{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T21:06:12Z","timestamp":1783112772868,"version":"3.54.6"},"reference-count":66,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T00:00:00Z","timestamp":1777766400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/Y513003\/1"],"award-info":[{"award-number":["BB\/Y513003\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The loss of chromosome Y (LOY) in leukocytes is the most prevalent form of clonal mosaicism observed in older men. Previous studies provided multiple pieces of evidence for the effect of LOY on the immune system and connected LOY to elevated risk of all major causes of mortality, including cardiovascular diseases and cancer. Despite these associations, the dynamic effects of LOY across the developmental trajectories of immune cell populations remain unclear. We utilized single\u2010cell RNA\u2010sequencing data from the peripheral blood mononuclear cells of 416 male donors (median age\u2009=\u200968) from the OneK1K cohort. LOY was identified in 45,304 cells (8.76%) and exhibited cell type\u2013specific effects on immune cells along the differentiation trajectories. The largest frequency was detected in monocytes (18.6% in classical and 17.1% in nonclassical) with a progressive decrease along the transition trajectory from 22.6% to 15.8% (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>adj<\/jats:sub>\n                    \u2009=\u20092.00\u2009\u00d7\u200910\n                    <jats:sup>\u221211<\/jats:sup>\n                    ), and a gradual reduction in the expression of nonclassical markers\n                    <jats:italic>LYPD2<\/jats:italic>\n                    and\n                    <jats:italic>C1QA<\/jats:italic>\n                    . LOY is associated with a profibrotic signature in classical monocytes marked by downregulation of\n                    <jats:italic>IL1B<\/jats:italic>\n                    (log FC\u2009=\u2009\u22120.22,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>fdr<\/jats:sub>\n                    \u2009=\u20092.84\u2009\u00d7\u200910\n                    <jats:sup>\u22126<\/jats:sup>\n                    ) and MYC\u2010regulated genes (log FC\u2009=\u2009\u22120.25,\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>fdr<\/jats:sub>\n                    \u2009=\u20092.22\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ), consistent with previous observations that LOY\u2010associated macrophages are polarized toward a fibrotic rather than inflammatory phenotype in cardiac and pulmonary injury. Notably, we detected aberrant expression of\n                    <jats:italic>XIST<\/jats:italic>\n                    , the essential X\u2010chromosome\u2010inactivation lncRNA that is not normally expressed in males, and upregulation of genes known to escape X\u2010inactivation, including male\u2010biased cancer\u2010related genes\n                    <jats:italic>KDM6A<\/jats:italic>\n                    ,\n                    <jats:italic>DDX3X<\/jats:italic>\n                    ,\n                    <jats:italic>KDM5C<\/jats:italic>\n                    , and\n                    <jats:italic>ZRSR2<\/jats:italic>\n                    . Our results indicate associations between LOY and cell type\u2013specific transcriptional changes, including aberrant X\u2010inactivation features.\n                  <\/jats:p>","DOI":"10.1111\/acel.70528","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T21:02:29Z","timestamp":1777842149000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of Chromosome Y Associates With Altered Immune Cell Trajectories and X\u2010Inactivation Features"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0164-7773","authenticated-orcid":false,"given":"Ahmed","family":"Dawoud","sequence":"first","affiliation":[{"name":"School of Biological Sciences University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Green","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Southampton  Southampton UK"},{"name":"Faculty of Medicine University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4390-0872","authenticated-orcid":false,"given":"Owen","family":"Rackham","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.266601"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010021\u201002414\u2010y"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010020\u20100591\u20103"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/348448a0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1032"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022015646"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931\u2010023\u201002357\u2010x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade9746"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010021\u201003822\u2010w"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.014"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3726"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010015\u20100844\u20105"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2966"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","unstructured":"Francis M. B. R.Gorman T. B.Bigdeli et\u00a0al.2024.\u201cMulti\u2010Ancestry Genome\u2010Wide Association Meta\u2010Analysis of Mosaic Loss of Chromosome Y in the Million Veteran Program Identifies 167 Novel Loci.\u201dmedRxiv.https:\/\/doi.org\/10.1101\/2024.04.24.24306301.","DOI":"10.1101\/2024.04.24.24306301"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409405"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010492"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.116.001544"},{"key":"e_1_2_10_21_1","volume-title":"Hoffbrand's Essential Haematology","author":"Hoffbrand V.","year":"2024"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.09430915"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2270"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408617"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100414\u20106"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2271"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201059963\u20108"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.18338"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0321-x"},{"key":"e_1_2_10_30_1","volume-title":"Package \u2018Diptest\u2019. R Package Version 0.75\u20135. R: A Language and Environment for Statistical Computing","author":"Maechler M.","year":"2013"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201094588\u20105"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864\u2010024\u201010168\u20107"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.041"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010019\u20100336\u20103"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2022.01.003"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170355"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.06.006"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/53A.1.M20"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2022.10.002"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn3100"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3542"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102009\u201008\u2010236422"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.16417.1"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-631747"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864\u2010018\u20104772\u20100"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201012705\u20105"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1765-3"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.Cd\u201020\u20101513"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature24265"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100089\u20109"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010021\u201000913\u2010z"},{"key":"e_1_2_10_53_1","doi-asserted-by":"crossref","unstructured":"Wang D. N.Hadad S.Moss et\u00a0al.2024.\u201cAssociation Between Mosaic Loss of Chromosome Y and Pulmonary Fibrosis Susceptibility and Severity.\u201dPreprint bioRxiv.https:\/\/doi.org\/10.1101\/2024.05.25.595885.","DOI":"10.1101\/2024.05.25.595885"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201005806\u20101"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421\u2010020\u20100168\u20109"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaf657"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201060049\u2010y"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102010\u201012\u2010326355"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3821"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010023\u201001075\u20107"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201011947\u20107"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf3041"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124347"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/jimmun\/vkaf370"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3545"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-030409-101212"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70528","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70528","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70528","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T22:19:31Z","timestamp":1779401971000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":66,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1111\/acel.70528"],"URL":"https:\/\/doi.org\/10.1111\/acel.70528","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"2025-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70528"}}