Estimation of the mutation rate of Mycobacterium tuberculosis in cases with recurrent tuberculosis using whole genome sequencing

Abstract

The study of tuberculosis latency is problematic due to the difficulty of isolating the bacteria in the dormancy state. Despite this, several in vivo approaches have been taken to mimic the latency process. Our group has studied the evolution of the bacteria in 18 cases of recurrent tuberculosis. We found that HIV positive patients develop recurrent tuberculosis earlier, generally in the first two years (p value = 0.041). The genome of the 36 Mycobacterium tuberculosis paired isolates (first and relapsed isolates) showed that none of the SNPs found within each pair was observed more than once, indicating that they were not directly related to the recurrence process. Moreover, some IS6110 movements were found in the paired isolates, indicating the presence of different clones within the patient. Finally, our results suggest that the mutation rate remains constant during all the period as no correlation was found between the number of SNPs and the time to relapse.

Mycobacterium tuberculosis is less likely to acquire pathogenic mutations during latent infection than during active disease

“…In addition to the scenario under active disease, previous studies also demonstrated the accumulation of SNPs and other genomic mutations in the Mtb genome during LTBI. Interestingly, while similar SNP accumulation rates were observed in macaques for LTBI and active disease, the former had a slower rate than the latter in humans ( 7 , 15 – 18 ). However, whether other characteristics of genomic mutations, including population diversification and signs of selective pressures, are unique to LTBI or similar to active disease remains unknown.…”

“…4F and G ), while that of all aSNPs was slower in LTBI and active disease. It was reported that the mutation rate of all detected SNPs during LTBI is slower than that during active disease in humans, whereas it was equivalent in macaques ( 7 , 15 – 18 ). Although our results from synonymous SNPs and all aSNPs comprised reports in macaques and humans, respectively, the sample size is statically small to reach any conclusion.…”

“…Approximately 10% of LTBIs are estimated to develop into active TB disease in an individual’s lifetime ( 5 ). In countries with low TB incidence, most new active TB cases are predicted to be reactivations of LTBI ( 6 , 7 ). Thus, preventing LTBI activation has become a significant strategy for TB elimination in these countries.…”

Implementation of national whole-genome sequencing of Mycobacterium tuberculosis, National Public Health Laboratory, Singapore, 2019—2022

“… Mycobacterium tuberculosis is estimated to have an average mutation rate of 0.5 SNPs per genome per year [23], although the mutation rate may be higher in settings with selective pressure of antituberculous therapy, such as in settings of high MDR-TB prevalence [24]. The slow rate of evolution of M.…”

“… Mycobacterium tuberculosis is estimated to have an average mutation rate of 0.5 SNPs per genome per year [ 23 ], although the mutation rate may be higher in settings with selective pressure of antituberculous therapy, such as in settings of high MDR-TB prevalence [ 24 ]. The slow rate of evolution of M. tuberculosis gives rise to relatively few SNPs in clinical isolates, which contributes to the challenge of phylogenetic reconstruction of the evolutionary relationships of clinical isolates [ 25 ], particularly in Singapore’s moderate-incidence setting.…”