Comparative Genomics of Drug Resistant Mycobacterium Tuberculosis.

摘要

Tuberculosis (TB) remains one of the major causes of illness and death globally. Although the number of new TB cases per capita has been falling since 2003, the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) cases of TB poses new threat to the successful worldwide control of the disease (WHO, 2008; Iseman, 2007). The Beijing lineage of Mycobacterium tuberculosis (MTB) has received much attention over the past decade due to its prevalence throughout Asia, parts of the former Soviet Union, and several other geographical locations including the United States. The strain also demonstrated hypervirulence in animal models and an increased likelihood to develop multidrug resistance. The current definition of XDR in TB is defined as resistance to at least isoniazid and rifampicin, any fluoroquinolone, and with at least one of the three second-line drugs. Here we show that our knowledge of the biology of this pathogen is still limited. We performed genome sequencing and reported the complete genomes of five Beijing isolates from Hong Kong and Fujian, of which two were shown to have drug resistance that is far beyond the current XDR standard—a “Totally Drug Resistance” (TDR) phenotype. Comparative genomics of the five Beijing isolates provided us insights into the virulence-related genes in the Beijing family. A distinct region of about 4 kb in size that are absent in all known complete genomes of MTB was also identified. The evolutionary implications of this region were discussed. When we investigated the unique genetic changes in drug resistant Beijing strains, a correlation to DNA repair and geraniol degradation was implicated. We have also observed that the big deletions (D) and truncations (T) events were significant higher when compare with frameshift (F) mutations. Moreover, the FDT events in TDR strains were more frequently found in genes that are involved in growth attenuation and retained in the genome of the Mycobacterium leprae. This evidence suggests that MTB develops its extreme drug resistance through the reductive evolution. The significant decrease in the fitness may explain the rareness of TDR strains.