Single nucleotide polymorphisms in DNA repair genes in drug resistant Mycobacterium tuberculosis isolates from India
Mycobacterium tuberculosis is often associated with acquisition of drug resistance associated mutations. However, the underlying mechanisms are not well studied. It is known that the genomic polymorphisms in DNA repair, replication and recombination (3R) genes contribute to genetic diversity and helps in acquiring polymorphisms which favour survival in different stress conditions such as drug pressure. Super families of 3R gene protein have been previously described by whole genome analysis. However, there is very little understanding about how the genetic diversity in the 3R genes is associate with the types and frequency of polymorphisms in the drug resistance associated loci of the multidrug resistant (MDR) and extensively drug-resistant (XDR) strains. We therefore compared the MDR/XDR and drug susceptible (DS) clinical isolates of 4489 M. tuberculosis genomes (Resistant Isolates: 1217 and Susceptible isolates: 3272, respectively) of having Rifampicin phenotype through whole genome sequence (WGS). The reference strain H37Rv was used for identifying the SNPs in the 3R genes. It was observed that a few unique polymorphisms in 3R genes such as recD, uvrC, polA, adnB, adnA, nth, recR, tatD and ligC were present in MDR/XDR strains which were either completely absent from the drug susceptible strains or were present at very low frequencies. The p-value (1.82e-69) of Susceptible vs Resistant represents the statistically significant difference between the mutation frequency in 3R related genes/sites. In addition, the uniqueness of recR polymorphism(s) occurring exclusively in Beijing genotype strains suggest its association with drug resistance in Beijing genotype. Further investigations into the role of recR in accumulation of drug resistance associated mutations can help in elucidating currently unknown and unexplored mechanisms of drug resistance.
Mukul Sharma1, Arup Ghosh2, Sunil Raghav2, Pushpendra Singh*1,
1 Indian Council of Medical Research-National Institute of Research in Tribal Health,
Jabalpur, Madhya Pradesh, India
2Institute of Life Sciences, Nalco Square, Bhubaneswar, India