biostudies-literatureUnknownCulviner PHNIAID NIH HHS<i>Mycobacterium tuberculosis</i> (Mtb) has co-evolved with humans for thousands of years causing variation in virulence, transmissibility, and disease phenotypes. To identify bacterial contributors to phenotypic diversity, we developed new RNA-seq and phylogenomic tools to capture hundreds of Mtb isolate transcriptomes, link transcriptional and genetic variation, and find associations between variants and epidemiologic traits. Across 274 Mtb clinical isolates, we uncovered unexpected diversity in expression of virulence genes which we linked to known and previously unrecognized regulators. Surprisingly, we found that many isolates harbor variants associated with decreased expression of EsxA (Esat6) and EsxB (Cfp10), which are virulence effectors, dominant T cell antigens, and immunodiagnobioRxiv : the preprint server for biology2025.05.01.651750https://www.ebi.ac.uk/biostudies/studies/S-EPMC12247772biostudies-literatureEvolution of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; transcription regulation is associated with increased transmission and drug resistance.PMC12247772F32 AI174653R21 AI187884R01 AI184469P01 AI143575Le Quang NLecca LThu DDACaws MFortune SMThuong NTTLiu QThai PVKMurray MBFrey AMCulviner PHHa DTMCalderon RDunstan SJfalseEvolution of &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt; transcription regulation is associated with increased transmission and drug resistance.<i>Mycobacterium tuberculosis</i> (Mtb) has co-evolved with humans for thousands of years causing variation in virulence, transmissibility, and disease phenotypes. To identify bacterial contributors to phenotypic diversity, we developed new RNA-seq and phylogenomic tools to capture hundreds of Mtb isolate transcriptomes, link transcriptional and genetic variation, and find associations between variants and epidemiologic traits. Across 274 Mtb clinical isolates, we uncovered unexpected diversity in expression of virulence genes which we linked to known and previously unrecognized regulators. Surprisingly, we found that many isolates harbor variants associated with decreased expression of EsxA (Esat6) and EsxB (Cfp10), which are virulence effectors, dominant T cell antigens, and immunodiagno2025-01-01T00:00:00Z2025 May2026-06-07T03:10:39.621Z2026-06-07T03:06:59.03ZS-EPMC122477724065465210.1101/2025.05.01.651750