Updated Erdman reveals tandem repeat copy number is phase-variable and impacts <i>M. tuberculosis</i> adaptation across evolutionary timescales

<i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), the pathogen responsible for tuberculosis, is often described as genetically stable. Our findings reveal an overlooked evolutionary adaptation mechanism: phase variation driven by tandem repeat copy number changes in gene promoters. Enabled by ultra-deep, long-read sequencing, we corrected errors in the Erdman reference genome and uncovered frequent, spontaneous expansions and contractions of promoter repeats upstream of genes linked to nitric oxide resistance, drug efflux, and biofilm formation. Through altering promoter strength, these dynamic promoter variants may generate phenotypic diversity within subpopulations and across diverse clinical lineages, suggesting a conserved evolutionary advantage for navigating host-imposed stress. This reframes <i>Mtb</i>'s evolutionary potential, highlighting how adaptive flexibility has been underestimated due to reliance on short-read sequencing and limited resolution of subpopulations at standard genomic depths. Our findings underscore the need to integrate structural variation-aware approaches into studies of <i>Mtb</i> pathogenesis, evolution, and drug response.