Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility

Abstract

The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosome-Y (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10-8) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10-6). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.

Human Y-chromosome variation in the genome-sequencing era

“…LOY is the most common known acquired human mutation in surveyed populations 96 , and its frequency increases with age ( Figure 3A), and is associated with smoking 97 . It has also been associated with decreased survival time from all causes ( Figure 3B), including cancer ( Figure 3C) 96 , and with increased risk of Alzheimer disease ( Figure 3D) 98 ; these associations have been replicated in some but not all studies [99][100][101][102] . The SNP rs2887399 near TCL1A on chromosome 14 is associated with LOY risk (OR = 1.55, 95% CI = 1.36-1.78; P = 1.37 x 10 -10 ) 101 and more recently 18 additional associated genomic regions have been identified 102,103 .…”

Copy‐number analysis of Y‐linked loci in young men with non‐obstructive azoospermia: Implications for the rarity of early onset mosaic loss of chromosome Y

“…1,2 The results of this study, in conjunction with the previous reports by Shin et al 8 Furthermore, there are no data whether mLOY in young men is associated with early death and the risk of various disorders, as is the case for elderly people. 1,4,5 In this context, Thompson et al 3 raised questions about the pathogenicity of mLOY in blood cells.…”

“…1-3 Aging-related mLOY has been associated with shorter life expectancy and increased risks of cancer and other disorders. 1,4,5 The frequency of mLOY in men under 40 years of age remains unknown, but is predicted to be extremely low. 4,5…”

A strategic research alliance: Turner syndrome and sex differences

“…Indeed, researchers have found that loss of the Y chromosome in men correlates with increased risk of Alzheimer’s disease and cancer (Dumanski et al, 2016; Forsberg et al, 2014). It is worth noting that general chromosomal instability predisposing to cancer may result in Y loss simply because this chromosome is easier to lose, so more research must be done to prove causality (Wright et al, 2017). Mosaicism is also a common phenomenon in women with TS; in fact, it is thought that all women with TS must be mosaic for cells of another karyotype, such as 46,XX, because ~99% of fetuses with a complete 45,X karyotype do not survive fetal development (Hook & Warburton, 1983, 2014).…”