Immune cells lacking Y chromosome have widespread dysregulation of autosomal genes

Abstract

Mosaic loss of chromosome Y (LOY) in blood is linked to increased risk for morbidity and mortality in men. LOY is the most common acquired mutation and is associated with diseases such as cancer and Alzhemer's disease. We studied DNA, RNA and proteins in bulk, sorted-and single-cells in vivo and in vitro. We show that Alzheimer's disease and prostate cancer patients had more LOY in NK cells and CD4+ T-lymphocytes, respectively. Furthermore, gene expression was profoundly altered in cells with LOY in a pleiotropic fashion and autosomal genes important for normal immune cell functions showed LOY associated transcriptional effect. Proteomic analysis also indicated that LOY leaves a footprint in the plasma proteome. We provide the first mechanistic explanation for the associations between LOY in blood and risk for disease in other organs.Recent epidemiological analyses have challenged the view that LOY in blood cells is phenotypically neutral. Studies have identified increased risks for men with LOY in connection with all-cause mortality [8,9], Alzheimer's disease [10], various forms of cancer [8,[11][12][13], autoimmune conditions [14,15], age-related macular degeneration [16], cardiovascular disease [17], type 2 diabetes and obesity [9]. Furthermore, it has been known for centuries that males have a shorter life expectancy [18][19][20]. Hence, LOY as a male specific risk factor, showing reproducible associations with various common disorders, could help explaining this difference.LOY in blood is the most frequent post-zygotic mutation, detectable in 20% of the UK Biobank male population [21], reaching 40% in 80 years old males [22], and 57% in 93 years old males [23]. Furthermore, LOY is not restricted to the hematopoietic system, since it has also been described in other non-cancerous tissues, although with much lower frequencies [17,23]. Our understanding of why LOY occurs is also limited. Strong associations with age and smoking have been reported [8,10,24,25] and these factors are related to a continuously increasing mutational load throughout the genome in all somatic cells, eventually also affecting genes that are responsible for correct segregation of chromosomes. Inherited genetic predisposition for LOY has also been described [21,25,26].It is not known whether associations between LOY and increased risks for disease represent causal relationships, and if so, what the underlying mechanisms could be. The challenge that we address here is to move from epidemiological associations to mechanistic explanations on multiple levels of analysis such as DNA, mRNA and proteins. Specifically, we studied: (i) frequency of LOY in subsets of leukocytes from patients with prostate cancer (PC), Alzheimer's disease (AD) as well as controls; (ii) changes in transcriptomes of single cells and cellular subsets in bulk; and (iii) alterations of plasma protein levels in men with LOY. Different distribution of LOY in six types of sorted leukocytes among men with AD and PCStudies of associations between LOY and various outcomes hav...

Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals

“…It is therefore unknown which blood cell type(s) that were affected with LOY in the subjects of the dataset, and thus, if the observed variation in clonal trajectories are an effect from LOY in different cell types. However, results from a recent analysis [18] shows that the level of LOY varies substantially between different types of leukocytes in blood, with generally higher levels in myeloid compared with lymphoid lineages, and that LOY often occurs as an oligoclonal event in peripheral blood. To further elucidate if and how the developmental trajectories of LOY-clones varies between the different types of leukocytes in blood, studies of the frequency of LOY in different cells types in serially collected subjects will be informative.…”

“…However, recent studies suggest that the opposite as LOY has been found to be associated with increased risk for all-cause mortality [4,5] as well as a growing list of disease such as various forms of cancer [4,[6][7][8][9][10], autoimmune conditions [11,12], Alzheimer's disease [13], major cardiovascular events [5,14], schizophrenia [15], diabetes [5] as well as age-related macular degeneration (AMD) [16]. As a male specific genetic risk factor for common disease, LOY in leukocytes might help explain why men live shorter lives [1,4,13,17], likely as an effect of compromised immune system functions in circulating immune cells without chromosome Y [18].…”

Sex Differences in Immunity to Viral Infections

“…The effect of ChrY polymorphisms on IAV pathogenesis are independent of sex steroids, underpinning the mechanistical features of genetic effects on sex-differences in immunity ( 152 ). Another important mechanism associated to the XY complement is loss of the Y chromosomes (LOY) primarily in leukocytes during aging, leading to widespread dysregulation of autosomal genes among leukocytes in men with possible implications on immunity ( 153 – 155 ). Taken together, sex chromosome complement, activity of regulatory elements on sex chromosomes, and the expression of sex chromosomal genes contribute to sex differences in immunity to viral infections.…”

Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

“…It is detectable in whole blood DNA from >40% of the men above the age of 70 years [3] and reaches 57% in the analysis of 93year-old men, indicating an increasing frequency with age [4]. Recent single-cell analyses of peripheral blood mononuclear cells (PBMCs) from 29 aging men (median age 80 years, range 64-94 years) identified cells with LOY in every studied subject, making this the most common post-zygotic mutation [5]. In serial analysis of male blood samples LOY is a dynamic process [6].…”

“…Thus, carriers of LOY have an increased risk for diseases both inside and outside of the hematopoietic system and the mechanism(s) behind these associations largely remain to be elucidated. Recent studies suggest that LOY could have a direct physiological role through LOY-associated transcriptional effects (LATE) on global gene expression in a pleiotropic manner as well as being a biomarker of genomic instability in somatic tissues [5]. Moreover, dysregulation of immune genes, including pathways related to viral life-cycle, was pronounced in LOY-cells [5,15].…”