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Mosaic loss of chromosome Y is associated with common variation near TCL1A.

ABSTRACT: Mosaic loss of chromosome Y (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematological cancer in three prospective cohorts (8,679 cancer cases and 5,110 cancer-free controls) and genetic susceptibility to mLOY. Overall, mLOY was observed in 7% of men, and its prevalence increased with age (per-year odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.12-1.15; P < 2 × 10(-16)), reaching 18.7% among men over 80 years old. mLOY was associated with current smoking (OR = 2.35, 95% CI = 1.82-3.03; P = 5.55 × 10(-11)), but the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (for example, bladder, lung or prostate cancer) nor with cancer survival after diagnosis (multivariate-adjusted hazard ratio = 0.87, 95% CI = 0.73-1.04; P = 0.12). In a genome-wide association study, we observed the first example of a common susceptibility locus for genetic mosaicism, specifically mLOY, which maps to TCL1A at 14q32.13, marked by rs2887399 (OR = 1.55, 95% CI = 1.36-1.78; P = 1.37 × 10(-10)).

SUBMITTER: Zhou W

PROVIDER: S-EPMC4848121 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mutagenesis. Smoking is associated with mosaic loss of chromosome Y.

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Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.

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Rats exhibit age-related mosaic loss of chromosome Y.

Project description: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.

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Genetic predisposition to mosaic Y chromosome loss in blood.

Project description:Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

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Mosaic chromosome Y loss and testicular germ cell tumor risk.

Project description:Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. Cohort studies investigating mLOY and mortality have reported contradictory results. Previous work found that a 1.6?Mb deletion of the AZFc region on the Y chromosome (the 'gr/gr' deletion) is associated with both male infertility and increased risk of testicular germ cell tumors (TGCT). We investigated whether mosaic loss across the entire Y chromosome was associated with TGCT. We obtained blood- and buccal-derived DNA from two case-control studies: the NCI Familial Testicular Cancer Study (cases=172; controls=163) and the NCI US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (cases=506; controls=611). We used 15 quantitative polymerase chain reactions spanning the Y chromosome to assess mLOY. Multivariate logistic regression models adjusted for study batch effects detected no significant overall relationship between mean chromosome Y target-to-reference (T/R) ratio and TGCT (odds ratio=0.34, 95% confidence interval=0.10-1.17, P=0.09). When restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls (0.993 vs 1.014, P-value=0.01). Our study suggests that mLOY, as measured by 15 probes spanning the Y chromosome, could be associated with familial TGCT, but larger studies are required to confirm this observation.

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Reply to 'Mosaic loss of chromosome Y in leukocytes matters'.

Project description: Not available

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Mosaic loss of chromosome Y promotes leukemogenesis and clonal hematopoiesis.

Project description: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.

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Project description:Mosaic loss of Y chromosome (mLOY) is the most frequently detected somatic copy number alteration in leukocytes of men. In this study, we investigate blood cell counts as a potential mechanism linking mLOY to disease risk in 206,353 UK males. Associations between mLOY, detected by genotyping arrays, and blood cell counts were assessed by multivariable linear models adjusted for relevant risk factors. Among the participants, mLOY was detected in 39,809 men. We observed associations between mLOY and reduced erythrocyte count (-0.009 [-0.014, -0.005] × 1012 cells/L, p = 2.75 × 10-5) and elevated thrombocyte count (5.523 [4.862, 6.183] × 109 cells/L, p = 2.32 × 10-60) and leukocyte count (0.218 [0.198, 0.239] × 109 cells/L, p = 9.22 × 10-95), particularly for neutrophil count (0.174 × [0.158, 0.190]109 cells/L, p = 1.24 × 10-99) and monocyte count (0.021 [0.018 to 0.024] × 109 cells/L, p = 6.93 × 10-57), but lymphocyte count was less consistent (0.016 [0.007, 0.025] × 109 cells/L, p = 8.52 × 10-4). Stratified analyses indicate these associations are independent of the effects of aging and smoking. Our findings provide population-based evidence for associations between mLOY and blood cell counts that should stimulate investigation of the underlying biological mechanisms linking mLOY to cancer and chronic disease risk.

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