Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Abstract

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, 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. Genetic susceptibility to LOY is associated with non-haematological 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 how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

Immune cells lacking Y chromosome have widespread dysregulation of autosomal genes

“…For scRNAseq results, each sequenced cell with expression of autosomal genes, but without any transcripts from genes located in the male specific region of chromosome Y (MSY) was considered as a LOY cell. The single cell analyses of PBMCs collected from 29 men (26 diagnosed with AD) generated a scRNAseq dataset encompassing 73,606 cells analyzed using established algorithms, as described in methods and elsewhere [21]. The distribution and level of LOY estimated from scRNAseq in four major cell types (i.e.…”

“…Strong associations with age and smoking have been reported [8,10,24,25] and these factors are related to a continuously increasing mutational load throughout the genome in all somatic cells, eventually also affecting genes that are responsible for correct segregation of chromosomes. Inherited genetic predisposition for LOY has also been described [21,25,26].…”

“…Furthermore, it has been known for centuries that males have a shorter life expectancy [18][19][20]. Hence, LOY as a male specific risk factor, showing reproducible associations with various common disorders, could help explaining this difference.LOY in blood is the most frequent post-zygotic mutation, detectable in 20% of the UK Biobank male population [21], reaching 40% in 80 years old males [22], and 57% in 93 years old males [23]. Furthermore, LOY is not restricted to the hematopoietic system, since it has also been described in other non-cancerous tissues, although with much lower frequencies [17,23].…”

“…Strong associations with age and smoking have been reported [8,10,24,25] and these factors are related to a continuously increasing mutational load throughout the genome in all somatic cells, eventually also affecting genes that are responsible for correct segregation of chromosomes. Inherited genetic predisposition for LOY has also been described [21,25,26].It is not known whether associations between LOY and increased risks for disease represent causal relationships, and if so, what the underlying mechanisms could be. The challenge that we address here is to move from epidemiological associations to mechanistic explanations on multiple levels of analysis such as DNA, mRNA and proteins.…”

“…LOY in blood is the most frequent post-zygotic mutation, detectable in 20% of the UK Biobank male population [21], reaching 40% in 80 years old males [22], and 57% in 93 years old males [23]. Furthermore, LOY is not restricted to the hematopoietic system, since it has also been described in other non-cancerous tissues, although with much lower frequencies [17,23].…”