An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome
Abstract Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. Ho...
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doaj-81df4f864ec84de0b601906353fb88042020-12-08T08:18:13ZengNature Publishing GroupScientific Reports2045-23222019-03-019111110.1038/s41598-019-41692-2An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylomePaula J. Gomez-Gonzalez0Nuria Andreu1Jody E. Phelan2Paola Florez de Sessions3Judith R. Glynn4Amelia C. Crampin5Susana Campino6Philip D. Butcher7Martin L. Hibberd8Taane G. Clark9Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineGenome Institute of SingaporeFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical MedicineFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineInstitute for Infection & Immunity, St George’s University of LondonFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineFaculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical MedicineAbstract Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA, likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation.https://doi.org/10.1038/s41598-019-41692-2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paula J. Gomez-Gonzalez Nuria Andreu Jody E. Phelan Paola Florez de Sessions Judith R. Glynn Amelia C. Crampin Susana Campino Philip D. Butcher Martin L. Hibberd Taane G. Clark |
spellingShingle |
Paula J. Gomez-Gonzalez Nuria Andreu Jody E. Phelan Paola Florez de Sessions Judith R. Glynn Amelia C. Crampin Susana Campino Philip D. Butcher Martin L. Hibberd Taane G. Clark An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome Scientific Reports |
author_facet |
Paula J. Gomez-Gonzalez Nuria Andreu Jody E. Phelan Paola Florez de Sessions Judith R. Glynn Amelia C. Crampin Susana Campino Philip D. Butcher Martin L. Hibberd Taane G. Clark |
author_sort |
Paula J. Gomez-Gonzalez |
title |
An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
title_short |
An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
title_full |
An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
title_fullStr |
An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
title_full_unstemmed |
An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
title_sort |
integrated whole genome analysis of mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2019-03-01 |
description |
Abstract Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA, likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation. |
url |
https://doi.org/10.1038/s41598-019-41692-2 |
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