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Do Evolutionary Changes to Drug Resistant Mycobacterium Tuberculosis Genome Follow a Recently Propos

Justin Carbone, Nicholas Paradis, Chun Wu


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Mycobacterium Tuberculosis (MtB) is one of 9 gram negative mycobacterium associated with severe respiratory illness, Tuberculosis, the leading cause for death by infectious disease in adults. Mycobacterium have evolved to produce defense mechanisms to increase survival in harsh conditions and in antimicrobial presence. One protein linked to such resistance is a transporter protein within the Resistance Nodulation Drug Efflux transporters (RND) family that transport cell wall components or drugs out of the cytoplasm by proton motive force (PMF). MmpL3 uses PMF to transport critical cell wall component Trehalose Monomycolate to periplasmic space where it is incorporated into the cell wall composition giving MtB its characteristic waxy coat for primary environmental protection and drug resistance. Inhibition of this protein causes unrecoverable damage to the bacteria making MmpL3 a prime target for new drug resistant mutations. MtB is proposed to follow Darwinian positive selection theory where advantageous mutations overtake a population for increased survivability. We hypothesize that MtB follows a newly proposed theory that combines Kimura's Neutral Selection theory, Ohta Nearly-Neutral, and Darwin's Selectionist theory to be Near Neutral Balanced Selection Theory (NNBST) that has explained the evolution of SARS CoV 2 to become multidrug resistant. While an evolution theory is unconfirmed for MtB, NNBST may be the cause for mutations causing incurable strains Tuberculosis. By utilizing the H37Rv reference sequence of the MtB genome and on selective proteins linked to drug resistance such as MmpL3 and MmpL5, we believe the relative substitution rate to mutation rate (c/u) of each coding nucleotide/amino acid can be calculated. Additionally the rate of mutations in protein sequence (Ka-non-synonymous mutations) to non-mutated protein sequences (Ks-synonymous mutations) will be calculated and when plotted graphically as c/u and Ks/Ka, it will produce an L-shape distribution proving MtB follows a Near Neutral Balanced Selection theory.

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