A genome language model for mapping DNA replication origins

A genome language model for mapping DNA replication origins | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results A genome language model for mapping DNA replication origins Pauline L. Pfuderer , View ORCID Profile Francisco Berkemeier , Joelle Nassar , Alastair Crisp , Jedrzej J. Jaworski , Jessica Moore , View ORCID Profile Julian E. Sale , View ORCID Profile Michael A. Boemo doi: https://doi.org/10.64898/2026.01.29.702604 Pauline L. Pfuderer 1 Cancer Research UK Cambridge Centre, Li Ka Shing Centre , Robinson Way, Cambridge, CB2 0RE, UK 2 Department of Pathology, University of Cambridge , Tennis Court Road, Cambridge, CB2 1QP, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: plp27{at}cam.ac.uk mb915{at}cam.ac.uk Francisco Berkemeier 2 Department of Pathology, University of Cambridge , Tennis Court Road, Cambridge, CB2 1QP, UK 3 Department of Genetics, University of Cambridge , Downing Street, Cambridge, CB2 3EH, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Francisco Berkemeier Joelle Nassar 4 Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge, CB2 0QH, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alastair Crisp 4 Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge, CB2 0QH, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jedrzej J. Jaworski 4 Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge, CB2 0QH, UK 5 Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital , Headley Way, Headington, Oxford OX3 9DU, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jessica Moore 1 Cancer Research UK Cambridge Centre, Li Ka Shing Centre , Robinson Way, Cambridge, CB2 0RE, UK 6 Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus , Cambridge, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julian E. Sale 4 Division of Protein & Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge, CB2 0QH, UK 7 Wellcome Sanger Institute, Wellcome Genome Campus , Hinxton, Cambridge, CB10 1SA, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Julian E. Sale Michael A. Boemo 2 Department of Pathology, University of Cambridge , Tennis Court Road, Cambridge, CB2 1QP, UK 3 Department of Genetics, University of Cambridge , Downing Street, Cambridge, CB2 3EH, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael A. Boemo For correspondence: plp27{at}cam.ac.uk mb915{at}cam.ac.uk Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Origin firing is a central process during DNA replication, but specific sequences defining replication origin usage have not been defined in human cells. Here, we show that a genome language model can accurately predict which sequences can act as an origin of replication, thereby enabling the fast and cost-effective creation of genome-wide replication origin maps. We fine-tuned a genome language model on the primary sequence of mapped human origins to establish ORILINX (ORIgin of replication Language-model Inference via Nucleotide conteXt) and found that it learns a rich representation of sequence features linked to replication initiation, extending beyond known predictive features such as GC-content and G-quadruplex motifs. When applied genome-wide, the model’s sequence-derived origin calling closely mirrors origin efficiency inferred from replication timing, suggesting that intrinsic sequence context encodes information relevant to initiation frequency. Furthermore, we performed Short Nascent Strand sequencing (SNS-seq) and Repli-seq to demonstrate that ORILINX can generalise to other mammalian genomes, such as those of mice and sheep, as well as other vertebrates such as chickens. Finally, we packaged ORILINX into a simple, easy-to-use tool which is available at https://github.com/Pfuderer/ORILINX.git . Competing Interest Statement The authors have declared no competing interest. Footnotes https://github.com/Pfuderer/ORILINX Funder Information Declared Cancer Research UK , C9685/A25117 Leverhulme Trust , RPG-2022-028 BBSRC , UKRI1912 MRC , MC_U105178808 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted January 30, 2026. Download PDF Data/Code Email Thank you for your interest in spreading the word about bioRxiv. 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Pfuderer , Francisco Berkemeier , Joelle Nassar , Alastair Crisp , Jedrzej J. Jaworski , Jessica Moore , Julian E. Sale , Michael A. Boemo bioRxiv 2026.01.29.702604; doi: https://doi.org/10.64898/2026.01.29.702604 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Genomics Subject Areas All Articles Animal Behavior and Cognition (8164) Biochemistry (19027) Bioengineering (15171) Bioinformatics (45807) Biophysics (22958) Cancer Biology (20247) Cell Biology (27493) Clinical Trials (138) Developmental Biology (14233) Ecology (21529) Epidemiology (2067) Evolutionary Biology (25940) Genetics (16436) Genomics (23978) Immunology (19175) Microbiology (43481) Molecular Biology (18481) Neuroscience (95833) Paleontology (717) Pathology (3064) Pharmacology and Toxicology (5253) Physiology (8339) Plant Biology (16378) Scientific Communication and Education (2123) Synthetic Biology (4675) Systems Biology (10449) Zoology (2436)

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