Programmed DNA variability as a general evolutionary principle: insights from analysis of PE_PGRS genes in Mycobacterium tuberculosis

Programmed DNA variability as a general evolutionary principle: insights from analysis of PE_PGRS genes in Mycobacterium tuberculosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Programmed DNA variability as a general evolutionary principle: insights from analysis of PE_PGRS genes in Mycobacterium tuberculosis Veranika Slizen, Henadz Hurevich This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7880908/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The PE_PGRS gene family in Mycobacterium tuberculosis (Mtb) exhibits extensive sequence variability across genotypes, supporting 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 are structurally optimized for mutability: they are enriched in sterically active tetramers such as CGGC (1.7–7.4% against a genome average of 1.62%) and depleted in out-of-frame stop codons, conferring robustness to 1-nt and 2-nt frameshifts. CGGC motifs are predicted to promote secondary DNA structures that destabilize replication and lead to replication errors, while the low abundance of out-of-frame stop codons allows continued translation beyond frameshifts, generating abrupt changes in protein sequence and length. This dual organization may underlie the extraordinary adaptability of Mtb and highlight a broader principle by which pathogens evolve under strong constraints on horizontal gene transfer. We propose that CGGC-rich regions function as universal programmed mutational hotspots across a wide range of microorganisms. Biological sciences/Microbiology/Microbial genetics/Bacterial genetics Health sciences/Medical research/Genetics research Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTablesexplanation.docx Explanatory notes for supplementary tables S1-S4 Supplementarytables1234.docx Supplementary tables S1-S4 Supplementaryfigure1explanation.docx Explanatory notes for Supplementary figure S1 Supplementaryfigure1.docx Supplementary figure 1 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7880908","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":531130306,"identity":"7e122829-a93f-4da2-b158-f83440e387c6","order_by":0,"name":"Veranika 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