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Front Microbiol. 2019 Feb 26;10:309. doi: 10.3389/fmicb.2019.00309. eCollection 2019.

Whole Genome Sequencing of Mycobacterium tuberculosis Clinical Isolates From India Reveals Genetic Heterogeneity and Region-Specific Variations That Might Affect Drug Susceptibility.

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Institute of Bioinformatics, International Technology Park, Bengaluru, India.
Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India.
Manipal Academy of Higher Education, Manipal, India.
School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India.
Department of Microbiology and Molecular Biology, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India.
Department of Neuromicrobiology, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Intermediate Reference Laboratory, State Tuberculosis Training and Demonstration Centre, Someshwaranagar, SDSTRC and RGICD Campus, Bengaluru, India.
Department of Cardio Thoracic Surgery, Super Specialty State Referral Hospital for Chest Diseases, Someshwaranagar First Main Road, Dharmaram College Post, Bengaluru, India.
School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, India.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.


Whole genome sequencing (WGS) of Mycobacterium tuberculosis has been constructive in understanding its evolution, genetic diversity and the mechanisms involved in drug resistance. A large number of sequencing efforts from across the globe have revealed genetic diversity among clinical isolates and the genetic determinants for their resistance to anti-tubercular drugs. Considering the high TB burden in India, the availability of WGS studies is limited. Here we present, WGS results of 200 clinical isolates of M. tuberculosis from North India which are categorized as sensitive to first-line drugs, mono-resistant, multi-drug resistant and pre-extensively drug resistant isolates. WGS revealed that 20% of the isolates were co-infected with M. tuberculosis and non-tuberculous mycobacteria species. We identified 12,802 novel genetic variations in M. tuberculosis isolates including 343 novel SNVs in 38 genes which are known to be associated with drug resistance and are not currently used in the diagnostic kits for detection of drug resistant TB. We also identified M. tuberculosis lineage 3 to be predominant in the northern region of India. Additionally, several novel SNVs, which may potentially confer drug resistance were found to be enriched in the drug resistant isolates sampled. This study highlights the significance of employing WGS in diagnosis and for monitoring further development of MDR-TB strains.


fluoroquinolones; metagenomics; molecular genotyping; mycobacterial genetic heterogeneity; next generation sequencing

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