Proteogenomic Investigation of Strain Variation in Clinical Mycobacterium tuberculosis Isolates

Abstract
Mycobacterium tuberculosis consists of a large number of different strains that display unique virulence characteristics. Whole-genome sequencing has revealed substantial genetic diversity among clinical M. tuberculosis isolates, and elucidating the phenotypic variation encoded by this genetic diversity will be of utmost importance to fully understand M. tuberculosis biology and pathogenicity. In this study we integrated whole-genome sequencing and mass spectrometry (GeLC-MS/MS) to reveal strain-specific characteristics in the proteomes of two clinical M. tuberculosis Latin American-Mediterranean isolates. Using this approach we identified 59 peptides containing single amino acid variants, which covered ~9% of all total coding nonsynonymous single nucleotide variants detected by whole-genome sequencing. Furthermore, we identified 29 distinct peptides that mapped to a hypothetical protein not present in the M. tuberculosis H37Rv reference proteome. Here we provide evidence for the expression of this protein in the clinical M. tuberculosis SAWC3651 isolate. The strain-specific databases enabled confirmation of genomic differences (i.e. large genomic regions of difference and nonsynonymous single nucleotide variants) in these two clinical M. tuberculosis isolates and allowed strain differentiation at the proteome level. Our results contribute to the growing field of clinical microbial proteogenomics and can improve our understanding of phenotypic variation in clinical M. tuberculosis isolates.

Citation
Heunis T, Dippenaar A, Warren RM, van Helden PD, van der Merwe RG, et al. (2017) Proteogenomic Investigation of Strain Variation in Clinical Mycobacterium tuberculosis Isolates. Journal of Proteome Research. Available: http://dx.doi.org/10.1021/acs.jproteome.7b00483.

Acknowledgements
This work was supported by the South African National Research Foundation (NRF), South African Medical Research Council (SAMRC), Harry Crossley Foundation, Claude Leon Foundation, the Department of Biomedical Sciences, Stellenbosch University and King Abdullah University of Science and Technology (KAUST award number BAS/1/1020-01-01). S.L. Sampson is funded by the South African Research Chairs Initiative of the Department of Science and Technology and NRF of South Africa, award number UID 86539. D.L. Tabb is funded by the SAMRC under the South African Tuberculosis Bioinformatics Initiative.

Publisher
American Chemical Society (ACS)

Journal
Journal of Proteome Research

DOI
10.1021/acs.jproteome.7b00483

Additional Links
http://pubs.acs.org/doi/abs/10.1021/acs.jproteome.7b00483

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