TY - JOUR
T1 - Drivers and sites of diversity in the DNA adenine methylomes of 93 mycobacterium tuberculosis complex clinical isolates
AU - Modlin, Samuel J.
AU - Conkle-Gutierrez, Derek
AU - Kim, Calvin
AU - Mitchell, Scott N.
AU - Morrissey, Christopher
AU - Weinrick, Brian C.
AU - Jacobs, William R.
AU - Ramirez-Busby, Sarah M.
AU - Hoffner, Sven E.
AU - Valafar, Faramarz
N1 - Publisher Copyright:
© Modlin et al.
PY - 2020/10
Y1 - 2020/10
N2 - This study assembles DNA adenine methylomes for 93 Mycobacterium tuberculosis complex (MTBC) isolates from seven lineages paired with fully-annotated, finished, de novo assembled genomes. Integrative analysis yielded four key results. First, methyltransferase allele-methylome mapping corrected methyltransferase variant effects previously obscured by reference-based variant calling. Second, heterogeneity analysis of partially active methyltransferase alleles revealed that intracellular stochastic methylation generates a mosaic of methylomes within isogenic cultures, which we formalize as ‘intercellular mosaic methylation’ (IMM). Mutation-driven IMM was nearly ubiquitous in the globally prominent Beijing sublineage. Third, promoter methylation is widespread and associated with differential expression in the DhsdM transcriptome, suggesting promoter HsdM-methylation directly influences transcription. Finally, comparative and functional analyses identified 351 sites hypervariable across isolates and numerous putative regulatory interactions. This multi-omic integration revealed features of methylomic variability in clinical isolates and provides a rational basis for hypothesizing the functions of DNA adenine methylation in MTBC physiology and adaptive evolution.
AB - This study assembles DNA adenine methylomes for 93 Mycobacterium tuberculosis complex (MTBC) isolates from seven lineages paired with fully-annotated, finished, de novo assembled genomes. Integrative analysis yielded four key results. First, methyltransferase allele-methylome mapping corrected methyltransferase variant effects previously obscured by reference-based variant calling. Second, heterogeneity analysis of partially active methyltransferase alleles revealed that intracellular stochastic methylation generates a mosaic of methylomes within isogenic cultures, which we formalize as ‘intercellular mosaic methylation’ (IMM). Mutation-driven IMM was nearly ubiquitous in the globally prominent Beijing sublineage. Third, promoter methylation is widespread and associated with differential expression in the DhsdM transcriptome, suggesting promoter HsdM-methylation directly influences transcription. Finally, comparative and functional analyses identified 351 sites hypervariable across isolates and numerous putative regulatory interactions. This multi-omic integration revealed features of methylomic variability in clinical isolates and provides a rational basis for hypothesizing the functions of DNA adenine methylation in MTBC physiology and adaptive evolution.
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U2 - 10.7554/eLife.58542
DO - 10.7554/eLife.58542
M3 - Article
C2 - 33107429
AN - SCOPUS:85094823261
SN - 2050-084X
VL - 9
SP - 1
EP - 33
JO - eLife
JF - eLife
M1 - e58542
ER -