Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage

Abstract

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

Figure 1:. Biogeographical structure of the M. tuberculosis Beijing lineage.

(a) MStree based on 24 MIRU-VNTR markers delineating the clonal complexes (CCs) gathered from a worldwide collection (n = 4,987). Major nodes and associated multi-locus variants were grouped into six CCs and a basal sublineage (BL). (b) Genetic variability in the different Beijing lineage CCs and the BL calculated using a rarefaction procedure (each CC included a subsample of 457 strains drawn randomly from its source population). Dots correspond to the mean allelic richness, boxes correspond to mean values ± s.e.m. and error bars correspond to mean values ± s.d. (c) Worldwide distribution of the Beijing CCs and BL. Each circle corresponds to a country, and circle sizes are proportional to the number of strains. Note that the results for CC3 and CC4, less supported by whole genome-based analysis, are only given as an indication. (d) Genetic erosion out of China. Mean allelic richness within geographical populations is plotted against geographical distance from the Yangtze River basin. Filled squares denote the Eurasian samples used for the regression; filled circles correspond to the global collection. Confidence intervals are represented by dashed lines.

Figure 2:. Phylogenetic reconstruction of the MTBC Beijing lineage and change in population size through time.

(a) Midpoint-rooted maximum-likelihood tree based on 110 genomes and a total of 6,001 concatenated SNPs. Characteristic mutations differentiating modern and ancestral Beijing strain types are mapped on the tree—mutT4 encoding p.Arg48Gly (branch a), ogt encoding p.Arg37Leu (branch b) and mutT2 encoding p.Gly58Arg (branch c)—as is the absence of the RD181 and RD150 regions of difference. Black squares correspond to strains with an MDR or extremely multidrug-resistant (XDR) phenotype, and a number sign indicates strains lacking drug susceptibility test information. Numbers on branches correspond to bootstrap values. The tree topology remains the same when H37Rv is used as an outgroup. (b) Bayesian skyline plot indicating changes in the Beijing lineage over time with a relaxed molecular clock set at 1 × 10−7 mutations per nucleotide per year. The shaded area represents the 95% confidence intervals, and the green colored boxes represent major socioeconomic events that might have affected the demography of M. tuberculosis.

Figure 3:

Proportions of MDR tuberculosis strains among the six CCs and BL of the Beijing lineage. Note that CC2 comprises significantly (P < 0.001) more MDR strains than the other complexes. The total number of strains with available drug susceptibility test information in each group is given above the corresponding column.

Figure 4:

SNP-based Bayesian factor model analysis for detecting genes involved in positive selection in the Beijing lineage. (a,b) Latent factors of the 6,001 SNPs and 110 strains with the first 2 factors (a) and the 2 consecutive ones (b). (c) Manhattan plot representing the selection scan and the outliers that are related to the different latent factors.