Research led by Dr John Perry and Dr Deborah Thompson (a former member of the Centre for Cancer Genetic Epidemiology) has found that loss of the Y chromosome from circulating white blood cells is a biomarker of biological ageing that reflects broader genome instability across other tissues.
Published in Nature, the study builds on observations made over 50 years ago that the Y chromosome is frequently lost in a fraction of the white blood cells of up to 40% of men aged over 70. By measuring this form of clonal mosaicism in almost 1 million men across several studies including UK Biobank and 23andMe, the researchers were able to better understand the causes and consequences of this biological phenomenon.
Their analyses identified 156 autosomal genetic determinants of mosaic Y chromosome loss, which were preferentially found near genes involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. These genomic analyses were complemented by single cell RNA sequencing of cells lacking the Y chromosome. Together they demonstrate that Y loss is likely to occur through predisposition to processes that either promote errors in cells division, or help create an environment where it is more likely that aneuploid cells – cells with an abnormal number of chromosomes – can proliferate.
Further analyses highlighted that individuals with high genetic predisposition to mosaic Y chromosome loss were at an increased risk for several cancer types. These same genetic variants also impacted other aspects of health and disease, notably reproductive ageing and type 2 diabetes.
Dr Perry said:
“These findings help advance a body of work that highlights the DNA damage response as a biological mechanism underpinning patterns of growth, reproductive ageing, diabetes, and cancer, and acting across the life course. We propose that loss of the Y chromosome is determined by a “common soil” of shared mechanisms that predispose to genome instability and cancer across many cell types”
- Full paper: Thompson D.J. et al. Genetic predisposition to mosaic Y chromosome loss in blood Nature, 20 Nov 2019 .