Mycobacterium tuberculosis has killed more than a billion in the last 200 years. Its mortality domination is due to this dynamic bacterium’s differential gene expression under a multitude of conditions and the evolution of its virulence factors. These mechanisms allow quick adaptation to evade host immune response and to thrive, despite this bacterium’s slow growth and replication rate. Translational selection on codon usage significantly correlates with gene expression in most model organisms and has been correlated with growth phenotype. Previous works show M. tuberculosis codon usage relies on other mechanisms, not simply translational selection. But no studies have yet to address the duality of rapid virulence evolution and quick amelioration necessary to endure selection de novo. The following treatise on codon evolution in M. tuberculosis are derived to address this: An exploration of M. tuberculosis’ reliance on translational selection from the perspective of de novo clinical isolates. Further exploration of selection mechanisms on codon usage not considered (intragenic signatures of codon usage bias for mRNA stability, and mutational biases like N3-N1 bias). Exploration of codon context to detect pseudogenes. And exploration of regions of unique genomic context (genomic islands) across M. tuberculosis lineages. These exploration of trends in genomic context are derived from a pangenome analysis of 97 finished genomes of Euro-American, East-Asian, East-African-Indian, and Indo-Oceanic clinical isolates. Accessory genes that evolved de novo in the pangenome provide a novel scope of evolutionary forces acting on M. tuberculosis, beyond translational selection, influencing codon usage.