SummaryIncidence and mortality for sex-unspecific cancers is higher among men and is largely unexplained1,2. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal haematopoietic cells3,4, but the phenotypic consequences of LOY have been elusive5–10. From analysis of 1153 elderly men, we report that LOY was associated with risks of all-cause mortality (HR=1.91, 95% CI=1.17-3.13, events=637) and non-haematological cancer mortality (HR=3.62, CI=1.56-8.41, events=132). LOY affected at least 8.2% of subjects in this cohort and median survival among men with LOY was 5.5 years shorter. Risk of all-cause mortality and LOY was validated in an independent cohort (HR=3.66), in which 20.5% of subjects displayed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism 1-5 , yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (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 involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. We demonstrate that genetic susceptibility to LOY is associated with nonhaematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into why clonal expansion of these cells may occur. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.
Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of, and mortality from, most non-sex-specific cancers, remain unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of non-hematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts (TwinGene: odds ratio [OR]=4.3, 95% CI =2.8-6.7; ULSAM: OR=2.4, 95% CI=1.6-3.6; and PIVUS: OR=3.5, 95% CI=1.4-8.4) encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY-status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.
We examined the reproductive success of 48 adult brown trout (Salmo trutta L.) which were allowed to reproduce in a stream that was controlled for the absence of other trout. Parentage analyses based on 11 microsatellites permitted us to infer reproductive success and mate choice preferences in situ. We found that pairs with intermediate major histocompatibility complex (MHC) dissimilarity mated more often than expected by chance. It appears that female choice was the driving force behind this observation because, compared with other individuals, males with intermediate MHC dissimilarity produced a larger proportion of offspring, whereas female reproductive output did not show this pattern. Hence, rather than seeking mates with maximal MHC dissimilarity, as found in several species, brown trout seemed to prefer mates of intermediate MHC difference, thus supporting an optimality‐based model for MHC‐dependent mate choice.
Recent discoveries have shown that harboring cells without the Y chromosome in the peripheral blood is associated with increased risk for all-cause mortality and disease such as different forms of cancer, Alzheimer’s disease, as well as other conditions in aging men. In the entire world, the life expectancy of men is shorter compared to women, a sex difference that has been known for centuries, but the underlying mechanism(s) are not well understood. As a male-specific genetic risk factor, an increased risk for pathology and mortality associated with mosaic loss of chromosome Y (LOY) in blood cells could help to explain that men on average live shorter lives compared to women. This review primarily focuses on observed associations between LOY in blood and various diseases in aging men. Other topics covered are known risk factors for LOY, methods to detect LOY, and a discussion regarding mechanisms such as immunosurveillance, that could possibly explain how an acquired mutation in blood cells can be associated with disease processes in other organs.
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