AI-Driven Comparative Genomics for Human Regenerative Gene Discovery Using Axolotl as a Model

AI-Driven Comparative Genomics for Human Regenerative Gene Discovery Using Axolotl as a Model | 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 Research Article AI-Driven Comparative Genomics for Human Regenerative Gene Discovery Using Axolotl as a Model Honore BAHO VITA, Dawit Fsaha Welegebriel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9321844/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 Humans typically repair injuries through incomplete structural restoration and fibrosis, whereas axolotls can regenerate complex appendages. Whether this difference reflects loss of key regeneration genes or incomplete deployment of conserved programs remains unresolved. Here, we integrated public axolotl limb regeneration RNA-seq data with cross-species mapping and supervised machine learning to prioritize human-side counterparts of regeneration-associated genes. A total of 710 genes were consistently upregulated across 3, 6, and 14 days post amputation. OrthoFinder directly mapped 558 genes to human orthologs, and a local BLASTp rescue workflow increased the total number of genes with human protein matches to 690, leaving 20 unresolved. After removing genes already used in model training, 640 candidates were scored by a Random Forest classifier, and 590 exceeded the workflow decision threshold for downstream analysis. Functional enrichment with g:Profiler showed strong overrepresentation of cell cycle, DNA replication, embryo development, protein localization to chromosome, and nuclear organization terms. Together, these findings support a model in which humans retain a broad set of genes associated with regenerative programs observed in axolotl, while also emphasizing that computational conservation and prioritization alone do not prove functional activation in human injury contexts. This study provides a ranked candidate set for future experimental validation. Computational Biology Bioinformatics Epigenetics & Genomics comparative genomics axolotl regeneration RNA-seq analysis differential expression ortholog detection machine learning feature engineering gene ranking regenerative genes bioinformatics Full Text Additional Declarations The authors declare 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. 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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-9321844","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":617593702,"identity":"265b6723-b1cc-41ae-a653-5ecc2edd6343","order_by":0,"name":"Honore BAHO VITA","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYBACAwh1AMRgfABk8fCRooUZxOFhI0ULmwSISVCLOXvvwccVFXfkzdl7zCq/5tjJsDEwP3x0A48Wy55zyYZnzjwz3Nlzxuy27LZkoMPYjI1z8DnsRo6ZZGPbYcYNN9LSbktuYwZq4WGTJqzl32F7kJZiyW31xGppOJy44UbyMcaP2w4ToeXMGWPDhmPPkjecOXxYmnHbcR42ZkJ+Od5j+LCh5o7thuONjR9/bqu252dvfvgYnxYUwMwDJolVDgKMP0hRPQpGwSgYBSMGAAAKgUyQMVdaYwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9416-2451","institution":"Grigore T. 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