003e H37RV contains other toxin-encoding genes such as mazF, relE, higB, and parE. The mazF gene encodes an endoribonuclease that disrupts ribosome biogenesis. The relE, higB, and parE toxin genes regulate cellular protein translation under nutritional stress conditions, control biofilm formation and the expression of type III secretion system genes, and are involved in cell elongation and the significant increase of recA and lexA gene expression, respectively. Based on the result of this finding the following core point was recommended.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMake further studies to investigate the potential of disrupting of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain antibiotics resistance genes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eConduct further genetic studies to understand the regulatory mechanisms controlling \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain bacteria toxin-encoding genes\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe genome comparison of \u003cem\u003eM. tuberculosis\u003c/em\u003e H37Rv strain absence of detectable similarity. This result warrants further investigation to validate the findings.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e1. Temam Gemeda Genemo\" wrote the main manuscript text, prepared figures all the figures and Reviewed the manuscript2. Hunduma Dinka \" Reviewed the manuscript and advise the main manuscript wroter\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003e\"Sequence data that support the findings of this study have been deposited in the NCBI (European Nucleotide Archive) with the primary accession number NC_000962.3\"\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDar, H. A. et al. Pangenome analysis of Mycobacterium tuberculosis reveals core-drug targets and screening of promising lead compounds for drug discovery. \u003cem\u003eAntibiotics\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e (11), 819 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLamanna, A. 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Microbiol.\u003c/em\u003e \u003cb\u003e90\u003c/b\u003e (2), e00681\u0026ndash;e00623 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"katG gene, M. tuberculosis H37Rv strain, Toxin, VapBC toxin-antitoxin","lastPublishedDoi":"10.21203/rs.3.rs-5966480/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5966480/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, primarily affects the lungs but can spread to other organs. It is a major global health issue, leading to nearly 2\u0026nbsp;million deaths annually. Early diagnosis is vital for effective treatment, yet traditional methods like culture and smear microscopy can take 6\u0026ndash;8 weeks. This highlights the need for molecular diagnostics that can rapidly detect TB DNA. Therefore, the present study aims to predict genes encoding toxins in the \u003cem\u003eM.tuberculosis\u003c/em\u003e strain H37Rv, widely used in tuberculosis research. For this purpose, a total of one whole genome sequence of M. tuberculosis strain H37Rv was retrieved from NCBI, and the 16s RNA, MGE, resistance genes, toxin-encoding genes, and proteins associated with the toxin genes were analyzed using; NCBI, ContEst16S, Rapid Annotation Search Tool (RAST), Rapid Annotation using Subsystem Technology (RAST) quality report and TubercuList website. This finding identified 47 16S rRNA genes and 59 toxin-encoding genes associated with various toxin proteins. We assessed genome similarities and Average Nucleotide Identity (ANI) among toxin genes. Notably, except for two toxin genes, all other sequences showed a 0.00% OrthoANI value. Additionally, antibiotic resistance genes identified include gidB, gyrA, gyrB, rpoB, rpsL, rrs, inhA, embB, katG, and pncA, with the latter four being specific to M. tuberculosis. The results of this study also revealed homologs of VapC toxins in M.tuberculosis, linked to VapBC toxin-antitoxin systems. These findings lay the groundwork for future research on toxin-encoding genes and antibiotic resistance in M.tuberculosis H37Rv.\u003c/p\u003e","manuscriptTitle":"Prediction of genes encoding toxin of Mycobacterium tuberculosis H37RV strain","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-14 12:52:28","doi":"10.21203/rs.3.rs-5966480/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f2d2c84b-a9c9-4613-8f06-d0370e1388b4","owner":[],"postedDate":"February 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44225434,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":44225435,"name":"Biological sciences/Molecular biology"}],"tags":[],"updatedAt":"2025-06-19T06:53:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-14 12:52:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5966480","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5966480","identity":"rs-5966480","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}