Expanded Genomic "Barcode" and Software Tool Rapidly Evaluates M. tuberculosis Structure
Key findings
- The aim of this study was to analyze in depth the structure of the major lineages of Mycobacterium tuberculosis, particularly the less well-studied lineages 1 and 3
- 22 novel sublineages and eight additional internal groups were validated, including seven in lineage 1 and four in lineage 3
- 20 of the 30 newly identified clades had a consistent geographically restricted or unrestricted pattern
- The four major lineages showed a spectrum of transmissibility, another indication of differential adaptation
- A "barcode" of 95 single-nucleotide substitutions rapidly identified 69 sublineages and 26 internal groups; it should have utility in predicting outbreaks of tuberculosis and evaluating which populations will respond to specific antitubercular drugs
In 2014, a paper in Nature Communications introduced a "barcode" for improving the classification of Mycobacterium tuberculosis (Mtb). It uses 62 single-nucleotide substitutions (SNS) as markers of genetic variation for phylogenetic analysis.
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The barcode described 53 sublineages within the four major lineages, but the results were uneven. The ancient Indo-Oceanic lineage 1 (L1) and the modern Central Asian L3 were not as well-described as L2 and L4, which are prevalent in countries where pathogen sequencing has been more widely applied.
Now, Luca Freschi, PhD, postdoctoral fellow at Harvard Medical School, Maha Reda Farhat, MD, MSc, physician in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, and colleagues have expanded the barcode to 95 SNSs. Their report in Nature Communications provides the most detailed picture yet of the Mtb population structure.
The team also developed a software package, dubbed fast-lineage-caller, that rapidly assigns Mtb sublineage designations from the barcode's genomic data. It is freely available online.
Methods
The researchers initially classified 9,584 Mtb isolates sampled from 49 countries. Using the original 62-SNS barcode, they grouped them by major lineage. 4,939 of the isolates were pan-susceptible (susceptible to both isoniazid and rifampicin, as well as other antibiotics if data were available).
Based on genomic sequences from those isolates, the team identified and validated 30 new genetically distinct clades: 22 novel geographically restricted sublineages and eight additional internal groups (genetically divergent groups found in sublineages that could not be further partitioned).
Results by Major Lineage
- L1, the most ancestral of the four major lineages—Seven new sublineages/internal groups were identified, including one found almost exclusively in Malawi (a country in sub-Saharan Africa) and another found at high frequencies only in Vietnam and Thailand. Furthermore, there was evidence of a geographically unrestricted generalist sublineage
- L2 showed limited internal diversity—The results supported three of the four groups previously described as proto-Beijing or ancient-Beijing and identified a new sublineage of the ancient-Beijing group. The data provided no evidence of sublineages inside the modern-Beijing group but did support three internal groups
- L3 was partitioned into four sublineages (previous publications characterized only a single group with one sublineage)
- L4—The data supported previously published schema for L4 but expanded them by defining 11 new sublineages and five internal groups
Altogether, 20 of the newly identified sublineages/internal groups had a consistent geographically restricted or unrestricted pattern.
Transmissibility
As judged by their phylogeny, L2 and L4 were the most transmissible lineages, with little difference between them. L1 was least transmissible, and L3 exhibited an intermediate level of transmissibility.
Benefits of More Granular Information
Geographically restricted sublineages may have adapted to specific human populations, supporting the recent proposal that Mtb has co-evolved with its human hosts for millennia. Conversely, genetic features of geographically unrestricted sublineages may allow them to spread efficiently in many different populations.
The expanded barcode allowed rapid identification of 69 sublineages and 26 internal groups. It should help public health officials more rapidly assess the potential for tuberculosis outbreaks. Susceptibility to certain antitubercular drugs varies by lineage, so refining Mtb classification at the sublineage level may also permit better prediction of medication response profiles.
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