Evolutionary Genetic Analysis of the Pyrazinamidase Gene in Seven Global Populations of Mycobacterium tuberculosis.

Abstract

Background: This study aims to identify the signatures of natural selection in the pyrazinamidase (pncA) gene to see if genetic adaptations by Darwinian natural selection have shaped genetic composition of Mycobacterium tuberculosis (Mtb).

Methods: The present analyses were based on 209 DNA sequences (561 bp) of the pncA gene of the bacterial pathogen, Mtb from seven different counties (Peru, Pakistan, South Africa, Mexico, India, China, and Kuwait) endemic to tuberculosis (TB). Before conducting tests for Darwinian natural selection in the pncA gene, we conducted several tests for neutrality in all the available DNA sequences after retrieval from public domains. Several statistical analyses under different algorithms were conducted and biological/evolutionary inferences were drawn.

Results: The 209 sequences of the pncA gene in Mtb belonging to seven different countries were found to be perfectly aligned with the reference sequence. Data analyses under different population genetic models revealed the highest genetic diversity in India, followed by Peru; the lowest was in China. Interestingly, four populations; Peru, Pakistan, India, and Kuwait were found to be deviated from neutral model of evolution based on Tajima'D (TD) values; two populations (India and Peru) based on Fu and Li's D and F (FLD and FLF) test values and five populations (India, Peru, Pakistan, South Africa, and Kuwait) based on Fay and Wu's H (FWH) test. Moreover, based on the statistically significant results of neutrality tests, evidence for positive selection in three populations (Peru [P < 0.02945], Pakistan [P < 0.01767], and Kuwait [P < 0.00301]) at P < 0.05 level of significance] was found.

Conclusion: The present evolutionary genetic analysis of the pncA gene indicates different levels of genetic diversity in seven different country populations. As almost all the global populations showed deviation from neutral model and three populations showed signatures of natural selection, with no specific hotspot region identified for PZA resistance, this gene needs to be studied with larger population size covering countries with TB incidences to study the evolution of drug resistance in Mtb. This will help in the management of drug resistance and TB elimination plan.