Low rates of synonymous mutations in sequences of Mycobacterium tuberculosis GyrA and KatG genes

Summary Partial sequences of KatG and GyrA genes have been obtained from multi and extensively drug-resistant (MDR and XDR) clinical isolates of Mycobacterium tuberculosis . Nonsynonymous (DN) and synonymous (DS) distances between those sequences have been calculated by Kumar method. Results revealed that DN is significantly higher than DS between some pairs of partial GyrA sequences. We found out that DN is higher than DS in many other partial and complete sequences of KatG and GyrA coding regions deposited in GenBank. The cause of the DN > DS situation is in several nonsynonymous substitutions occurrence (which may be associated with drug-resistance or not) in the absence of synonymous substitutions. Low rates of synonymous mutations occurrence is a consequence of the strong mutational GC-pressure. Due to the high saturation of third codon positions by guanine and cytosine (78.81 ± 0.17% for all the genes from M. tuberculosis H37Rv genome), the probability to be synonymous for the nucleotide mutation of preferable (AT to GC) direction is low. Fixation of a single nonsynonymous mutation leading to drug-resistance is a consequence of Darwinian selection. This clear example of Darwinian selection on the molecular level can be confirmed by selection test (DN > DS) only in case of DN and DS calculation in pairs of sequences possessing at least two additional nonsynonymous mutations which may be neutral or excessive.