Convergent evolution and topologically disruptive polymorphisms among multidrug-resistant tuberculosis in Peru.


Grandjean, L; Gilman, RH; Iwamoto, T; Köser, CU; Coronel, J; Zimic, M; Török, ME; Ayabina, D; Kendall, M; Fraser, C; Harris, S; Parkhill, J; Peacock, SJ; Moore, DAJ; Colijn, C; (2017) Convergent evolution and topologically disruptive polymorphisms among multidrug-resistant tuberculosis in Peru. PLoS One, 12 (12). e0189838. ISSN 1932-6203 DOI: https://doi.org/10.1371/journal.pone.0189838

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Abstract

Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. Here, we use novel genome-wide analysis techniques to identify polymorphisms that are associated with drug resistance, adaptive evolution and the structure of the phylogenetic tree. A total of 471 samples from different patients collected between 2009 and 2013 in the Lima suburbs of Callao and Lima South were sequenced on the Illumina MiSeq platform with 150bp paired-end reads. After alignment to the reference H37Rv genome, variants were called using standardized methodology. Genome-wide analysis was undertaken using custom written scripts implemented in R software. High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosis ESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs. Correlation of homoplastic variant sites identified that many were significantly correlated, suggestive of epistasis. Variation in genes coding for ESX secreted proteins also significantly disrupted phylogenetic structure. Mutations in ESX genes in key antigenic epitope positions were also found to disrupt tree topology. Variation in these genes have a biologically plausible effect on immunogenicity and virulence. This makes functional characterization warranted to determine the effects of these polymorphisms on bacterial fitness and transmission.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
Research Centre: Antimicrobial Resistance Centre (AMR)
TB Centre
PubMed ID: 29281674
URI: http://researchonline.lshtm.ac.uk/id/eprint/4646010

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