• Tomotada Iwamoto.
• Department of Microbiology, Kobe Institute of Health, 4-6, Minatojima-nakamachi, Chuo-ku, Kobe-shi, Hyogo 650-0046, Japan. tomotada_iwamoto@office.city.kobe.lg.jp
• Kekkaku. 2009 Dec 1; 84 (12): 755-9.

AbstractThe Beijing family is a genotypic lineage of M. tuberculosis that reportedly predominates throughout eastern Asia and in parts of Russia yet dispersed worldwide. About 80% of clinical isolates in Japan are belonging to this family. The predominance of a narrow range of genotypes, in this case predominance by Beijing family strains, hypothesized that these strains may have a selective advantage either with virulence or transmissibility that led to clonal expansion. The strains are monophyletic within the M. tuberculosis species and also reveal further sublineages within this family. It is believed that the genetic and evolutionary background of M. tuberculosis strains influence on the propensity to gain drug resistance as well as the pathogen's transmissibility. Thus, understanding the population genetic structure and its dynamics of Beijing family strains will undoubtedly help to unravel the basis for the considerable success and spread of this genotype in Japan. During the past few years, we intensively studied this notorious clade, M. tuberculosis Beijing family, to reconstruct their evolutionary events and phylogeny and to elucidate their epidemiological characteristics at the sublineage levels through the population structure analysis. Here, I summarized the findings of our research in the past few years. Singularity of the genetic diversity of Beijing family strains in Japan. We reconstructed the phylogenetic trees of Beijing family strains by the 15-MIRU-VNTR genotyping method and validated them through profiling of the NTF region, large sequence polymorphisms (LSP), and single-nucleotide polymorphisms (SNPs). Interestingly, we could demonstrate that the ancient Beijing sublineage has remained endemic to Japan, in contrast to the worldwide spread of the modern Beijing sublineage. Moreover, we found that the ancient sublineage strains corresponding to four monophyletic subgroups. The singularity of the genetic diversity of Beijing family strains in Japan, i.e., its high diversity and dominance of the ancient sublineage in contrast to the modern sublineage found worldwide, suggested that they became endemic independently from the evolutionary stream that led to the dominant modern Beijing sublineage in outside Japan. Population structure dynamics of Beijing family strains in Japan. We inferred the population structure dynamics of Beijing family strains during the past decades in Japan by comparing the isolates from elderly TB patients (these strains represent the population structure that existed decades ago) and young TB patients (these strains reflect the population structure of currently prevalent strains). The comparison between the cohorts born in different years suggested that the population structure of the M. tuberculosis Beijing family strains in Japan before World War II--when TB was highly prevalent--was significantly different from that of the currently prevalent strains. The results revealed that the spread of a modern sub-lineage that has high transmissibility is currently increasing, while the spread of an ancient sublineage, STK, has significantly decreased in younger generations. It is interesting to assume that the observed trends in the case of the modern and STK strains may be associated with the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination. Association between sublineages of Beijing family and multidrug resistance. Mycobacterium tuberculosis Beijing family strains are suspected to be an evolving lineage of M. tuberculosis that has acquired the advantage of drug resistance. However, the association between this genotype and drug resistance varies in different countries. This may be due to heterogeneity in the fitness of the sublineages of the Beijing family and different proportions of these sublineages in the local population. To determine whether certain sublineages are associated with multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, the population structure of the Beijing strains based on 10 synonymous single nucleotide polymorphisms (sSNPs) was analyzed in pan drug-sensitive (DS), MDR, and XDR strains. The results revealed that two evolutionary subgroups (ST 26 and ST3), which are belonging to an ancient sublineage, occurred with a significantly higher frequency in the MDR/XDR population than in the DS population. This suggests that different sublineages of the Beijing family may differ in their mechanism of adaptation to drug-selective pressure. The greater vigilance in monitoring the occurrence of these strains is indispensable for achieving better TB control in this region. In the combination of molecular epidemiological data with recent advances in mycobacterial genomics and population genetics, we could provide novel insights into genetic diversity and phylogeny of M. tuberculosis Beijing family strains circulating in Japan. This would be a good start to approaching the genetic determinants causing variations in virulence and transmissibility of M. tuberculosis. We are currently applying the next-generation sequencing technology to get the whole genome sequencing of the representative strains from each monophyletic subgroup within M. tuberculosis Beijing family.

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