Population structure, biogeography and transmissibility ofMycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis is a clonal pathogen proposed to have co-evolved with its human host for millennia, yet our understanding of its genomic diversity and biogeography remains incomplete. Here we use a combination of phylogenetics and dimensionality reduction to reevaluate the population structure of M. tuberculosis, providing the first in-depth analysis of the ancient East African Indian Lineage 1 and the modern Central Asian Lineage 3 and expanding our understanding of Lineages 2 and 4. We assess sub-lineages using genomic sequences from 4,939 pan-susceptible strains and find 30 new genetically distinct clades that we validate in a dataset of 4,645 independent isolates. We characterize sub-lineage geographic distributions and demonstrate a consistent geographically restricted and unrestricted pattern for 20 groups, including three groups of Lineage 1. We assess the transmissibility of the four major lineages by examining the distribution of terminal branch lengths across the M. tuberculosis phylogeny and identify evidence supporting higher transmissibility in Lineages 2 and 4 than 3 and 1 on a global scale. We define a robust expanded barcode of 95 single nucleotide substitutions (SNS) that allows for the rapid identification of 69 Mtb sub-lineages and 26 additional internal groups. Our results paint a higher resolution picture of the Mtb phylogeny and biogeography.

GenTB: A user-friendly genome-based predictor for tuberculosis resistance powered by machine learning

“…GenTB's output reports novel variants not linked to resistance in addition to those that are resistance associated. The phylogenetic lineage calling procedure implemented in GenTB [24] uses currently available typing schemes, including the spoligotype nomenclature, to facilitate comparisons across lineage schemes.…”

“…We used 75% (15,267 isolates) of the dataset to train the model and 25% (5,098 isolates) to validate its performance. During retraining, we excluded silent variants, those that occurred only in phenotypically susceptible isolates, or known phylogenetic variants, and the final model was trained on 393 variants occurring in 3,262 phenotypically pyrazinamide resistant isolates [24]. We chose the randomForest mtry variable that yielded the smallest out-of-bag error and varied the classwt variable to maximize the sum of sensitivity and specificity.…”

“…Variants are called with pilon (parameters: default) [23] to obtain SNPs and indels in the variant calling format (VCF) requiring that they have a PASS or Amb filter tags with read allele frequency >0.40. Fast-Lineage-Caller then detects the M. tuberculosis lineage based on five lineage typing schemes as implemented by Freschi et al [24]. Subsequently, invariant sites in the VCF file are removed, and a custom Perl script annotates each variant as frameshift, synonymous or non-synonymous, stop codon, indel along with the H37Rv locus tag for each respective gene.…”

The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance inMycobacterium tuberculosiscomplex

“…Next, we excluded 1,663 isolates with missing calls in >10% of SNP sites yielding a genotypes matrix with dimensions 835,979×32,210. We used an expanded 96-SNP barcode to type the global lineage of each isolate in our sample (Freschi et al, 2020). We further excluded 325 isolates that either did not get assigned a global lineage, assigned to more than one global lineage, or were typed as lineage 7.…”

Evolutionary Genetics of Mycobacterium Tuberculosis and HIV-1: “The Tortoise and the Hare”

“…Transmissibility of a pathogen might ultimately dictate its prevalence among host populations. The transmission potential of “modern” MTBC lineage strains has a tendency to be higher than in their “ancient” partners [ 15 , 52 ]. Increases in relative prevalence have been consistently reported in several world regions for Lineage 2 [ 15 , 53 , 54 , 55 ].…”