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Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates

BACKGROUND: Although Mycobacterium tuberculosis (Mtb) strains exhibit genomic homology of >99%, there is considerable variation in the phenotype. The underlying mechanisms of phenotypic heterogeneity in Mtb are not well understood but epigenetic variation is thought to contribute. At present the...

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Autores principales: Ndhlovu, Victor, Kiran, Anmol, Sloan, Derek J., Mandala, Wilson, Nliwasa, Marriott, Everett, Dean B., Kumwenda, Benjamin, Mwapasa, Mphatso, Kontogianni, Konstantina, Kamdolozi, Mercy, Corbett, Elizabeth, Caws, Maxine, Davies, Gerry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749660/
https://www.ncbi.nlm.nih.gov/pubmed/33362962
http://dx.doi.org/10.7717/peerj.10432
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author Ndhlovu, Victor
Kiran, Anmol
Sloan, Derek J.
Mandala, Wilson
Nliwasa, Marriott
Everett, Dean B.
Kumwenda, Benjamin
Mwapasa, Mphatso
Kontogianni, Konstantina
Kamdolozi, Mercy
Corbett, Elizabeth
Caws, Maxine
Davies, Gerry
author_facet Ndhlovu, Victor
Kiran, Anmol
Sloan, Derek J.
Mandala, Wilson
Nliwasa, Marriott
Everett, Dean B.
Kumwenda, Benjamin
Mwapasa, Mphatso
Kontogianni, Konstantina
Kamdolozi, Mercy
Corbett, Elizabeth
Caws, Maxine
Davies, Gerry
author_sort Ndhlovu, Victor
collection PubMed
description BACKGROUND: Although Mycobacterium tuberculosis (Mtb) strains exhibit genomic homology of >99%, there is considerable variation in the phenotype. The underlying mechanisms of phenotypic heterogeneity in Mtb are not well understood but epigenetic variation is thought to contribute. At present the methylome of Mtb has not been completely characterized. METHODS: We completed methylomes of 18 Mycobacterium tuberculosis (Mtb) clinical isolates from Malawi representing the largest number of Mtb genomes to be completed in a single study using Single Molecule Real Time (SMRT) sequencing to date. RESULTS: We replicate and confirm four methylation disrupting mutations in 4 lineages of Mtb. For the first time we report complete loss of methylation courtesy of C758T (S253L) mutation in the MamB gene of Indo-oceanic lineage of Mtb. Additionally, we report a novel missense mutation G454A (G152S) in the MamA gene of the Euro-American lineage which could potentially be attributed to total disruption of methylation in the CCCAG motif but partial loss in a partner motif. Through a genomic and methylome comparative analysis with a global sample of sixteen, we report previously unknown mutations affecting the pks15/1 locus in L6 isolates. We confirm that methylation in Mtb is lineage specific although some unresolved issues still remain.
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spelling pubmed-77496602020-12-24 Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates Ndhlovu, Victor Kiran, Anmol Sloan, Derek J. Mandala, Wilson Nliwasa, Marriott Everett, Dean B. Kumwenda, Benjamin Mwapasa, Mphatso Kontogianni, Konstantina Kamdolozi, Mercy Corbett, Elizabeth Caws, Maxine Davies, Gerry PeerJ Genomics BACKGROUND: Although Mycobacterium tuberculosis (Mtb) strains exhibit genomic homology of >99%, there is considerable variation in the phenotype. The underlying mechanisms of phenotypic heterogeneity in Mtb are not well understood but epigenetic variation is thought to contribute. At present the methylome of Mtb has not been completely characterized. METHODS: We completed methylomes of 18 Mycobacterium tuberculosis (Mtb) clinical isolates from Malawi representing the largest number of Mtb genomes to be completed in a single study using Single Molecule Real Time (SMRT) sequencing to date. RESULTS: We replicate and confirm four methylation disrupting mutations in 4 lineages of Mtb. For the first time we report complete loss of methylation courtesy of C758T (S253L) mutation in the MamB gene of Indo-oceanic lineage of Mtb. Additionally, we report a novel missense mutation G454A (G152S) in the MamA gene of the Euro-American lineage which could potentially be attributed to total disruption of methylation in the CCCAG motif but partial loss in a partner motif. Through a genomic and methylome comparative analysis with a global sample of sixteen, we report previously unknown mutations affecting the pks15/1 locus in L6 isolates. We confirm that methylation in Mtb is lineage specific although some unresolved issues still remain. PeerJ Inc. 2020-12-16 /pmc/articles/PMC7749660/ /pubmed/33362962 http://dx.doi.org/10.7717/peerj.10432 Text en ©2020 Ndhlovu et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Genomics
Ndhlovu, Victor
Kiran, Anmol
Sloan, Derek J.
Mandala, Wilson
Nliwasa, Marriott
Everett, Dean B.
Kumwenda, Benjamin
Mwapasa, Mphatso
Kontogianni, Konstantina
Kamdolozi, Mercy
Corbett, Elizabeth
Caws, Maxine
Davies, Gerry
Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title_full Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title_fullStr Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title_full_unstemmed Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title_short Characterization of DNA methylation in Malawian Mycobacterium tuberculosis clinical isolates
title_sort characterization of dna methylation in malawian mycobacterium tuberculosis clinical isolates
topic Genomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749660/
https://www.ncbi.nlm.nih.gov/pubmed/33362962
http://dx.doi.org/10.7717/peerj.10432
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