{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:14:30Z","timestamp":1778670870210,"version":"3.51.4"},"posted":{"date-parts":[[2025,10,8]]},"group-title":"Genomics","reference-count":90,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"National Institutes of Health Intramural Research Program","award":["Z1AES103266"],"award-info":[{"award-number":["Z1AES103266"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Somatic mutations are inevitable in human genomes and can lead to tumorigenesis, yet baseline mutagenesis in non-cancerous normal cells remain poorly understood. Here, we analyzed the mutation profiles of 11,949 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load (MEML) in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C\u2192T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We revealed another clock-like motif, T\u2192C substitutions in aTn motif associated with exposure to small epoxides and other S\n                  <jats:sub>N<\/jats:sub>\n                  2 electrophiles, in several tissues. Donors with several non-cancerous diseases showed significantly higher, age-independent, and concordant accumulation of aTn and nCg motifs compared to healthy donors. Motifs associated with chemical exposures showed sporadic, tissue and disease-specific mutagenesis. APOBEC-induced C\u2192T and C\u2192G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most. Together, our analyses elucidated several ongoing mutagenic processes in normal human tissues and provided a robust analytical framework for identifying mutagenic sources from somatic mutation catalogues.\n                <\/jats:p>","DOI":"10.1101\/2025.10.07.681015","type":"posted-content","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T08:50:14Z","timestamp":1759913414000},"source":"Crossref","is-referenced-by-count":3,"title":["Motif-Centered Analyses Reveal Universal and Tissue-Specific Mutagenic Mechanisms Operating in the Human Body"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1022-1822","authenticated-orcid":false,"given":"Safia Mahabub","family":"Sauty","sequence":"first","affiliation":[{"name":"Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1189-6511","authenticated-orcid":false,"given":"Yun-Chung","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3048-2576","authenticated-orcid":false,"given":"Leszek J.","family":"Klimczak","sequence":"additional","affiliation":[{"name":"Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Durham, NC 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-1836","authenticated-orcid":false,"given":"Dmitry A.","family":"Gordenin","sequence":"additional","affiliation":[{"name":"Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC 27709"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051303350542000_2025.10.07.681015v4.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12213"},{"key":"2026051303350542000_2025.10.07.681015v4.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3816"},{"key":"2026051303350542000_2025.10.07.681015v4.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477"},{"key":"2026051303350542000_2025.10.07.681015v4.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.70.8.2281"},{"issue":"9","key":"2026051303350542000_2025.10.07.681015v4.5","first-page":"2311","article-title":"Errors in DNA replication as a basis of malignant changes","volume":"34","year":"1974","journal-title":"Cancer research"},{"key":"2026051303350542000_2025.10.07.681015v4.6","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5742(03)00010-3"},{"key":"2026051303350542000_2025.10.07.681015v4.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2014.06.001"},{"key":"2026051303350542000_2025.10.07.681015v4.8","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mrrev.2015.12.002","article-title":"The importance of de novo mutations for pediatric neurological disease--It is not all in utero or birth trauma","volume":"767","year":"2016","journal-title":"Mutation research Reviews in mutation research"},{"key":"2026051303350542000_2025.10.07.681015v4.9","doi-asserted-by":"publisher","DOI":"10.1002\/em.22215"},{"key":"2026051303350542000_2025.10.07.681015v4.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab4082"},{"key":"2026051303350542000_2025.10.07.681015v4.11","doi-asserted-by":"crossref","unstructured":"Maslov AY , Vijg J . Somatic mutation burden in relation to aging and functional life span: implications for cellular reprogramming and rejuvenation. Curr Opin Genet Dev. 2023;83:102132.","DOI":"10.1016\/j.gde.2023.102132"},{"issue":"2","key":"2026051303350542000_2025.10.07.681015v4.12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41596-023-00914-8","article-title":"Analyzing somatic mutations by single-cell whole-genome sequencing","volume":"19","year":"2024","journal-title":"Nature protocols"},{"key":"2026051303350542000_2025.10.07.681015v4.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-111320-090436"},{"issue":"D1","key":"2026051303350542000_2025.10.07.681015v4.14","doi-asserted-by":"crossref","first-page":"D1291","DOI":"10.1093\/nar\/gkaf1297","article-title":"SomaMutDB 2.0: A comprehensive database for exploring somatic mutations and their functional impact in normal human tissues","volume":"54","year":"2026","journal-title":"Nucleic Acids Res"},{"key":"2026051303350542000_2025.10.07.681015v4.15","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab914"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.16","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1038\/s41598-023-34631-9","article-title":"Mutational signatures association with replication timing in normal cells reveals similarities and differences with matched cancer tissues","volume":"13","year":"2023","journal-title":"Scientific reports"},{"key":"2026051303350542000_2025.10.07.681015v4.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03822-7"},{"key":"2026051303350542000_2025.10.07.681015v4.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1943-3"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.19","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.celrep.2012.12.008","article-title":"Deciphering signatures of mutational processes operative in human cancer","volume":"3","year":"2013","journal-title":"Cell reports"},{"key":"2026051303350542000_2025.10.07.681015v4.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00920-0"},{"key":"2026051303350542000_2025.10.07.681015v4.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922472117"},{"key":"2026051303350542000_2025.10.07.681015v4.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.10.016"},{"issue":"7","key":"2026051303350542000_2025.10.07.681015v4.23","doi-asserted-by":"crossref","first-page":"104535","DOI":"10.1016\/j.isci.2022.104535","article-title":"APOBEC mutagenesis is low in most types of non-B DNA structures","volume":"25","year":"2022","journal-title":"iScience"},{"issue":"6","key":"2026051303350542000_2025.10.07.681015v4.24","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.celrep.2015.09.077","article-title":"APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions","volume":"13","year":"2015","journal-title":"Cell reports"},{"issue":"6","key":"2026051303350542000_2025.10.07.681015v4.25","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1016\/j.celrep.2014.05.012","article-title":"APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development","volume":"7","year":"2014","journal-title":"Cell reports"},{"key":"2026051303350542000_2025.10.07.681015v4.26","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3670"},{"key":"2026051303350542000_2025.10.07.681015v4.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.1253462"},{"key":"2026051303350542000_2025.10.07.681015v4.28","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256930"},{"key":"2026051303350542000_2025.10.07.681015v4.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0576-7"},{"key":"2026051303350542000_2025.10.07.681015v4.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.007"},{"key":"2026051303350542000_2025.10.07.681015v4.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.08.005"},{"key":"2026051303350542000_2025.10.07.681015v4.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1969-6"},{"key":"2026051303350542000_2025.10.07.681015v4.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.07.014"},{"key":"2026051303350542000_2025.10.07.681015v4.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0708-0"},{"key":"2026051303350542000_2025.10.07.681015v4.35","doi-asserted-by":"publisher","DOI":"10.1038\/nature21386"},{"key":"2026051303350542000_2025.10.07.681015v4.36","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3378"},{"key":"2026051303350542000_2025.10.07.681015v4.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.02.012"},{"key":"2026051303350542000_2025.10.07.681015v4.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04972-y"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.39","doi-asserted-by":"crossref","first-page":"4711","DOI":"10.1038\/s41467-025-59923-8","article-title":"APOBEC affects tumor evolution and age at onset of lung cancer in smokers","volume":"16","year":"2025","journal-title":"Nature communications"},{"key":"2026051303350542000_2025.10.07.681015v4.40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009302"},{"key":"2026051303350542000_2025.10.07.681015v4.41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad611"},{"key":"2026051303350542000_2025.10.07.681015v4.42","doi-asserted-by":"crossref","unstructured":"Lodato MA , Rodin RE , Bohrson CL , et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science. 2017.","DOI":"10.1101\/221960"},{"key":"2026051303350542000_2025.10.07.681015v4.43","doi-asserted-by":"crossref","unstructured":"Miller MB , Huang AY , Kim J , et al. Somatic genomic changes in single Alzheimer\u2019s disease neurons. Nature. 2022.","DOI":"10.1038\/s41586-022-04640-1"},{"key":"2026051303350542000_2025.10.07.681015v4.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.aab1785"},{"key":"2026051303350542000_2025.10.07.681015v4.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1672-7"},{"key":"2026051303350542000_2025.10.07.681015v4.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.02.025"},{"key":"2026051303350542000_2025.10.07.681015v4.47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006385"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.48","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13073-018-0539-0","article-title":"MutationalPatterns: comprehensive genome-wide analysis of mutational processes","volume":"10","year":"2018","journal-title":"Genome Medicine"},{"key":"2026051303350542000_2025.10.07.681015v4.49","doi-asserted-by":"crossref","unstructured":"Wang Y , Robinson PS , Coorens THH , et al. APOBEC mutagenesis is a common process in normal human small intestine. Nat Genet. 2023.","DOI":"10.1038\/s41588-022-01296-5"},{"key":"2026051303350542000_2025.10.07.681015v4.50","doi-asserted-by":"crossref","unstructured":"Li R , Du Y , Chen Z , et al. Macroscopic somatic clonal expansion in morphologically normal human urothelium. 2020;370(6512):82-9.","DOI":"10.1126\/science.aba7300"},{"key":"2026051303350542000_2025.10.07.681015v4.51","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad756"},{"key":"2026051303350542000_2025.10.07.681015v4.52","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2702"},{"key":"2026051303350542000_2025.10.07.681015v4.53","doi-asserted-by":"crossref","unstructured":"Wickham H. Data analysis. ggplot2: elegant graphics for data analysis: Springer; 2016. p. 189\u2013201.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"2026051303350542000_2025.10.07.681015v4.54","unstructured":"Hoppe J. Adobe Illustrator CC: a complete course and compendium of features. 1st edition ed. San Rafael, CA: Rocky Nook, Inc.; 2020."},{"key":"2026051303350542000_2025.10.07.681015v4.55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107696200"},{"key":"2026051303350542000_2025.10.07.681015v4.56","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-31390-7_10"},{"key":"2026051303350542000_2025.10.07.681015v4.57","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad305"},{"key":"2026051303350542000_2025.10.07.681015v4.58","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa150"},{"key":"2026051303350542000_2025.10.07.681015v4.59","doi-asserted-by":"crossref","unstructured":"Vijayraghavan S , Porcher L , Mieczkowski PA , Saini N . Acetaldehyde makes a distinct mutation signature in single-stranded DNA. Nucleic Acids Res. 2022.","DOI":"10.1101\/2022.03.22.485364"},{"key":"2026051303350542000_2025.10.07.681015v4.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2016.05.027"},{"key":"2026051303350542000_2025.10.07.681015v4.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03836-1"},{"key":"2026051303350542000_2025.10.07.681015v4.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.06.036"},{"key":"2026051303350542000_2025.10.07.681015v4.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.03.030"},{"key":"2026051303350542000_2025.10.07.681015v4.64","doi-asserted-by":"crossref","unstructured":"Mertz TM , Collins CD , Dennis M , Coxon M , Roberts SA . APOBEC-Induced Mutagenesis in Cancer. Annu Rev Genet. 2022.","DOI":"10.1146\/annurev-genet-072920-035840"},{"key":"2026051303350542000_2025.10.07.681015v4.65","doi-asserted-by":"publisher","DOI":"10.1021\/bi960001x"},{"key":"2026051303350542000_2025.10.07.681015v4.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.04.024"},{"key":"2026051303350542000_2025.10.07.681015v4.67","doi-asserted-by":"crossref","unstructured":"Saini N , Gordenin DA . Hypermutation in single-stranded DNA. DNA Repair (Amst). 2020;91\u201392:102868.","DOI":"10.1016\/j.dnarep.2020.102868"},{"issue":"10","key":"2026051303350542000_2025.10.07.681015v4.68","doi-asserted-by":"crossref","first-page":"jkae196","DOI":"10.1093\/g3journal\/jkae196","article-title":"Hypomorphic mutation in the large subunit of replication protein A affects mutagenesis by human APOBEC cytidine deaminases in yeast","volume":"14","year":"2024","journal-title":"G3 Genes|Genomes|Genetics"},{"key":"2026051303350542000_2025.10.07.681015v4.69","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000464"},{"key":"2026051303350542000_2025.10.07.681015v4.70","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-112414-054714"},{"key":"2026051303350542000_2025.10.07.681015v4.71","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03477-4"},{"key":"2026051303350542000_2025.10.07.681015v4.72","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1670-9"},{"key":"2026051303350542000_2025.10.07.681015v4.73","doi-asserted-by":"crossref","unstructured":"Yoshida K , Gowers KHC , Lee-Six H , et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature. 2020.","DOI":"10.1164\/ajrccm-conference.2020.201.1_MeetingAbstracts.A4090"},{"key":"2026051303350542000_2025.10.07.681015v4.74","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06333-9"},{"issue":"8","key":"2026051303350542000_2025.10.07.681015v4.75","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1158\/2767-9764.CRC-24-0496","article-title":"Characterization of Mutational Signatures in Tumors from a Large Chinese Population","volume":"5","year":"2025","journal-title":"Cancer Research Communications"},{"key":"2026051303350542000_2025.10.07.681015v4.76","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09219-0"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.77","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","year":"2013","journal-title":"Pharmacology & therapeutics"},{"key":"2026051303350542000_2025.10.07.681015v4.78","doi-asserted-by":"crossref","unstructured":"Chen C , Wang DW . Chapter Seven - Cytochrome P450-CYP2 Family-Epoxygenase Role in Inflammation and Cancer. In: Hardwick JP, editor. Advances in Pharmacology: Academic Press; 2015. p. 193-221.","DOI":"10.1016\/bs.apha.2015.04.005"},{"key":"2026051303350542000_2025.10.07.681015v4.79","doi-asserted-by":"crossref","unstructured":"Kay J , Thadhani E , Samson L , Engelward B . Inflammation-induced DNA damage, mutations and cancer. DNA Repair. 2019;83:102673.","DOI":"10.1016\/j.dnarep.2019.102673"},{"key":"2026051303350542000_2025.10.07.681015v4.80","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp615"},{"issue":"12","key":"2026051303350542000_2025.10.07.681015v4.81","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1038\/s43587-025-01011-z","article-title":"Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis","volume":"5","year":"2025","journal-title":"Nature Aging"},{"key":"2026051303350542000_2025.10.07.681015v4.82","doi-asserted-by":"crossref","unstructured":"Sauty SM , Shine J , Bostan H , et al. Comparative whole-genome analyses of articular chondrocytes and skin fibroblasts reveal distinct genome instability landscapes in mesenchymal cell types. bioRxiv. 2026.","DOI":"10.64898\/2026.02.13.705814"},{"key":"2026051303350542000_2025.10.07.681015v4.83","doi-asserted-by":"publisher","DOI":"10.1111\/ahg.70013"},{"issue":"1","key":"2026051303350542000_2025.10.07.681015v4.84","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1038\/s41467-022-31341-0","article-title":"Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells","volume":"13","year":"2022","journal-title":"Nature Communications"},{"key":"2026051303350542000_2025.10.07.681015v4.85","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00930-y"},{"key":"2026051303350542000_2025.10.07.681015v4.86","doi-asserted-by":"publisher","DOI":"10.1038\/s44320-024-00054-5"},{"key":"2026051303350542000_2025.10.07.681015v4.87","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.03.018"},{"key":"2026051303350542000_2025.10.07.681015v4.88","doi-asserted-by":"crossref","unstructured":"Querido I , Pinto C , Arinto P , et al. A Novel Deleterious Variant and a Founder Effect in Four New Families of MBD4-Associated Neoplasia Syndrome Recruited Over a Period of 20 Years. Clinical genetics. 2025.","DOI":"10.1111\/cge.70014"},{"key":"2026051303350542000_2025.10.07.681015v4.89","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2955"},{"key":"2026051303350542000_2025.10.07.681015v4.90","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgx131"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.07.681015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T10:35:33Z","timestamp":1778668533000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.07.681015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":90,"URL":"https:\/\/doi.org\/10.1101\/2025.10.07.681015","relation":{},"subject":[],"published":{"date-parts":[[2025,10,8]]},"subtype":"preprint"}}