Leukocytes with chromosome Y loss have reduced abundance of the cell surface immunoprotein CD99

Mattisson, Jonas; Danielsson, Marcus; Hammond, Maria; Davies, Hanna; Gallant, Caroline J.; Nordlund, Jessica; Raine, Amanda; Edén, Malin; Kilander, Lena; Ingelsson, Martin; Dumanski, Jan P.; Halvardson, Jonatan; Forsberg, Lars A.

doi:10.1038/s41598-021-94588-5

Cited by 29 publications

(48 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, blood, brain, and liver are three tissues where LOY has been detected or inferred in humans 11 , 25 – 27 , 32 . Possibly, mosaic loss of the Y chromosome has a direct effect on the functioning of cells as seen in the blood 40 . We found that differences in the frequency of LOY between tissues in the PCR approach were no longer significant when we examined the data from whole-genomes; we noted that this result may seem contradictory.…”

Section: Discussionmentioning

confidence: 99%

Rats exhibit age-related mosaic loss of chromosome Y

Orta¹,

Bush

Gutiérrez-Mariscal³

et al. 2021

Commun Biol

View full text Add to dashboard Cite

Mosaic loss of the Y chromosome (LOY) is the most frequent chromosomal aberration in aging men and is strongly correlated with mortality and disease. To date, studies of LOY have only been performed in humans, and so it is unclear whether LOY is a natural consequence of our relatively long lifespan or due to exposure to human-specific external stressors. Here, we explored whether LOY could be detected in rats. We applied a locus-specific PCR and target sequencing approach that we used as a proxy to estimate LOY in 339 samples covering eleven tissues from young and old individuals. We detected LOY in four tissues of older rats. To confirm the results from the PCR screening, we re-sequenced 60 full genomes from old rats, which revealed that the Y chromosome is the sole chromosome with low copy numbers. Finally, our results suggest that LOY is associated with other structural aberrations on the Y chromosome and possibly linked to the mosaic loss of the X chromosome. This is the first report, to our knowledge, demonstrating that the patterns of LOY observed in aging men are also present in a rodent, and conclude that LOY may be a natural process in placental mammals.

show abstract

Section: Discussionmentioning

confidence: 99%

Rats exhibit age-related mosaic loss of chromosome Y

Orta¹,

Bush

Gutiérrez-Mariscal³

et al. 2021

Commun Biol

View full text Add to dashboard Cite

show abstract

“…Moreover, almost 500 autosomal genes have been shown to display LOY-associated transcriptional effect (LATE) by dysregulation in peripheral leukocytes with LOY, including many genes important for physiological immune functions [ 11 ]. Leukocytes with chromosome Y loss also display a reduced abundance of the cell surface immunoprotein CD99, encoded by a gene positioned in the pseudoautosomal regions of chromosomes X and Y, and essential for several key properties of leukocytes and immune system functions [ 26 ]. In aggregate, LOY in blood cells could either act as a barometer of genomic imbalance in- and outside of the hematopoietic system and furthermore, it is plausible that immune cells with this aneuploidy could be directly linked with disease etiology in human disease conditions with an immunological component.…”

Section: Discussionmentioning

confidence: 99%

“…Epidemiological investigations show that the presence of LOY in blood leukocytes is associated with increased risk for all-cause mortality [ 2 , 12 ] and a range of common diseases in men, such as hematological and non-hematological cancer [ 2 , 10 , 13 – 17 ], Alzheimer’s disease [ 3 ], autoimmune diseases [ 18 , 19 ], cardiovascular events [ 12 , 20 ], age-related macular degeneration [ 21 ] and type 2 diabetes [ 12 ]. The diverse range of associated outcomes suggest that LOY could act as a biomarker of generalized genomic instability [ 4 , 5 ] as well as be linked with direct physiological effects; through impaired functions of affected leukocytes [ 2 – 6 , 11 , 17 , 22 – 26 ]. Hence, identification of men with LOY occurring in peripheral blood could help to pinpoint men in the general population who are at the highest risk of common disease from an earlier age, for targeted intervention.…”

Section: Introductionmentioning

confidence: 99%

A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer’s disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men. Results We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62–1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05–6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61–0.64] to 0.695 [CI 0.67–0.71], p < 0.001). Conclusions Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Bruhn-Olszewska

Davies

Sarkisyan

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

COVID-19 shows an unexplained, strong male bias for severity and mortality. Loss of Y (LOY) in myeloid cells is a risk factor candidate in COVID-19 because of associations with many age-related diseases and its effect on transcription of immune genes. We report the highest levels of LOY in cells that are crucial for the development of severe COVID-19 phenotype, such as low-density neutrophils, granulocytes, and monocytes reaching 46%, 32%, and 29%, respectively, from men with critical COVID-19 (n=139). LOY in sorted subpopulations of leukocytes correlated with increased thrombocyte count, thromboembolic events, invasive mechanical ventilation and a history of vessel disease. In recovered patients, LOY decreased in whole blood and peripheral blood mononuclear cells. Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, notably affecting HLA class I and II genes important for antigen presentation. The data support a link between LOY and emergency myelopoiesis as well as the role of LOY in modulation of COVID-19 severity. Our results might also be relevant for other viral infections showing similar male bias.

show abstract

Leukocytes with chromosome Y loss have reduced abundance of the cell surface immunoprotein CD99

Cited by 29 publications

References 55 publications

Rats exhibit age-related mosaic loss of chromosome Y

Rats exhibit age-related mosaic loss of chromosome Y

A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells

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

Contact Info

Product

Resources

About