scholarly journals An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Victoria Furió ◽  
Miguel Moreno-Molina ◽  
Álvaro Chiner-Oms ◽  
Luis M. Villamayor ◽  
Manuela Torres-Puente ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Large Scale ◽  
Resistance Mechanism ◽  
Clinical Strain ◽  
Resistance Mutations ◽  
Isoniazid Resistance ◽  
Resistance Determinants ◽  
Main Target ◽  
New Antibiotics ◽  
Candidate Regions

AbstractEfforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.

scholarly journals An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis

2020 ◽  
Author(s):  
Victoria Furió ◽  
Miguel Moreno-Molina ◽  
Álvaro Chiner-Oms ◽  
Luis M Villamayor ◽  
Manuela Torres-Puente ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Large Scale ◽  
Resistance Mechanism ◽  
Clinical Strain ◽  
Resistance Mutations ◽  
Isoniazid Resistance ◽  
Resistance Determinants ◽  
Main Target ◽  
New Antibiotics ◽  
Candidate Regions

AbstractEfforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.

scholarly journals Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2640-2649 ◽  
Author(s):  
Manzour Hernando Hazbón ◽  
Michael Brimacombe ◽  
Miriam Bobadilla del Valle ◽  
Magali Cavatore ◽  
Marta Inírida Guerrero ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Sample Selection ◽  
Multidrug Resistant ◽  
Small Sample ◽  
Inverse Association ◽  
Resistance Mutations ◽  
Isoniazid Resistance ◽  
Large Scale Analysis ◽  
Small Sample Sizes

ABSTRACT The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.

scholarly journals Meeting Highlights: Genome Sequencing and Biology 2001

2001 ◽  
Vol 2 (4) ◽  
pp. 243-251
Author(s):  
Jo Wixon
Keyword(s):  
Comparative Genomics ◽  
Functional Genomics ◽  
Genome Sequencing ◽  
Large Scale ◽  
Model Organism

We bring you a report from the CSHL Genome Sequencing and Biology Meeting, which has a long and prestigious history. This year there were sessions on large-scale sequencing and analysis, polymorphisms (covering discovery and technologies and mapping and analysis), comparative genomics of mammalian and model organism genomes, functional genomics and bioinformatics.

Rice Functional Genomics by Transposon Mutagenesis

2002 ◽  
Vol 06 (24) ◽  
pp. 930-935 ◽  
Author(s):  
Chang-deok Han
Keyword(s):  
Tissue Culture ◽  
Transposable Elements ◽  
Functional Genomics ◽  
Large Scale ◽  
Expression Patterns ◽  
Transposon Mutagenesis ◽  
Transposon Tagging ◽  
Genomic Sequences ◽  
Knock Out ◽  
Genetic Cross

Transposable elements are powerful mutagens. Along with genomic sequences, knock-out phenotypes and expression patterns are important information to elucidate the function of genes. In this review, I propose a strategy to develop tranposant lines on a large scale by combining genetic cross and tissue culture of Ac and Ds lines. Based on the facts that Ds tends to be inactive in F2 or later generation and Ds becomes reactivated via tissue culture, a large scale of transposants can be produced by tissue culture of seeds carrying Ac and inactive Ds. In this review, I describe limitations and considerations in operating transposon tagging systems in rice. Also, I discuss the efficiency of our gene trap system and technical procedures to clone Ds flanking DNA.

scholarly journals MiDRMpol: A High-Throughput Multiplexed Amplicon Sequencing Workflow to Quantify HIV-1 Drug Resistance Mutations against Protease, Reverse Transcriptase, and Integrase Inhibitors

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 806
Author(s):  
Shambhu G. Aralaguppe ◽  
Anoop T. Ambikan ◽  
Manickam Ashokkumar ◽  
Milner M. Kumar ◽  
Luke Elizabeth Hanna ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
Polymorphism Analysis ◽  
Resistance Mutations ◽  
Subtype C ◽  
Bioinformatics Pipeline ◽  
Drug Resistance Mutations ◽  
Hiv 1

The detection of drug resistance mutations (DRMs) in minor viral populations is of potential clinical importance. However, sophisticated computational infrastructure and competence for analysis of high-throughput sequencing (HTS) data lack at most diagnostic laboratories. Thus, we have proposed a new pipeline, MiDRMpol, to quantify DRM from the HIV-1 pol region. The gag-vpu region of 87 plasma samples from HIV-infected individuals from three cohorts was amplified and sequenced by Illumina HiSeq2500. The sequence reads were adapter-trimmed, followed by analysis using in-house scripts. Samples from Swedish and Ethiopian cohorts were also sequenced by Sanger sequencing. The pipeline was validated against the online tool PASeq (Polymorphism Analysis by Sequencing). Based on an error rate of <1%, a value of >1% was set as reliable to consider a minor variant. Both pipelines detected the mutations in the dominant viral populations, while discrepancies were observed in minor viral populations. In five HIV-1 subtype C samples, minor mutations were detected at the <5% level by MiDRMpol but not by PASeq. MiDRMpol is a computationally as well as labor efficient bioinformatics pipeline for the detection of DRM from HTS data. It identifies minor viral populations (<20%) of DRMs. Our method can be incorporated into large-scale surveillance of HIV-1 DRM.

scholarly journals Colony size measurement of the yeast gene deletion strains for functional genomics

2021 ◽  
Author(s):  
Negar Memarian ◽  
Matthew Jessulat ◽  
Javad Alirezaie ◽  
Nadereh Mir-Rashed ◽  
Jianhua Xu ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Colony Size ◽  
Large Scale ◽  
Model Organism ◽  
Antifungal Compound ◽  
Image Analysis System ◽  
Yeast Saccharomyces Cerevisiae ◽  
Inspection Method ◽  
Manual Inspection ◽  
Growth Differences

Background Numerous functional genomics approaches have been developed to study the model organism yeast, Saccharomyces cerevisiae, with the aim of systematically understanding the biology of the cell. Some of these techniques are based on yeast growth differences under different conditions, such as those generated by gene mutations, chemicals or both. Manual inspection of the yeast colonies that are grown under different conditions is often used as a method to detect such growth differences. Results Here, we developed a computerized image analysis system called Growth Detector (GD), to automatically acquire quantitative and comparative information for yeast colony growth. GD offers great convenience and accuracy over the currently used manual growth measurement method. It distinguishes true yeast colonies in a digital image and provides an accurate coordinate oriented map of the colony areas. Some post-processing calculations are also conducted. Using GD, we successfully detected a genetic linkage between the molecular activity of the plant-derived antifungal compound berberine and gene expression components, among other cellular processes. A novel association for the yeast mek1 gene with DNA damage repair was also identified by GD and confirmed by a plasmid repair assay. The results demonstrate the usefulness of GD for yeast functional genomics research. Conclusion GD offers significant improvement over the manual inspection method to detect relative yeast colony size differences. The speed and accuracy associated with GD makes it an ideal choice for large-scale functional genomics investigations.

scholarly journals IDENTIFICATION OF THE kdr MUTATIONS IN VGSC GENE OF THE DENGUE MOSQUITOES AEDES ALBOPICTUS COLLECTED FROM HANOI AND HAIPHONG

2018 ◽  
Vol 16 (2) ◽  
pp. 273-278
Author(s):  
Nguyen Thi Kim Lien ◽  
Nguyen Thu Hien ◽  
Nguyen Huy Hoang ◽  
Nguyen Thi Hong Ngoc ◽  
Nguyen Thi Huong Binh
Keyword(s):  
Sodium Channel ◽  
Aedes Albopictus ◽  
Novel Mutation ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Resistance Mutations ◽  
Well Control ◽  
Voltage Gated ◽  
Activity Of Enzymes ◽  
Dengue Epidemic

Vietnam is one of the countries that is affected by dengue fever in Southeast Asia. The dengue epidemic is becoming increasingly more complex so it is necessary to have a well control to vectors in order to limit the spread of the disease. The Aedes albopictus mosquito is determined as one of the two major vectors that transmitted the dengue. Recent research shows that A. albopictus is present in some parts of Hanoi and Haiphong. In order to control the vector as well as the disease, it is necessary to understand the level of resistance and the resistance mechanism of the vector. Two important resistance mechanisms of insect were known as the mutations in the target protein of the insecticides and enhancing the activity of enzymes that participate in the resolution of the insecticides. In this study, the mosquito samples were collected from Hanoi and Haiphong to identify the level of resistance and detect the knock down resistance mutations in voltage gated sodium channel (VGSC) in membrane of nervecell of mosquito. The results of insecticide susceptibility test showed that A. albopictus in Hanoi and Haiphong were still sensitive to organophosphate but resistant to DDT, carbamate and pyrethroid. Ser989Pro, Ile1011Met, Val1016Gly and Phe1534Cys mutations were not deteced in A. albopictus in Hanoi and Haiphong. However, we detected a novel mutation Tyr986His in VGSC protein.

Phenotypic Screen and Transcriptomics Approach Complement Each Other in Functional Genomics of Defensive Stink Gland Physiology

2021 ◽  
Author(s):  
Sabrina Lehmann ◽  
Bibi Atika ◽  
Daniela Grossmann ◽  
Christian Schmitt-Engel ◽  
Nadi Strohlein ◽  
...  
Keyword(s):  
Functional Genomics ◽  
Large Scale ◽  
Reverse Genetics ◽  
Expression Profiles ◽  
Forward Genetics ◽  
Large Set ◽  
Knock Down ◽  
Genome Wide ◽  
Phenotypic Screen ◽  
A Genome

Abstract Background Functional genomics uses unbiased systematic genome-wide gene disruption or analyzes natural variations such as gene expression profiles of different tissues from multicellular organisms to link gene functions to particular phenotypes. Functional genomics approaches are of particular importance to identify large sets of genes that are specifically important for a particular biological process beyond known candidate genes, or when the process has not been studied with genetic methods before. Results Here, we present a large set of genes whose disruption interferes with the function of the odoriferous defensive stink glands of the red flour beetle Tribolium castaneum. This gene set is the result of a large-scale systematic phenotypic screen using a reverse genetics strategy based on RNA interference applied in a genome-wide forward genetics manner. In this first-pass screen, 130 genes were identified, of which 69 genes could be confirmed to cause knock-down gland phenotypes, which vary from necrotic tissue and irregular reservoir size to irregular color or separation of the secreted gland compounds. The knock-down of 13 genes caused specifically a strong reduction of para-benzoquinones, suggesting a specific function in the synthesis of these toxic compounds. Only 14 of the 69 confirmed gland genes are differentially overexpressed in stink gland tissue and thus could have been detected in a transcriptome-based analysis. Moreover, of the 29 previously transcriptomics-identified genes causing a gland phenotype, only one gene was recognized by this phenotypic screen despite the fact that 13 of them were covered by the screen. Conclusion Our results indicate the importance of combining diverse and independent methodologies to identify genes necessary for the function of a certain biological tissue, as the different approaches do not deliver redundant results but rather complement each other. The presented phenotypic screen together with a transcriptomics approach are now providing a set of close to hundred genes important for odoriferous defensive stink gland physiology in beetles.

scholarly journals Recent advances in functional genome analysis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1968 ◽  
Author(s):  
Roderic Guigo ◽  
Michiel de Hoon
Keyword(s):  
Functional Genomics ◽  
Human Genome ◽  
Large Scale ◽  
Massively Parallel Sequencing ◽  
Genome Project ◽  
Biological Traits ◽  
Cellular Behavior ◽  
Sequencing Technologies ◽  
Recent Advances ◽  
The Human Genome Project

At the beginning of this century, the Human Genome Project produced the first drafts of the human genome sequence. Following this, large-scale functional genomics studies were initiated to understand the molecular basis underlying the translation of the instructions encoded in the genome into the biological traits of organisms. Instrumental in the ensuing revolution in functional genomics were the rapid advances in massively parallel sequencing technologies as well as the development of a wide diversity of protocols that make use of these technologies to understand cellular behavior at the molecular level. Here, we review recent advances in functional genomic methods, discuss some of their current capabilities and limitations, and briefly sketch future directions within the field.

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