Mosaic Loss Of Chromosome Research Articles

Mosaic loss of chromosome Y, tobacco smoking, and risk of age-related lung diseases: insights from two prospective cohorts.

Little is known about the underlying relationship between mosaic loss of chromosome Y (mLOY), the most common chromosomal alterations in older men, and the risk of age-related lung diseases. We included 217 780 participants from the UK Biobank and 42 859 participants from the China Kadoorie Biobank. The mLOY events were detected using the Mosaic Chromosomal Alterations pipeline. Outcomes included all lung diseases, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). Cox proportional hazard models were fitted to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of mLOY with lung diseases in both cohorts. The combined HRs were derived from meta-analysis. Results from two cohorts showed that expanded mLOY was associated with increased risks of all lung diseases [HR (95% CI): 1.19 (1.04, 1.37)], COPD [HR (95% CI): 1.20 (1.13, 1.28)], lung cancer [HR (95% CI): 1.34 (1.21, 1.48)], and IPF [HR (95% CI): 1.34 (1.16, 1.56) in UKB]. There was evidence of positive interactions between mLOY and smoking behavior [relative excess risk due to interaction (97.5%CI)>0]. Additionally, we observed that current smokers with expanded mLOY had the highest risk of incident lung diseases in both cohorts. mLOY may be a novel predictor for age-related lung diseases. For current smokers carrying mLOY, adopting quitting smoking behavior may contribute to substantially reduce their risk of incident lung diseases.

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity.

We adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length. The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. Our study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study

Mosaic loss of chromosome Y (mLOY) is the most common somatic alteration as men aging and may reflect genome instability. PM exposure is a major health concern worldwide, but its effects with genetic factors on mLOY has never been investigated. Here we explored the associations of PM2.5 and PM10 exposure with mLOY of 10,158 males measured via signal intensity of 2186 probes in male-specific chromosome-Y region from Illumina array data. The interactive and joint effects of PM2.5 and PM10 with genetic factors and smoking on mLOY were further evaluated. Compared with the lowest tertiles of PM2.5 levels in each exposure window, the highest tertiles in the same day, 7-, 14-, 21-, and 28-day showed a 0.005, 0.006, 0.007, 0.007, and 0.006 decrease in mLRR-Y, respectively (all P < 0.05), with adjustment for age, BMI, smoking pack-years, alcohol drinking status, physical activity, education levels, season of blood draw, and experimental batch. Such adverse effects were also observed in PM10-mLOY associations. Moreover, the unweighted and weighted PRS presented significant negative associations with mLRR-Y (both P < 0.001). Participants with high PRS and high PM2.5 or PM10 exposure in the 28-day separately showed a 0.018 or 0.019 lower mLRR-Y level [β (95 %CI) = −0.018 (−0.023, −0.012) and − 0.019 (−0.025, −0.014), respectively, both P < 0.001], when compared to those with low PRS and low PM2.5 or PM10 exposure. We also observed joint effects of PM with smoking on exacerbated mLOY. This large study is the first to elucidate the impacts of PM2.5 exposure on mLOY, and provides key evidence regarding the interactive and joint effects of PM with genetic factors on mLOY, which may promote understanding of mLOY development, further modifying and increasing healthy aging in males.

Loss of chromosome Y in regulatory T cells

BackgroundMosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples.ResultsRegulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells.ConclusionsHere, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.

Mosaic loss of chromosome Y and cardiovascular disease.

Mosaic loss of chromosome Y and cardiovascular disease.

Glyphosate Use and Mosaic Loss of Chromosome Y among Male Farmers in the Agricultural Health Study.

Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce. We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers. We analyzed blood-derived DNA from 1,606 farmers years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or mLOY affecting of cells (expanded mLOY). Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; (95% CI: 1.00, 3.07), ] but not with overall mLOY; the associations with expanded mLOY were most apparent among older ( years of age) men [ (95% CI: 1.13, 4.67), ], never smokers [ (95% CI: 1.04, 5.21), ], and nonobese men [ (95% CI: 0.99, 4.19), ]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use. High lifetime glyphosate use could be associated with mLOY affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies. https://doi.org/10.1289/EHP12834.

Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke.

Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke. The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses. LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses (P<0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5]). We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted.

Issue Information

Front cover: Urashima Taro, the protagonist of a Japanese fairy tale, returned from his undersea utopia with his youth intact after hundreds of years, but as soon as he was exposed to the smoke from the souvenir Tamatebako (jeweled box), he turned into an old man. This painting depicts how the smoke causes Urashima Taro to lose not only his youth but also the Y chromosome in a part of his cells. Mosaic loss of chromosome Y (mLOY) is commonly observed in older men and has been linked to ageing and cancer, and has also been found to increase the risk of heart disease (Sano et al. (2022) Science 377: 292–297, DOI: 10.1126/science.abn3100). We referred to Fukami &amp; Miyado (2022) Reprod. Med. Biol. 21: e12445, DOI: 10.1002/rmb2.12445 for the depiction of chromosomes. Designed by TRAIS Co., Ltd. (Kobe, Japan).image

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

CBMS-4 CHROMOSOMAL INSTABILITY IN GLIOMA USING SPECTRAL KARYOTYPING METHOD

Abstract Introduction Chromosomal instability, the cell condition in which chromosome mis-segregation occur at a high frequency during cell division, has been considered to be involved in the molecular mechanisms that give rise to the complex genetic background of glioma. However, most of this phenomenon has been based on researches using cell line, and there have been few studies of chromosomal instability in clinical specimens of gliomas. Methods Primary cell culture was obtained from 11 glioma specimens (eight Glioblastoma (GBM), one Anaplastic PXA (aPXA), one Astrocytoma, and one Ependymoma), which was removed at our hospital, and chromosomes of up to five cells per case were analyzed by the SKY method. Chromosome instability was quantified by two parameters, one was AS (Aneuploidy score), which means the number of gain or loss of whole of the chromosome, and the other was SS: Structural abnormality score, which means the number of chromosome structural abnormality per cell. In addition, the phenotypes, which were characteristic of chromosomal instability were observed individually. Results Each quantitative value was as follows: GBM; AS:2.30±0.51 /SS:1.64±0.38, aPXA; AS :1.40±1.33 / SS:8.20±0.99, Astrocytoma and Ependymoma; AS:0.00 /SS:0.00, suggesting that chromosomal instability was associated with GBM and aPXA. Chromosome 7 amplification was most frequent in GBM (57%), and Mosaic loss of chromosome Y was also observed in 60% of males. Some characteristic karyotypes which suggest the phenomenon of Chromothripsis or Double minute were also observed. The karyotype concordance rate in the cases with p53 mutation was 60%, and that with p53 wild type was 100%, indicating that the p53 mutation increased the genotype heterogeneity in the same specimen. Discussion In clinical specimens of gliomas, aneuploidy and structural abnormalities were identified in GBM and aPXA, suggesting that chromosomal instability contributes to their cellular phenotype and malignancy.

Mosaic Loss of Chromosome Y in Peripheral Blood Cells and Cognitive Status in the Amish

AbstractBackgroundMosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY as a risk factor for AD in the Mid‐Western Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.MethodThe median of the log R ratio (mLRRY) from SNP array data within the male‐specific region of chromosome Y was used to measure the degree of mLOY. A mLRRY value lower than the 99% confidence limit of the experimental distribution was scored to estimate the frequency of mLOY. The cognitive status was assigned via consensus review of cognitive examination results. Men in 3 age groups (65‐74, 75‐84, &gt;=85) were included. The linear mixed model with a polygenic component to account for relatedness and a transformation to address non‐normality was used to estimate familial correlations and heritability. A likelihood ratio test of association was performed with age at blood sampling and age of cognitive exam as covariates.ResultAfter extensive QC, 533 participants (mean age=75.42±6.17) were included and 39 (7.9%) had a detectable level of mLOY. mLOY frequency increased with age (p&lt;1.0x10‐6): 1.0% (65‐74; n=103), 8.4% (75‐84; n=334) and 14.3% (85+; n=96). Heritability of mLOY was 0.53 and the residual sibling correlation was 0.27 (n=201, p&lt;1.0x10‐2). A subset of 423 individuals were assigned to the cognitively impaired (n=134) or unimpaired (n=289) groups and mLOY was significantly higher in the cognitively impaired group (p&lt;0.0001). .ConclusionThe sibling correlation was significant for mLOY. We observed the same trend as reported in other European descent populations: mLOY increased with age and was more frequent in cognitively impaired individuals. The frequency of mLOY in Amish was lower than reported, overall and in each age stratum. Our results along with the lower prevalence of AD in Amish reinforces as a promising biomarker for the risk of AD.

Mosaic loss of Chromosome Y in aged human microglia.

Mosaic loss of Chromosome Y (LOY) is a common acquired structural mutation in the leukocytes of aging men that is correlated with several age-related diseases, including Alzheimer's disease (AD). The molecular basis of LOY in brain cells has not been systematically investigated. Here, we present a large-scale analysis of single-cell and single-nuclei RNA brain data sets, yielding 851,674 cells, to investigate the cell type-specific burden of LOY. LOY frequencies differed widely between donors and CNS cell types. Among five well-represented neural cell types, LOY was enriched in microglia and rare in neurons, astrocytes, and oligodendrocytes. In microglia, LOY was significantly enriched in AD subjects. Differential gene expression (DE) analysis in microglia found 172 autosomal genes, three X-linked genes, and 10 pseudoautosomal genes associated with LOY. To our knowledge, we provide the first evidence of LOY in the microglia and highlight its potential roles in aging and the pathogenesis of neurodegenerative disorders such as AD.

Mosaic loss of chromosome Y linked to cardiac disease

Mosaic loss of chromosome Y linked to cardiac disease

Mosaic loss of chromosome Y in peripheral blood cells is associated with age-related macular degeneration in men

BackgroundAge-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes.ResultsUsing STRING, a publically available database of all protein–protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis.ConclusionsmLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis.

Mosaic loss of chromosome Y (mLOY) in blood cells is one of the most frequent chromosome alterations in adult males. It is strongly associated with clonal hematopoiesis, hematopoietic malignancies, and other hematopoietic and nonhematopoietic diseases. However, whether there is a causal relationship between mLOY and human diseases is unknown. Here, we generated mLOY in murine hematopoietic stem and progenitor cells (HSPCs) with CRISPR/Cas9 genome editing. We found that mLOY led to dramatically increased DNA damage in HSPCs. Interestingly, HSPCs with mLOY displayed significantly enhanced reconstitution capacity and gave rise to clonal hematopoiesis in vivo. mLOY, which is associated with AML1-ETO translocation and p53 defects in patients with acute myeloid leukemia (AML), promoted AML in mice. Mechanistically, loss of KDM5D, a chromosome Y–specific histone 3 lysine 4 demethylase in both humans and mice, partially recapitulated mLOY in DNA damage and leukemogenesis. Thus, our study validates mLOY as a functional driver for clonal hematopoiesis and leukemogenesis.

Mosaic loss of chromosome Y in rats.

Mosaic loss of chromosome Y in rats.

Rats exhibit age-related mosaic loss of chromosome Y

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.

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

Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. The CD99 gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification of CD99 derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes.

GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes—CHEK2 and GIGYF1—reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04–11.81], p = 1.3 × 10−10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51–10.61], p = 1.8 × 10−12), 4 kg higher fat mass (p = 1.3 × 10−4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10−4) and 4.5 kg lower handgrip strength (p = 4.7 × 10−7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression

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.