Minimising mutation load as a mechanism for low-dose hyper-radiosensitivity and induced radioresistance

Minimising mutation load as a mechanism for low-dose hyper-radiosensitivity and induced radioresistance | 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 Minimising mutation load as a mechanism for low-dose hyper-radiosensitivity and induced radioresistance Szabolcs Polgár, Balázs Madas This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6674497/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 Low-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR) are unexpected features of cellular survival curves that challenge classical radiobiological models. While often interpreted phenomenologically, their underlying biological purpose remains unclear. Here we propose that these effects reflect an evolved strategy by which tissues minimise mutational burden through context-dependent cell elimination. We introduce the Minimum Mutation Load (MML) model, a mechanistic framework in which irradiated cells assess their survival based on local intercellular signals that reflect neighbourhood damage. This cooperative behaviour balances the benefit of removing highly damaged cells with the mutational cost of their replacement. Using a curated dataset of 99 clonogenic survival experiments, we show that the MML model replicates key features of HRS and IRR across diverse conditions, with an average adjusted R² of 0.74, and performs comparably to the established Induced Repair (IR) model. Unlike the IR model, which is phenomenological, the MML model provides biologically interpretable parameters with independent theoretical grounding. The model suggests that mutation minimisation may be an organising principle of tissue homeostasis. These findings support a new conceptual framework in which tissue-level cooperation, rather than purely cell-intrinsic responses, governs somatic maintenance and cancer suppression. Biological sciences/Computational biology and bioinformatics/Computational models Physical sciences/Physics/Biological physics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MMLmodel.txt Source code written in python 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-6674497","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":457362643,"identity":"f3427691-a94a-43a8-9642-850a4d78edaf","order_by":0,"name":"Szabolcs Polgár","email":"","orcid":"https://orcid.org/0000-0003-1133-3890","institution":"HUN-REN Centre for Energy Research, Institute for Energy Security and Environmental Safety","correspondingAuthor":false,"prefix":"","firstName":"Szabolcs","middleName":"","lastName":"Polgár","suffix":""},{"id":457362642,"identity":"a985d3a1-a082-4661-b580-1f82611d592f","order_by":1,"name":"Balázs Madas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBklEQVRIiWNgGAWjYBACAwbmBigzgYHhA5AwQEjh0sKI0MI4g2QtzDzEaDFnP9j48ccfhmj+9uTHn20q0hjMJXIPMFdU3AEyErBqsexJbJaQbGPInXHmmZl0zpkcBssZeQmMZ848AzKwazE4kNggYdjAkNtwI8GMObetgsHgRo75z8a2w0AGDi3nHzb/SPjDkDv/Rvrnz5b/wFoMGBv/4dFyI7FN4gAbQ+4GoEppxoYcqJYG3FosZzxss2xsk8jdeOZNmWTPsTQegzNvDBgbjh0GMh5gDzH+5MM3f/yxyZ13PH3zhx81yXIGx4G2NNQcBjKw2wIFEnAWDwZjFIyCUTAKRgHpAADQ7WVjard3RgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-0698-4982","institution":"HUN-REN Centre for Energy Research, Institute for Energy Security and Environmental Safety","correspondingAuthor":true,"prefix":"","firstName":"Balázs","middleName":"","lastName":"Madas","suffix":""}],"badges":[],"createdAt":"2025-05-15 16:31:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6674497/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6674497/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83673185,"identity":"5a5172ec-6164-4f7b-a731-83f15d4db617","added_by":"auto","created_at":"2025-05-30 13:59:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1024037,"visible":true,"origin":"","legend":"","description":"","filename":"manuscriptfinalwofc.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6674497/v1_covered_98f6caca-e30e-449d-9813-6adb5be22c62.pdf"},{"id":82892788,"identity":"f8fe501f-4d02-434f-9eee-668ab1f19b89","added_by":"auto","created_at":"2025-05-16 12:21:00","extension":"txt","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25069,"visible":true,"origin":"","legend":"Source code written in python","description":"","filename":"MMLmodel.txt","url":"https://assets-eu.researchsquare.com/files/rs-6674497/v1/dfa3ca9c1e3f43bd3f9638cf.txt"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Minimising mutation load as a mechanism for low-dose hyper-radiosensitivity and induced radioresistance","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6674497/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6674497/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLow-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR) are unexpected features of cellular survival curves that challenge classical radiobiological models. 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