Sequence-encoded determinants of regional mutational plasticity: comparative analysis of PE_PGRS genes in...

The PE_PGRS gene family in Mycobacterium tuberculosis exhibits extensive sequence variability across genotypes, which is consistent with antigenic divergence. Here we investigate how Mtb-despite lacking horizontal gene transfer-balances genomic stability with adaptive plasticity. Comparative analysis of 88 bacterial genomes reveals that PE_PGRS genes exhibit features facilitating mutability, including a significantly elevated CGGC tetramer density (mean 4.97 per 100 nt; range 1.7-7.4) compared with the genome-wide average (1.62 per 100 nt; p = 0.011) and depleted in out-of-frame stop codons, potentially conferring robustness to 1-nt and 2-nt frameshifts. Computational predictions suggest that CGGC motifs may promote secondary DNA structures, potentially destabilizing replication and contributing to replication errors, while the scarcity of out-of-frame stop codons allows continued translation beyond frameshifts, leading to changes in protein sequence and length. This dual organization may contribute to the observed adaptability of M. tuberculosis and could highlight a broader principle by which some pathogens evolve under strong constraints on horizontal gene transfer. We propose that CGGC-rich regions may function as programmed mutational hotspots across a wide range of microorganisms.