Population genomics of Mycobacterium tuberculosis in the Inuit - PubMed (original) (raw)
Population genomics of Mycobacterium tuberculosis in the Inuit
Robyn S Lee et al. Proc Natl Acad Sci U S A. 2015.
Abstract
Nunavik, Québec suffers from epidemic tuberculosis (TB), with an incidence 50-fold higher than the Canadian average. Molecular studies in this region have documented limited bacterial genetic diversity among Mycobacterium tuberculosis isolates, consistent with a founder strain and/or ongoing spread. We have used whole-genome sequencing on 163 M. tuberculosis isolates from 11 geographically isolated villages to provide a high-resolution portrait of bacterial genetic diversity in this setting. All isolates were lineage 4 (Euro-American), with two sublineages present (major, n = 153; minor, n = 10). Among major sublineage isolates, there was a median of 46 pairwise single-nucleotide polymorphisms (SNPs), and the most recent common ancestor (MRCA) was in the early 20th century. Pairs of isolates within a village had significantly fewer SNPs than pairs from different villages (median: 6 vs. 47, P < 0.00005), indicating that most transmission occurs within villages. There was an excess of nonsynonymous SNPs after the diversification of M. tuberculosis within Nunavik: The ratio of nonsynonymous to synonymous substitution rates (dN/dS) was 0.534 before the MRCA but 0.777 subsequently (P = 0.010). Nonsynonymous SNPs were detected across all gene categories, arguing against positive selection and toward genetic drift with relaxation of purifying selection. Supporting the latter possibility, 28 genes were partially or completely deleted since the MRCA, including genes previously reported to be essential for M. tuberculosis growth. Our findings indicate that the epidemiologic success of M. tuberculosis in this region is more likely due to an environment conducive to TB transmission than a particularly well-adapted strain.
Keywords: Mycobacterium tuberculosis; evolution; whole-genome sequencing.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Fig. 1.
Maximum likelihood tree of 163 M. tuberculosis isolates from Nunavik and 21 representative genomes of lineages 1–7. Phylogenetic clusters based on 9,016 single-nucleotide polymorphic loci identified across 184 genomes compared with H37Rv (solid black circle). The scale bars represent the number of substitutions per site. Bootstrap values from 1,000 replicates are shown for branches within the Mj and Mn sublineages. For clarity, only values ≥98 are shown.
Fig. 2.
Maximum likelihood tree of 163 M. tuberculosis isolates from Nunavik. Phylogenetic clusters were identified based on 1,288 single-nucleotide polymorphic loci compared with H37Rv. Solid and dashed lines indicate isolates of the Mj and Mn sublineages, respectively. Colored shapes represent the reference genome (bordered black square) and the villages of Nunavik: A (bordered blue triangle), B (full orange square), C (bordered purple circle), D (full green diamond), E (bordered purple diamond), K (full pink triangle), and other (full green circle). *Genome with a unique single-nucleotide polymorphism profile. #Phylogenetic clusters defined previously in ref. . Years of diagnosis are indicated. Bootstrap support from 1,000 replicates is shown. Branches supported by less than 80% of bootstrap replicates are collapsed.
Fig. S1.
Most recent common ancestors and deletion events during the evolution of the Mj sublineage of Nunavik. Because similar estimates with overlapping 95% highest posterior density intervals were obtained in all three MRCA analyses, MRCA dates obtained via analysis 1 are presented for simplicity. Arrows indicate the positions and annotations of the H37Rv reference genome. A phylogenetic cluster was defined as at least two genomes sharing a minimum of two single-nucleotide polymorphic loci. Gray and colored circles represent the common ancestors and phylogenetic clusters based on identified SNPs, respectively. Isolate 58385 had a unique single-nucleotide polymorphism profile (i.e., was not clustered) and, because the posterior density for the divergence date of this isolate was <0.8, has not been shown. The dashed line indicates the point estimate for the MRCA of Mj, under analysis 1. Left of the dashed line, prediversification; right of the dashed line, postdiversification.
Fig. 3.
Pairwise SNPs between isolates of the major sublineage of Nunavik. There were a total of 11,628 pairwise comparisons: 3,689 intravillage case pairs and 7,939 intervillage case pairs.
Fig. S2.
Bayesian skyline plots of M. tuberculosis in Nunavik. (A) All sublineages together. (B) The major sublineage. (C) The minor sublineage. The estimated effective population sizes through time are shown (black line). The shaded area represents the 95% credibility intervals.
Fig. 4.
Proportion of genes with nonsynonymous single-nucleotide polymorphisms (Top) and the number of deleted genes (Bottom) for the major sublineage, pre- and postdiversification. Gene categories are as defined in the publications: M. tuberculosis (MTB) deletions (36), bacillus Calmette–Guérin (BCG) deletions (37), essential genes in vitro (20), in macrophages (38), or in vivo (19), _M. tuberculosis_-specific genes (39), lateral gene transfer or duplication acquisition (39), human T-cell epitopes (7), genes coding membrane proteins (40), mobile elements (7), and genes coding PPE family proteins (7). Genes designated as PE/PGRS, PPE, or mobile elements were excluded from the SNP analysis (7).
References
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- Nguyen D, et al. Tuberculosis in the Inuit community of Quebec, Canada. Am J Respir Crit Care Med. 2003;168(11):1353–1357. -PubMed
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