Academic Journal
Sequence context and methylation interact to shape germline mutation rate variation at CpG sites.
| Τίτλος: | Sequence context and methylation interact to shape germline mutation rate variation at CpG sites. |
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| Συγγραφείς: | Chandra S; Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Gao Z; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. |
| Πηγή: | PLoS genetics [PLoS Genet] 2026 Jun 01; Vol. 22 (6), pp. e1011957. Date of Electronic Publication: 2026 Jun 01 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science, c2005- |
| Ιατρικοί όροι (MeSH): | DNA Methylation*/genetics , CpG Islands*/genetics , Germ-Line Mutation*/genetics , Mutation Rate*, Pan troglodytes/genetics ; Macaca mulatta/genetics ; Genome, Human/genetics ; Cytosine/metabolism ; Humans ; Animals ; Evolution, Molecular |
| Περίληψη: | A prominent example of sequence context-dependent mutation rate variation is the elevated transition rate at CpG sites, which is largely attributed to cytosine methylation. CpGs with different flanking sequences also exhibit mutation rate variation, but this variation is only partially correlated with context-specific methylation level. Here, we quantify the CpG mutation rate and mutagenic effect of methylation across sequence contexts. Using a regression framework that accounts for recurrent mutations, we analyze human polymorphisms from the gnomAD dataset to estimate mutation rates of unmethylated and methylated CpGs separately in each unique 4-mer or 6-mer context. We find that CpG mutation rate variation in the human genome is shaped by methylation at the focal cytosine, the flanking nucleotides, and interactions between them, suggesting distinct context-dependent mutation patterns for unmethylated and methylated cytosines. Our analysis further reveals that the context effects are driven by largely independent effects of upstream and downstream sequences. Notably, an upstream adenine markedly increases CpG mutation rates regardless of methylation status or downstream sequences. Furthermore, upstream and downstream sequences have similar effects in chimpanzee and rhesus macaque, indicating that some conserved, intrinsic sequence features shape CpG mutability. On the other hand, some inter-species differences, which are especially pronounced at methylated sites on the chimpanzee lineage, point to recent evolutionary changes, possibly in context-specificity of proteins governing DNA demethylation and repair processes. (Copyright: © 2026 Chandra, Gao. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.) |
| Competing Interests: | The authors have declared that no competing interests exist. |
| Σχόλια: | Update of: bioRxiv. 2026 May 10:2025.11.13.688199. doi: 10.1101/2025.11.13.688199.. (PMID: 42146426) |
| Grant Information: | R35 GM146810 United States GM NIGMS NIH HHS |
| Substance Nomenclature: | 8J337D1HZY (Cytosine) |
| Entry Date(s): | Date Created: 20260601 Date Completed: 20260608 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13245866 |
| DOI: | 10.1371/journal.pgen.1011957 |
| PMID: | 42224293 |
| Βάση Δεδομένων: | MEDLINE |
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