Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
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Published:2021-04
Issue:8
Volume:78
Page:4019-4033
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ISSN:1420-682X
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Container-title:Cellular and Molecular Life Sciences
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language:en
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Short-container-title:Cell. Mol. Life Sci.
Author:
Dumanski Jan P.ORCID, Halvardson Jonatan, Davies Hanna, Rychlicka-Buniowska Edyta, Mattisson Jonas, Moghadam Behrooz Torabi, Nagy Noemi, Węglarczyk Kazimierz, Bukowska-Strakova Karolina, Danielsson Marcus, Olszewski Paweł, Piotrowski Arkadiusz, Oerton Erin, Ambicka Aleksandra, Przewoźnik Marcin, Bełch Łukasz, Grodzicki Tomasz, Chłosta Piotr L., Imreh Stefan, Giedraitis Vilmantas, Kilander Lena, Nordlund Jessica, Ameur Adam, Gyllensten Ulf, Johansson Åsa, Józkowicz Alicja, Siedlar Maciej, Klich-Rączka Alicja, Jaszczyński Janusz, Enroth Stefan, Baran Jarosław, Ingelsson Martin, Perry John R. B., Ryś Janusz, Forsberg Lars A.ORCID
Abstract
AbstractEpidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
Funder
H2020 European Research Council Vetenskapsrådet Kjell och Märta Beijers Stiftelse Hjärnfonden Cancerfonden Alzheimerfonden Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse Science for Life Laboratory Fundacja na rzecz Nauki Polskiej Uppsala University
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Cellular and Molecular Neuroscience,Pharmacology,Molecular Biology,Molecular Medicine
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