Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks

Dumanski, J. P.; Halvardson, J.; Davies, H.; Rychlicka-Buniowska, E.; Mattisson, J.; Torabi Moghadam, B.; Nagy, N.; Weglarczyk, K.; Bukowska-Strakova, K.; Danielsson, M.; Olszewski, P.; Piotrowski, A.; Ambicka, A.; Przewoznik, M.; Belch, L.; Grodzicki, T.; Chlosta, P. L.; Imreh, S.; Giedraitis, V.; Lannfelt, L.; Kilander, L.; Nordlund, J.; Ameur, A.; Gyllensten, U.; Johansson, A.; Jozkowicz, A.; Siedlar, M.; Klich-Raczka, A.; Jaszczynski, J.; Enroth, S.; Baran, J.; Ingelsson, M.; Rys, J.; Forsberg, L. A.

doi:10.1101/673459

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bioRxiv · 10.1101/673459

Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks

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Abstract

Mosaic loss of chromosome Y (LOY) in leukocytes has been associated with many diseases, yet it remains unclear whether this form of clonal mosaicism exerts a direct physiological effect. Here we perform single-cell and bulk RNA sequencing in leukocytes, observing considerable variation in the rate of LOY across individuals, cell types and disease state. Cells with LOY demonstrated a profound degree of transcriptional dysregulation impacting [~]500 autosomal genes. These genes are preferentially 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". Furthermore, they support the hypothesis that altered immune function in leukocytes is a mechanism directly linking LOY to disease.

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Dumanski, J. P., Halvardson, J., Davies, H., Rychlicka-Buniowska, E., Mattisson, J., Torabi Moghadam, B., Nagy, N., Weglarczyk, K., Bukowska-Strakova, K., Danielsson, M., Olszewski, P., Piotrowski, A., Ambicka, A., Przewoznik, M., Belch, L., Grodzicki, T., Chlosta, P. L., Imreh, S., Giedraitis, V., Lannfelt, L., Kilander, L., Nordlund, J., Ameur, A., Gyllensten, U., Johansson, A., Jozkowicz, A., Siedlar, M., Klich-Raczka, A., Jaszczynski, J., Enroth, S., Baran, J., Ingelsson, M., Rys, J., Forsberg, L. A.. 2019-06-18. Loss of Y in leukocytes, dysregulation of autosomal immune genes and disease risks. https://doi.org/10.1101/673459

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