Methylation in Mycobacterium tuberculosis is lineage specific with associated mutations present globally

Abstract

DNA methylation is an epigenetic modification of the genome involved in regulating crucial cellular processes, including transcription and chromosome stability. Advances in PacBio sequencing technologies can be used to robustly reveal methylation sites. The methylome of the Mycobacterium tuberculosis complex is poorly understood but may be involved in virulence, hypoxic survival and the emergence of drug resistance. In the most extensive study to date, we characterise the methylome across the 4 major lineages of M. tuberculosis and 2 lineages of M. africanum, the leading causes of tuberculosis disease in humans. We reveal lineage-specific methylated motifs and strain-specific mutations that are abundant globally and likely to explain loss of function in the respective methyltransferases. Our work provides a set of sixteen new complete reference genomes for the Mycobacterium tuberculosis complex, including complete lineage 5 genomes. Insights into lineage-specific methylomes will further elucidate underlying biological mechanisms and other important phenotypes of the epi-genome.

Figure 1

Phylogeny of the Mycobacterium tuberculosis complex isolate consensus sequences (n = 18) annotated with loss of function mutations in MTase genes. A maximum likelihood phylogenetic tree, with the % of methylated motifs and potential loss of function mutations in MTase genes annotated. Allele frequencies of putative methylation related mutations across a global collection of M. tuberculosis isolates; *EAI6 stains, **lineages 4.3 to 4.9, - indicates absence.

Figure 2

Five methylation-affecting mutations in a global collection of isolates (n = 6465; lineage 1 617 (9.5%), lineage 2 1021 (15.8%), lineage 3 993 (15.4%), lineage 4 3834 (59.3%)).