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Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis.

ABSTRACT: Comparison of the pattern of synonymous nucleotide substitution between two complete genomes of Mycobacterium tuberculosis at 3298 putatively orthologous loci showed a mean percent difference per synonymous site of 0.000328 0.000022. Although 80.5% of loci showed no synonymous or nonsynonymous nucleotide differences, the level of polymorphism observed at other loci was greater than suggested by previous studies of a small number of loci. This level of nucleotide difference leads to the conservative estimate that the common ancestor of these two genotypes occurred approximately 35000 ago, which is twice as high as some recent estimates of the time of origin of this species. Our results suggest that a large number of loci should be examined for an accurate assessment of the level of nucleotide diversity in natural populations of pathogenic microorganisms.

SUBMITTER: Hughes AL

PROVIDER: S-EPMC2738538 | biostudies-literature | 2002 Nov

REPOSITORIES: biostudies-literature

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Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis.

Hughes Austin L AL Friedman Robert R Murray Megan M

Emerging infectious diseases 20021101 11

Comparison of the pattern of synonymous nucleotide substitution between two complete genomes of Mycobacterium tuberculosis at 3298 putatively orthologous loci showed a mean percent difference per synonymous site of 0.000328 0.000022. Although 80.5% of loci showed no synonymous or nonsynonymous nucleotide differences, the level of polymorphism observed at other loci was greater than suggested by previous studies of a small number of loci. This level of nucleotide difference leads to the conservat ...[more]

PMID: 12453367

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Project description:A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in Mycobacterium tuberculosis, the major causative agent of tuberculosis, using a combination of transposon insertion sequencing (Tn-seq) and comparative genomic analysis. To identify conditionally essential genes by Tn-seq, we used media with different nutrient compositions. Although many conditional gene essentialities were affected by the presence of relevant nutrient sources, we also found that the essentiality of genes in a subset of metabolic pathways was unaffected by metabolite availability. Comparative genomic analysis revealed that not all essential genes identified by Tn-seq were fully conserved within the M. tuberculosis complex, including some existing antitubercular drug target genes. In addition, we utilized an available M. tuberculosis genome-scale metabolic model, iSM810, to predict M. tuberculosis gene essentiality in silico Comparing the sets of essential genes experimentally identified by Tn-seq to those predicted in silico reveals the capabilities and limitations of gene essentiality predictions, highlighting the complexity of M. tuberculosis essential metabolic functions. This study provides a promising platform to study essential cellular functions in M. tuberculosis IMPORTANCE Mycobacterium tuberculosis causes 10 million cases of tuberculosis (TB), resulting in over 1 million deaths each year. TB therapy is challenging because it requires a minimum of 6 months of treatment with multiple drugs. Protracted treatment times and the emergent spread of drug-resistant M. tuberculosis necessitate the identification of novel targets for drug discovery to curb this global health threat. Essential functions, defined as those indispensable for growth and/or survival, are potential targets for new antimicrobial drugs. In this study, we aimed to define gene essentialities of M. tuberculosis on a genomewide scale to comprehensively identify potential targets for drug discovery. We utilized a combination of experimental (functional genomics) and in silico approaches (comparative genomics and flux balance analysis). Our functional genomics approach identified sets of genes whose essentiality was affected by nutrient availability. Comparative genomics revealed that not all essential genes were fully conserved within the M. tuberculosis complex. Comparing sets of essential genes identified by functional genomics to those predicted by flux balance analysis highlighted gaps in current knowledge regarding M. tuberculosis metabolic capabilities. Thus, our study identifies numerous potential antitubercular drug targets and provides a comprehensive picture of the complexity of M. tuberculosis essential cellular functions.

Dataset Information

Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis.

Publications

Genomewide pattern of synonymous nucleotide substitution in two complete genomes of Mycobacterium tuberculosis.

Similar Datasets

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