---
title: "Methylation shapes vertebrate dinucleotide composition: CpG depletion and AG/CT enrichment across"
id: "biorxiv-0-five-hundred-million-years-of-methylation-tracing-the-mutational-origins-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-five-hundred-million-years-of-methylation-tracing-the-mutational-origins-of"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1?rss=1"
published_at: "2026-09-05T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Methylation shapes vertebrate dinucleotide composition: CpG depletion and AG/CT enrichment across
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-five-hundred-million-years-of-methylation-tracing-the-mutational-origins-of
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1?rss=1)
- **Published At:** 2026-09-05T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study analysed 753 **vertebrate** and 481 **invertebrate** genomes to test how methylation-associated deamination shapes dinucleotide composition. - **CpG depletion** emerged as the dominant axis of dinucleotide variation among vertebrate genomes. - Unexpectedly, the strongest between-genome correlate of CpG loss was **AG/CT** enrichment rather than the immediate mutational products **TpG/CpA**, which showed dataset-wide mass balance but little intergenome variation. - A forward-evolution model based on measured seven-nucleotide human germline substitution rates failed to produce CpG depletion or AG/CT enrichment when **methylated-CpG mutability** was excluded. - Adding a single CpG-specific mutability term, calibrated only to the mammalian CpG ratio, reproduced both CpG depletion and AG/CT enrichment, indicating AG/CT arises as a second-order consequence of context-dependent mutation networks. - Within genomes, CpG depletion was strongest in **transposable elements** and decreased with distance from them. - Across vertebrates the methylation-associated axis tracked Amniota more closely than endothermy and associated with an expanded **GC-rich isochore** compartment. - A Machine Learning analysis identified CpG depletion and AG/CT enrichment as principal features distinguishing vertebrates from invertebrates, where both signals were substantially attenuated. - Overall, the authors conclude a long-term methylation-associated mutational axis organizes vertebrate dinucleotide composition, and the clearest marker is **AG/CT** enrichment rather than the immediate deamination products.
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Tania Bobbo 1 Institute of Agricultural Biology and Biotechnology, National Research Council; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tania%2BBobbo%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Bobbo%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATania%2BBobbo%2B) * [ORCID record for Tania Bobbo](http://orcid.org/0000-0003-0328-8903 "Open in new tab") Wageesha Widuranga Waththe Liyanage 2 University of Padova; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Wageesha%2BWiduranga%2BWaththe%2BLiyanage%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Waththe%20Liyanage%20WW&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AWageesha%2BWiduranga%2BWaththe%2BLiyanage%2B) * [ORCID record for Wageesha Widuranga Waththe Liyanage](http://orcid.org/0009-0000-0117-1803 "Open in new tab") Alessio Boattini 3 Universita degli Studi di Bologna; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Alessio%2BBoattini%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Boattini%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAlessio%2BBoattini%2B) * [ORCID record for Alessio Boattini](http://orcid.org/0000-0002-0758-4454 "Open in new tab") Pietro Lio 4 Department of Computer Science and Technology, University of Cambridge * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Pietro%2BLio%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Lio%20P&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3APietro%2BLio%2B) * [ORCID record for Pietro Lio](http://orcid.org/0000-0002-0540-5053 "Open in new tab") Cristian Taccioli 2 University of Padova; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Cristian%2BTaccioli%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Taccioli%20C&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ACristian%2BTaccioli%2B) * [ORCID record for Cristian Taccioli](http://orcid.org/0000-0003-2995-5612 "Open in new tab") * For correspondence: cristian.taccioli@unipd.it * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5759739/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5759739/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5759739/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5759739/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Methylation-associated deamination removes CpG from vertebrate genomes, but how it affects the dinucleotide profile remains unresolved. We analysed 753 vertebrate and 481 invertebrate genomes to test whether CpG loss defines a compositional axis and to identify its strongest signature. CpG depletion was the dominant axis of vertebrate dinucleotide variation. Unexpectedly, its strongest between-genome correlate was AG/CT rather than the direct mutational product TpG/CpA, which showed the expected dataset-wide mass balance but varied little among genomes. A forward-evolution model based on measured seven-nucleotide human germline substitution rates produced neither CpG depletion nor AG/CT enrichment when methylated-CpG mutability was excluded. Adding one CpG-specific mutability term, calibrated only to the mammalian CpG ratio, reproduced both features, identifying AG/CT as a second-order consequence of the context-dependent mutation network. Within genomes, CpG depletion was strongest in transposable elements and weakened with distance from them. Across vertebrates, the axis followed Amniota more closely than endothermy and was associated with an expanded GC-rich isochore compartment. A Machine Learning analysis shows that CpG depletion and AG/CT were the principal features separating vertebrates from invertebrates, in which both were markedly attenuated. Thus, a methylation-associated axis organises vertebrate dinucleotide composition, and its strongest marker is not the immediate product of CpG deamination. ### Competing Interest Statement The authors have declared no competing interest. 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-NC 4.0 International license](http://creativecommons.org/licenses/by-nc/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.09.02.747768v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/09/05/2026.09.02.747768.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Five hundred million years of methylation: tracing the mutational origins of vertebrate genome composition Tania Bobbo, Wageesha Widuranga Waththe Liyanage, Alessio Boattini, Pietro Lio, Cristian Taccioli bioRxiv 2026.09.02.747768; doi: https://doi.org/10.64898/2026.09.02.747768 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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