Genome-wide mutational biases fuel transcriptional diversity in the Mycobacterium tuberculosis complex

11 páginas, 6 figuras.The Mycobacterium tuberculosis complex (MTBC) members display different host-specificities and virulence phenotypes. Here, we have performed a comprehensive RNAseq and methylome analysis of the main clades of the MTBC and discovered unique transcriptional profiles. The majority of genes differentially expressed between the clades encode proteins involved in host interaction and metabolic functions. A significant fraction of changes in gene expression can be explained by positive selection on single mutations that either create or disrupt transcriptional start sites (TSS). Furthermore, we show that clinical strains have different methyltransferases inactivated and thus different methylation patterns. Under the tested conditions, differential methylation has a minor direct role on transcriptomic differences between strains. However, disruption of a methyltransferase in one clinical strain revealed important expression differences suggesting indirect mechanisms of expression regulation. Our study demonstrates that variation in transcriptional profiles are mainly due to TSS mutations and have likely evolved due to differences in host characteristics.This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programmes 638553 (TB-ACCELERATE to I.C.) and 637730 (MtbTransReg to T.C.). M.B. was funded by the National Institute of Health grant AI119573. W.R.J. was funded by the National Institutes of Health grant AI26170. In addition, this work was funded by projects SAF2016-77346-R from Ministerio de Economía y Competitividad (Spanish Government) and AICO/2018/113 from Generalitat Valenciana (to I.C.), BFU2014-58656-R, BFU2017-89594-R from Ministerio de Economía y Competitividad (Spanish Government), PROMETEO/2016/122 from Generalitat Valenciana (to FGC), Wellcome Trust grant 098051 to the Sanger Institute. A.C.O. is recipient of a FPU fellowship from Ministerio de Educación y Ciencia FPU13/00913 (Spanish Government).Peer reviewe