Sequencing meets cryptography: quadratic substitution error suppression through homotrimer redundancy

Sequencing meets cryptography: quadratic substitution error suppression through homotrimer redundancy | 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 Short Report Sequencing meets cryptography: quadratic substitution error suppression through homotrimer redundancy Jianfeng Sun, Adam P. Cribbs This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6710367/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 In cryptography, triple modular redundancy (TMR) is a fault-tolerant error correction technique in which a single data bit is copied and transmitted three times (e.g., 0 is encoded as 000) 1 . This technique has widely been used to protect data integrity in noisy communication channels across fields, such as aerospace systems 2 , satellite communications 3 , and safety-critical embedded devices 4 . In sequencing, the same principle of redundancy has been echoed and applied in homotrimer unique molecular identifier (UMI) demultiplexing to counteract synthesis errors and then remove PCR artefacts, ensuring accurate molecular quantification 5 . A homotrimer UMI consists of building blocks in which each nucleotide is tripled (e.g., A turns to AAA). Despite this being a simple modification, it has a positive impact on sequencing accuracy: most synthesis errors are effectively corrected through majority voting. While the empirical benefit of this approach is well established, its theoretical basis has not been formally articulated. Here, we present an interpretation grounded in information theory, specifically through the lens of repetition coding and error correction mechanisms. Molecular Biology Computational Biology Information Theory Biotechnology and Bioengineering Mathematical and Theoretical Biology Homotrimer UMI substitution errors sequencing error correction repetition code cryptography transcriptomics Full Text Additional Declarations The authors declare potential competing interests as follows: A.P.C is co-founder of Entelo Bio and inventor on several patents related to sequencing technologies filed by Oxford University Innovations. J.S declares no competing interests. 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-6710367","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":459501417,"identity":"556cde2a-f5be-4fe6-a28e-c5d62a6627b7","order_by":0,"name":"Jianfeng Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABIklEQVRIie2RMUvEMBTHUwJ1CXR9Ern7CjkKLXLe9au0FOzSm4Sjg0PhIDfJbZKPIQiHY0rAW/oNdKgIN9tFcBFz1YpKDm50yG9IeHn5kf8jCFks/xBnoZeir14Q/tXFf69/K3VfiEOUjl7B5BAFL/G2kcXjtPTq4HlyNx6E15sGtRwNvZL4zBjMDZmst2kJeejP6sw/eciZI2o0EpL4sXmWgLZcpQhIQGdcJYLmOmGBnBtEfGlUjl6heteKDkZPOyVrMGEo2q+QAKpSTRHKA+p0Ssx2ryQ7xRyMzEHeq9iF8/nxFc98oDmrRA2pUO6FafzRarMGeakiz1NreOPjAdDsqWn52WS1XNyCSSk/94T/PNUjwN6PHH7tkbltsVgsFs0H8IlZ9zvnJJoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1274-5080","institution":"University of Oxford","correspondingAuthor":true,"prefix":"","firstName":"Jianfeng","middleName":"","lastName":"Sun","suffix":""},{"id":459501502,"identity":"19883ce4-a8ed-4063-b6ca-ddb73f097e30","order_by":1,"name":"Adam P. 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