{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T11:59:35Z","timestamp":1780055975801,"version":"3.54.0"},"posted":{"date-parts":[[2025,7,30]]},"group-title":"Genetic and Genomic Medicine","reference-count":108,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here, we studied 43,617 autosomal mCAs that we ascertained in 484,081 UK Biobank participants using new, high-resolution computational methods to analyze blood-derived whole-genome sequencing data. Shorter mCAs (\u22641 Mb) clustered at 53 genomic hotspots (34 previously undetected), several of which implicated chromosomal fragile sites as a recurrent source of somatic deletions. Chronic lymphocytic leukemia (CLL)-associated deletions at 13q14 were detectable in 1% of 65- to 70-year-old individuals\u2014a five-fold higher rate than previously observed\u2014suggesting opportunities for incorporating this mosaic mutation in clinical screening and in genetic association studies. Rare protein-coding variants in 38 genes associated (\n                  <jats:italic>p<\/jats:italic>\n                  &lt;1.2\u00d710\n                  <jats:sup>-<\/jats:sup>\n                  <jats:sup>5<\/jats:sup>\n                  ; FDR&lt;0.01) with clonal expansions of copy-neutral loss of heterozygosity (CN-LOH) mutations that modified the allelic dosages of these variants, implicating genes in DNA damage response, cell cycle, cytokine signaling, and protein ubiquitination pathways as targets of clonal selection via CN-LOH-induced allelic substitution. For several genes with proliferation-increasing functions, CN-LOH mutations produced revertant mosaicism, removing deleterious inherited variants. Polygenic effects of common inherited variants within CN-LOH mutations also contributed modestly to clonal selection. These results show that our blood genomes are constantly evolving as we age and often accrue mCAs in predictable ways.\n                <\/jats:p>","DOI":"10.1101\/2025.07.30.25332451","type":"posted-content","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T03:40:11Z","timestamp":1753933211000},"source":"Crossref","is-referenced-by-count":4,"title":["Patterns and drivers of 43,617 mosaic chromosomal alterations in blood"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1174-7700","authenticated-orcid":false,"given":"David","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Kamitaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronen E.","family":"Mukamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Rubinacci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Ru","family":"Loh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025080103101005000_2025.07.30.25332451v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0497-0"},{"key":"2025080103101005000_2025.07.30.25332451v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.014"},{"key":"2025080103101005000_2025.07.30.25332451v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04786-y"},{"key":"2025080103101005000_2025.07.30.25332451v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4673"},{"key":"2025080103101005000_2025.07.30.25332451v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04785-z"},{"key":"2025080103101005000_2025.07.30.25332451v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2270"},{"key":"2025080103101005000_2025.07.30.25332451v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2271"},{"key":"2025080103101005000_2025.07.30.25332451v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409405"},{"key":"2025080103101005000_2025.07.30.25332451v1.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"2025080103101005000_2025.07.30.25332451v1.10","doi-asserted-by":"crossref","unstructured":"Young, A. 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