Consequences of genomic diversity in Mycobacterium tuberculosis

Abstract

The causative agent of human tuberculosis, Mycobacterium tuberculosis complex (MTBC), comprises seven phylogenetically distinct lineages associated with different geographical regions. Here we review the latest findings on the nature and amount of genomic diversity within and between MTBC lineages. We then review recent evidence for the effect of this genomic diversity on mycobacterial phenotypes measured experimentally and in clinical settings. We conclude that overall, the most geographically widespread Lineage 2 (includes Beijing) and Lineage 4 (also known as Euro-American) are more virulent than other lineages that are more geographically restricted. This increased virulence is associated with delayed or reduced pro-inflammatory host immune responses, greater severity of disease, and enhanced transmission. Future work should focus on the interaction between MTBC and human genetic diversity, as well as on the environmental factors that modulate these interactions.

Keywords: Diversity; Genome; Lineage; SNP; Transmission; Virulence.

Figure 1

A. Maximum likelihood phylogeny modified from Bos et al. [75]. Node support after 1000 bootstrap replications is shown on branches and the tree is rooted by the outgroup M. canettii. Large Sequence Polymorphisms (LSPs) described in [68] are indicated along branches. Scale bar indicates the number of nucleotide substitutions per site. B, C and D. Dominant MTBC lineages per country. Each dot corresponds to 1 of 80 countries represented in the 875 MTBC strains from the global strain collection analysed by Gagneux et al. [24]. The yellow and an orange dot represent Lineage 7 in Ethiopia [74] and the extinct MTBC strains from Peru, respectively [75]: panel B shows the most geographically widespread lineages, panel C the intermediately distributed lineages, and panel D the most geographically restricted lineages.

Figure 2

Number of pairwise difference between MTBC strains. The alignment of 217 human-adapted MTBC clincial strains published previously [76] were used to calculate the number of SNPs between any two strains (i.e. the SNP-distance). We calculated the SNP distance among each pair of strains includeding 44 clinical strains belonging to Lineage 1, 37 strains of Lineage 2, 36 strains of Lineage 3, 64 strains of Lineage 4, 16 strains of Lineage 5, 16 strains of Lineage 6 and 4 strains of Lineage 7. The results are shown in a box-plot generated with R grouping pairwise SNP-distances within each lineage (number of pairwise comparisons were Lineage 1: N=946, Lineage 2: N=666, Lineage 3: N=630, Lineage 4: N=2,016, Lineage 5: N=120, Lineage 6: N=120, Lineage 7: N=6), within “modern” lineages (6,274 pairwise comparisons), between Lineage 7 and Lineages 1, 5, 6 (75 pairwise comparisons), and 12,825 other inter-lineage comparisons.

Figure 3

Predicted functional impact of lineage-specific SNPs. A. Neighbour-joining phylogeny based on 28 globally representative MTBC strains, using 13,086 variable positions [227]. The six main lineages are named and branches coloured as reported previously [24,35]. The number of lineage specific SNPs are indicated along the main braches. B. Percentage predicted functional nonsynonymous SNPs per lineage based on the prediction algorithm SIFT [78].