Genetic geography of Mycobacterium tuberculosis Beijing genotype: A multifacet mirror of human history?

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Abstract

The Beijing genotype of Mycobacterium tuberculosis has been shown in many settings to be hypervirulent and associated with multi-drug resistance. Its presently global and rapid dissemination makes it an important issue of public health. Here, I present a significantly enlarged update of the MIRU-VNTR global database of the M. tuberculosis Beijing genotype (11 loci). I further attempted to link the observed mycobacterial diversity with relevant events of the known human history. Large water masses have been the most efficient and drastic generators of the genetic divergence between human populations. The same situation appears true also for M. tuberculosis, which general diversity pattern amazingly resembles that of its human host. At the same time, less expected affinities observed between distant populations of M. tuberculosis may reflect hidden patterns of human migrations or yet unknown epidemiological links between distant regions.

Introduction

Mycobacterium prototuberculosis, the hypothetical progenitor of M. tuberculosis was probably a panmyctic species (Gutierrez et al., 2005). Contrarily, modern members of the M. tuberculosis complex form a strictly clonal genospecies although few exceptions of this rule are known (reviewed in McEvoy et al., 2007). A strict clonality implies unidirectional evolution when divergence is generated via intragenomic variation unobscured by lateral gene transfer. M. tuberculosis Beijing genotype was first identified by IS6110-RFLP and spoligotyping in the M. tuberculosis strains isolated in the Beijing area in China in 1992–1994 (van Soolingen et al., 1995). Subsequent studies have shown that these strains are endemically prevalent in East Asia, South Africa, and Northern Eurasia (Bifani et al., 2002, Glynn et al., 2002). Unlike many other M. tuberculosis families frequently defined by relatively sophisticated bioinformatics approaches and for which the clear-cut molecular ID are being searched for, the Beijing family has a specific signature of the Direct Repeat (DR) locus that allows its unambiguous definition. The DR locus consists of minisatellite alternating exact direct repeats and variable spacers and represents a large polyphyletic family of DNA repeats found in many bacterial species, namely CRISPRs (Jansen et al., 2002, Mojica et al., 2005). Unlike, for example, Yersinia pestis (Pourcel et al., 2005), at present, this locus in M. tuberculosis is no more active while its changes are likely neutral and have occurred and are still occurring via consecutive irreversible deletions of either single units or contiguous blocks occasionally including IS6110 mediated disruption and recombination (Beggs et al., 2000, van Embden et al., 2000). In the Beijing genotype, most of the DR units were deleted during evolution, perhaps by a single event mediated by IS6110 recombination (Beggs et al., 2000). Thus the characteristic “abridged” structure of the DR locus is a marker that defines the Beijing genotype and distinguishes it from other families within M. tuberculosis. The deletion of the RD105 region thought to be ancestral in all Beijing genotype strains (Tsolaki et al., 2005) was recently found also in strains with complete 43-signal spoligoprofile (Flores et al., 2007). Accordingly, this deletion cannot serve as a specific marker for the Beijing strain. Nevertheless, a presence of this evolutionarily deeply rooted deletion in the Beijing genome implies ancient origin of this genotype although its exact dating remains unclear.

The current worldwide distribution of these strains (Glynn et al., 2002) raised question about underlying reasons that could be, e.g., increased transmissibility, hypervirulence, etc. The published data seem controversial and partly depend on the region of isolation of the Beijing strains. Furthermore, application of other molecular markers showed a heterogeneity of these strains, not only expected variation in polymorphic IS6110-RFLP and VNTRs, but also in some other loci that allowed rough subdivision of this family into ancient (ancestral, atypical) and modern (typical) sub-lineages (Mokrousov et al., 2002, Kremer et al., 2004) that appear to differ in terms of their mutability and acquisition of drug resistance (Rad et al., 2003, Kremer, 2005, Mokrousov et al., 2006).

Our previous study was based on VNTR data from only four areas of origin of the Beijing strains (Mokrousov et al., 2005). In this report, I present an updated global database of the M. tuberculosis Beijing genotype (11 MIRU loci) and its phylogeographic analysis in the light of known human history.

Section snippets

VNTR data collection

M. tuberculosis Beijing family isolates were defined based on spoligotyping: isolates showing hybridization to at least three of the spacers 35–43 and absence of hybridization to spacers 1–34 were defined as the Beijing genotype (Kremer et al., 2004).

Subsequent analysis of the genetic diversity was based on the VNTR loci. These included 11 loci of the “classical” 12-locus MIRU scheme: loci ##2, 4, 10, 16, 23, 24, 26, 27, 31, 39 and 40 (Supply et al., 2001). Locus MIRU-20 was excluded as it was

Results

A comparison of the available 11-loci VNTR data of the 1302 M. tuberculosis Beijing genotype strains identified a total of 204 different types. Compared to the previous version of the database (Mokrousov et al., 2005), this added 989 strains and 147 types. Evaluated with HGI, the most homogeneous were Russian populations with HGI below 0.7 in all four cases while the most heterogeneous were East Asian populations and Australia (Table S1 in Supplementary material, Fig. 1). The highest HGI (>0.9)

Discussion

The evolutionary histories of the human and microbial species are, at least partly, co-mirrored and co-shaped. Thirty years ago, W.H. McNeill demonstrated how human history was influenced by various local and global epidemics, the Black Death being the most notorious example (McNeill, 1976). More recently, comparative studies attempted timing of specific events in the genome evolution of M. tuberculosis (Mokrousov et al., 2005) and tracing hidden patterns of human migrations in the geographic

Acknowledgements

I am grateful to the anonymous reviewer for helpful comments and criticisms.

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