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Genetic predisposition to mosaic Y chromosome loss in blood
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. (Lars Forsberg)
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2019 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 575, p. 652-657Article in journal (Refereed) Published
Abstract [en]

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Place, publisher, year, edition, pages
2019. Vol. 575, p. 652-657
National Category
Medical Genetics
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-397756DOI: 10.1038/s41586-019-1765-3ISI: 000500036800057PubMedID: 31748747OAI: oai:DiVA.org:uu-397756DiVA, id: diva2:1372719
Funder
EU, European Research Council, 679744
Note

Lars Forsberg and John Perry contributed equally to this work

Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-01-13Bibliographically approved

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Halvardson, JonatanDanielsson, MarcusDavies, HannaIngelsson, MartinMattisson, JonasMoghadam, Behrooz TorabiDumanski, Jan P.Forsberg, Lars A.

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Halvardson, JonatanDanielsson, MarcusDavies, HannaIngelsson, MartinMattisson, JonasMoghadam, Behrooz TorabiDumanski, Jan P.Forsberg, Lars A.Perry, John R B
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Science for Life Laboratory, SciLifeLabMedicinsk genetik och genomikGeriatrics
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