Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

Jody E. Phelan; Francesc Coll; Indra Bergval; Richard M. Anthony; Rob Warren; Samantha L. Sampson; Nicolaas C. Gey van Pittius; Judith R. Glynn; Amelia C. Crampin; Adriana Alves; Theolis Barbosa Bessa; Susana Campino; Keertan Dheda; Louis Grandjean; Rumina Hasan; Zahra Hasan; Anabela Miranda; David J. Moore; Stefan Panaiotov; Joao Perdigao; Isabel Portugal; Patricia Sheen; Erivelton de Oliveira Sousa; Elizabeth M. Streicher; Paul D. van Helden; Miguel Viveiros; Martin L. Hibberd; Arnab Pain; Ruth McNerney; Taane G. Clark

doi:10.1186/s12864-016-2467-y

Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

Jody E. Phelan, Francesc Coll, Indra Bergval, Richard M. Anthony, Rob Warren, Samantha L. Sampson, Nicolaas C. Gey van Pittius, Judith R. Glynn, Amelia C. Crampin, Adriana Alves, Theolis Barbosa Bessa, Susana Campino, Keertan Dheda, Louis Grandjean, Rumina Hasan, Zahra Hasan, Anabela Miranda, David J. Moore, Stefan Panaiotov, Joao PerdigaoIsabel Portugal, Patricia Sheen, Erivelton de Oliveira Sousa, Elizabeth M. Streicher, Paul D. van Helden, Miguel Viveiros, Martin L. Hibberd, Arnab Pain, Ruth McNerney, Taane G. Clark

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Abstract

Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

Original language	English (US)
Journal	BMC Genomics
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s12864-016-2467-y
State	Published - Feb 29 2016

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https://repository.kaust.edu.sa/bitstream/10754/600452/1/art3A10.11862Fs12864-016-2467-y.pdf

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Phelan, J. E., Coll, F., Bergval, I., Anthony, R. M., Warren, R., Sampson, S. L., Gey van Pittius, N. C., Glynn, J. R., Crampin, A. C., Alves, A., Bessa, T. B., Campino, S., Dheda, K., Grandjean, L., Hasan, R., Hasan, Z., Miranda, A., Moore, D. J., Panaiotov, S., ... Clark, T. G. (2016). Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages. BMC Genomics, 17(1). https://doi.org/10.1186/s12864-016-2467-y

@article{fbfbe20c9b814dbc872fa3fe100f192e,

title = "Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages",

abstract = "Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.",

author = "Phelan, {Jody E.} and Francesc Coll and Indra Bergval and Anthony, {Richard M.} and Rob Warren and Sampson, {Samantha L.} and {Gey van Pittius}, {Nicolaas C.} and Glynn, {Judith R.} and Crampin, {Amelia C.} and Adriana Alves and Bessa, {Theolis Barbosa} and Susana Campino and Keertan Dheda and Louis Grandjean and Rumina Hasan and Zahra Hasan and Anabela Miranda and Moore, {David J.} and Stefan Panaiotov and Joao Perdigao and Isabel Portugal and Patricia Sheen and {de Oliveira Sousa}, Erivelton and Streicher, {Elizabeth M.} and {van Helden}, {Paul D.} and Miguel Viveiros and Hibberd, {Martin L.} and Arnab Pain and Ruth McNerney and Clark, {Taane G.}",

note = "KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: JP is supported by a Biotechnology and Biological Sciences Research Council UK PhD studentship. FC was the recipient of a Bloomsbury Research Fund PhD studentship. SLS receives funding from the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (UID 86539). AP is supported by the KAUST faculty baseline research fund (KAUST-BRF). TGC receives funding from the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

year = "2016",

month = feb,

day = "29",

doi = "10.1186/s12864-016-2467-y",

language = "English (US)",

volume = "17",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "Springer Verlag",

number = "1",

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Phelan, JE, Coll, F, Bergval, I, Anthony, RM, Warren, R, Sampson, SL, Gey van Pittius, NC, Glynn, JR, Crampin, AC, Alves, A, Bessa, TB, Campino, S, Dheda, K, Grandjean, L, Hasan, R, Hasan, Z, Miranda, A, Moore, DJ, Panaiotov, S, Perdigao, J, Portugal, I, Sheen, P, de Oliveira Sousa, E, Streicher, EM, van Helden, PD, Viveiros, M, Hibberd, ML, Pain, A, McNerney, R & Clark, TG 2016, 'Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages', BMC Genomics, vol. 17, no. 1. https://doi.org/10.1186/s12864-016-2467-y

TY - JOUR

T1 - Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

AU - Phelan, Jody E.

AU - Coll, Francesc

AU - Bergval, Indra

AU - Anthony, Richard M.

AU - Warren, Rob

AU - Sampson, Samantha L.

AU - Gey van Pittius, Nicolaas C.

AU - Glynn, Judith R.

AU - Crampin, Amelia C.

AU - Alves, Adriana

AU - Bessa, Theolis Barbosa

AU - Campino, Susana

AU - Dheda, Keertan

AU - Grandjean, Louis

AU - Hasan, Rumina

AU - Hasan, Zahra

AU - Miranda, Anabela

AU - Moore, David J.

AU - Panaiotov, Stefan

AU - Perdigao, Joao

AU - Portugal, Isabel

AU - Sheen, Patricia

AU - de Oliveira Sousa, Erivelton

AU - Streicher, Elizabeth M.

AU - van Helden, Paul D.

AU - Viveiros, Miguel

AU - Hibberd, Martin L.

AU - Pain, Arnab

AU - McNerney, Ruth

AU - Clark, Taane G.

N1 - KAUST Repository Item: Exported on 2020-10-01 Acknowledgements: JP is supported by a Biotechnology and Biological Sciences Research Council UK PhD studentship. FC was the recipient of a Bloomsbury Research Fund PhD studentship. SLS receives funding from the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (UID 86539). AP is supported by the KAUST faculty baseline research fund (KAUST-BRF). TGC receives funding from the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2016/2/29

Y1 - 2016/2/29

N2 - Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

AB - Background Approximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies. Results To elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules. Conclusions This, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.

UR - http://hdl.handle.net/10754/600452

UR - http://www.biomedcentral.com/1471-2164/17/151

UR - http://www.scopus.com/inward/record.url?scp=84959198490&partnerID=8YFLogxK

U2 - 10.1186/s12864-016-2467-y

DO - 10.1186/s12864-016-2467-y

M3 - Article

C2 - 26923687

SN - 1471-2164

VL - 17

JO - BMC Genomics

JF - BMC Genomics

IS - 1

ER -

Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

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Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

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