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Front. Microbiol. | doi: 10.3389/fmicb.2019.00309

Whole genome sequencing of Mycobacterium tuberculosis clinical isolates from India reveals genetic heterogeneity and region-specific variations that might affect drug susceptibility.

 Jayshree Advani1, 2, 3,  Renu Verma1,  Oishi Chatterjee1, 2, 4, Praveen K. Pachori5, Prashant Upadhyaya5, Rajesh Singh5, Jitendra Yadav5, Farah Naaz5, Raju Ravikumar6, Shashidhar Buggi7, Mrutyunjay Suar8, Umesh D. Gupta5, Akhilesh Pandey1, 3, 9, 10, 11, 12,  Devendra S. Chauhan5,  Srikanth P. Tripathy5,  Harsha Gowda1, 3 and  T. S. Keshava Prasad1, 2*
  • 1Institute of Bioinformatics (IOB), India
  • 2Center for Systems Biology and Molecular Medicine, Yenepoya University, India
  • 3Manipal Academy of Higher Education, India
  • 4Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, India
  • 5National JALMA Institute for Leprosy & Other Mycobacterial Diseases (ICMR), India
  • 6Department of Neuromicrobiology, National Institute of Mental Health and Neuroscience, India
  • 7Shantabai Devarao Shivaram Tuberculosis Research Centre and Rajiv Gandhi Institute Of Chest Diseases,, India
  • 8School of Biotechnology, KIIT University, India
  • 9McKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, United States
  • 10Department of Biological Chemistry, School of Medicine, Johns Hopkins University, United States
  • 11Department of Pathology, School of Medicine, Johns Hopkins University, United States
  • 12Department of Oncology, Johns Hopkins University School of Medicine, 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 whole genome sequencing studies is limited. Here we present, whole genome sequencing results of 200 clinical isolates of M. tuberculosis from North India which are categorised as sensitive to first-line drugs, mono-resistant, multi-drug resistant and pre-extensively drug resistant isolates. Whole genome sequencing revealed that 20% of the isolates were co-infected with M. tuberculosis and nontuberculous mycobacteria (NTM) 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 whole genome sequencing in diagnosis and for monitoring further development of MDR-TB strains.

Keywords: Fluoroquinolones, Metagenomics, Molecular genotyping, mycobacterial genetic heterogeneity, next generation sequencing

Received: 01 Nov 2018; Accepted: 05 Feb 2019.

Edited by:

Farhat Afrin, Taibah University, Saudi Arabia

Reviewed by:

Jason Sahl, Northern Arizona University, United States
Amit Kaushik, Johns Hopkins University, United States  

Copyright: © 2019 Advani, Verma, Chatterjee, Pachori, Upadhyaya, Singh, Yadav, Naaz, Ravikumar, Buggi, Suar, Gupta, Pandey, Chauhan, Tripathy, Gowda and Prasad. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. T. S. Keshava Prasad, Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, Karnataka, India,