GENOMICS

Getting wise about lost Ys

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, but its causes and effects are not well understood. Now, a study in Nature identifies genetic determinants of LOY, providing insight into how it might occur and its relationship to cancer and other ageing-related diseases.

Credit: P. Morgan/Springer Nature Limited

Using a custom computational approach, Thompson et al. detected LOY in 41,791 of 205,011 (20%) men aged 40–70 years in the UK Biobank. Heritability of LOY was estimated to be 31.7%, and a genome-wide association study identified 156 independent associations with a range of effect sizes (OR 1.03–2.02) and risk allele frequencies (0.25–99.8%). The robustness of these associations for sample type, measurement technique and ancestry was supported by replication in three independent data sets (23andMe, deCODE and Biobank Japan).

Potentially causal variants were identified for each association by fine-mapping. Subsequent analyses indicated that LOY-associated variants are enriched in haematopoietic stem cells and involved in biological pathways associated with cell cycle regulation and the DNA damage response. Moreover, the variants are preferentially found close to cancer-related genes, in keeping with the known association between clonal mosaicism and increased risk of developing haematological cancers. Using a polygenic risk score comprising the 156 LOY variants, the authors demonstrated that the association between genetic risk of LOY and increased cancer risk also extends to male-specific cancers (prostate cancer and testicular germ cell tumour) and non-sex-specific non-haematological cancers (glioma, renal cell carcinoma, lung cancer and colorectal cancer)

Importantly, in women LOY variants are associated with increased risk of female-specific cancers (breast, ovarian and endometrial cancers) and with age at natural menopause, indicating that the physiological effects associated with LOY cannot be caused solely by loss of Y-encoded functions. Instead, LOY in leukocytes is likely to be a biomarker of genome instability in other cell or tissue types.

The authors propose that the genetic mechanisms predisposing to LOY are shared with genome instability and cancer across multiple cell types. Furthermore, the nature of the genes and pathways associated with LOY suggest it is initiated by chromosome mis-segregation during mitosis and that defects in detecting and eliminating aneuploid cells facilitate subsequent clonal expansion.

“LOY in leukocytes is likely to be a biomarker of genome instability in other cell or tissue types”

Future experiments to test these theories will shed further light on the mechanisms involved in LOY and whether loss of the 45 proteins encoded on the Y-chromosome has any direct physiological consequences.

References

Original article

  1. Thompson, D. J. et al. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 575, 652–657 (2019)

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Correspondence to Dorothy Clyde.

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Clyde, D. Getting wise about lost Ys. Nat Rev Genet 21, 70 (2020). https://doi.org/10.1038/s41576-019-0202-7

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