Drivers and sites of diversity in the DNA adenine methylomes of 93 mycobacterium tuberculosis complex clinical isolates

Samuel J. Modlin, Derek Conkle-Gutierrez, Calvin Kim, Scott N. Mitchell, Christopher Morrissey, Brian C. Weinrick, William R. Jacobs, Sarah M. Ramirez-Busby, Sven E. Hoffner, Faramarz Valafar

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Article numbere58542
Pages (from-to)1-33
Number of pages33
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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