Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
Creators: name: Dumanski, Jan P.
name: Halvardson, Jonatan
name: Davies, Hanna
name: Rychlicka-Buniowska, Edyta
name: Mattisson, Jonas
name: Moghadam, Behrooz Torabi
name: Nagy, Noemi
name: Węglarczyk, Kazimierz
name: Bukowska-Strakova, Karolina
name: Danielsson, Marcus
name: Olszewski, Paweł
name: Piotrowski, Arkadiusz
name: Oerton, Erin
name: Ambicka, Aleksandra
name: Przewoźnik, Marcin
name: Bełch, Łukasz
name: Grodzicki, Tomasz
name: Chłosta, Piotr L.
name: Imreh, Stefan
name: Giedraitis, Vilmantas
name: Kilander, Lena
name: Nordlund, Jessica
name: Ameur, Adam
name: Gyllensten, Ulf
name: Johansson, Åsa
name: Józkowicz, Alicja
name: Siedlar, Maciej
name: Klich-Rączka, Alicja
name: Jaszczyński, Janusz
name: Enroth, Stefan
name: Baran, Jarosław
name: Ingelsson, Martin
name: Perry, John R. B.
name: Ryś, Janusz
name: Forsberg, Lars A.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Original Article
LOY
Mosaic loss of chromosome Y
Differential gene expression
LATE
LOY-associated transcriptional effects

description: Funder: Kjell och Märta Beijers Stiftelse (SE)
description: Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792
description: Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794
description: Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359
description: Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599
description: Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE)
description: Funder: Science for Life Laboratory (SE)
description: Funder: Fundacja na rzecz Nauki Polskiej (PL)
description: Funder: Uppsala University
description: Abstract: Epidemiological 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.