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Because mCAs arise in individual cells prior to clonal expansion, they are typically rare and obscured in bulk data. We develop CHASM, a method for detecting chromosomal copy number alterations (CNA) from single-cell chromatin accessibility (scATAC-seq) data, a scalable modality that captures both cell state and chromosomal alterations. CHASM estimates a CNA-null background for each cell, providing an individualized expectation for chromosomal accessibility, which is critical in non-neoplastic tissues where alteration-carrying cells are not readily distinguishable from normal. By comparing each cell against its expected background, CHASM distinguishes chromosomal alterations from background variation and achieves more stringent control of false positives. We validate CHASM using in silico spike-in experiments, cross-modality comparisons with matched single-cell DNA and RNA data, and established genome-instability contrasts, including p53 deficiency and chromosome Y loss. Applied to multiple aging data sets, CHASM consistently recovers mCA burden in age-susceptible cell populations and reveals aging-associated signatures not detected by existing methods. In a cohort of 99 human kidney samples spanning age and disease conditions, CHASM identifies enrichment of mCAs in injury-associated cell states (VCAM1-high proximal tubule cells). Notably, CHASM detects the age-associated emergence of mCAs in cancer-relevant genomic regions, including chromosomes 3 gains and losses and chromosome 7 gain, in ostensibly normal cell populations. Cells harboring mCAs exhibit activation of injury-response regulatory programs and reduced epithelial identity programs, while elevated mCA burden in specific epithelial populations are associated with increased immune and stromal infiltration. Overall, we develop CHASM for high-specificity detection of CNA at single cell resolution. Applied across tissues, CHASM reveals aging-patterns of genome instability within cell types and implicates mCAs in early, pre-disease cellular states.<\/jats:p>","DOI":"10.64898\/2026.08.02.741928","type":"posted-content","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T16:25:11Z","timestamp":1786033511000},"source":"Crossref","is-referenced-by-count":0,"title":["High-Specificity Detection of Chromosomal Mosaicism Reveals Cell-Type-Specific Genomic Alteration Patterns in Aging Tissues"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6125-3253","authenticated-orcid":false,"given":"Xinyi E.","family":"Chen","sequence":"first","affiliation":[{"name":"Graduate Program in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos G.","family":"Teneche","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Adams","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parker C.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Penn\/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA"},{"name":"Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy R.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Graduate Program in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080904451181000_2026.08.02.741928v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau3879"},{"key":"2026080904451181000_2026.08.02.741928v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw0726"},{"key":"2026080904451181000_2026.08.02.741928v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01537-1"},{"key":"2026080904451181000_2026.08.02.741928v1.4","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.trecan.2019.07.007","article-title":"Cancer-Associated Mutations but No Cancer: Insights into the Early Steps of Carcinogenesis and Implications for Early Cancer Detection","volume":"5","year":"2019","journal-title":"Trends Cancer"},{"key":"2026080904451181000_2026.08.02.741928v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4673"},{"key":"2026080904451181000_2026.08.02.741928v1.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"2026080904451181000_2026.08.02.741928v1.7","doi-asserted-by":"publisher","DOI":"10.1101\/2025.03.05.25323443"},{"key":"2026080904451181000_2026.08.02.741928v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1765-3"},{"key":"2026080904451181000_2026.08.02.741928v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01371-0"},{"key":"2026080904451181000_2026.08.02.741928v1.10","doi-asserted-by":"crossref","first-page":"101342","DOI":"10.1016\/j.arr.2021.101342","article-title":"Decoding and rejuvenating human ageing genomes: Lessons from mosaic chromosomal alterations","volume":"68","year":"2021","journal-title":"Ageing Res. 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