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Genetic predisposition to mosaic Y chromosome loss in blood.

ABSTRACT: 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.

SUBMITTER: Thompson DJ

PROVIDER: S-EPMC6887549 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genetic predisposition to mosaic Y chromosome loss in blood.

Thompson Deborah J DJ Genovese Giulio G Halvardson Jonatan J Ulirsch Jacob C JC Wright Daniel J DJ Terao Chikashi C Davidsson Olafur B OB Day Felix R FR Sulem Patrick P Jiang Yunxuan Y Danielsson Marcus M Davies Hanna H Dennis Joe J Dunlop Malcolm G MG Easton Douglas F DF Fisher Victoria A VA Zink Florian F Houlston Richard S RS Ingelsson Martin M Kar Siddhartha S Kerrison Nicola D ND Kinnersley Ben B Kristjansson Ragnar P RP Law Philip J PJ Li Rong R Loveday Chey C Mattisson Jonas J McCarroll Steven A SA Murakami Yoshinori Y Murray Anna A Olszewski Pawel P Rychlicka-Buniowska Edyta E Scott Robert A RA Thorsteinsdottir Unnur U Tomlinson Ian I Moghadam Behrooz Torabi BT Turnbull Clare C Wareham Nicholas J NJ Gudbjartsson Daniel F DF Kamatani Yoichiro Y Hoffmann Eva R ER Jackson Steve P SP Stefansson Kari K Auton Adam A Ong Ken K KK Machiela Mitchell J MJ Loh Po-Ru PR Dumanski Jan P JP Chanock Stephen J SJ Forsberg Lars A LA Perry John R B JRB

Nature 20191120 7784

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism<sup>1-5</sup>, 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 th ...[more]

PMID: 31748747

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Project description:BackgroundAge-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes.ResultsUsing STRING, a publically available database of all protein-protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis.ConclusionsmLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

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Genetic predisposition to mosaic Y chromosome loss in blood.

Publications

Genetic predisposition to mosaic Y chromosome loss in blood.

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