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Here we investigate how\n                    <jats:italic>Mtb<\/jats:italic>\n                    \u2014despite lacking horizontal gene transfer\u2014balances 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\u20137.4) compared with the genome-wide average (1.62 per 100 nt;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.011) 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\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-47170-w","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T15:43:46Z","timestamp":1777736626000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sequence-encoded determinants of regional mutational plasticity: comparative analysis of PE_PGRS genes in Mycobacterium tuberculosis and other bacteria"],"prefix":"10.1038","volume":"16","author":[{"given":"Veranika","family":"Slizen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henadz","family":"Hurevich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"47170_CR1","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/ni981","volume":"4","author":"SM Hingley-Wilson","year":"2003","unstructured":"Hingley-Wilson, S. 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