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The effects of loss of Y chromosome on male health

Nature Reviews Genetics (2025)Cite this article

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Abstract

Loss of Y chromosome (LOY) is the most commonly occurring post-zygotic (somatic) mutation in male individuals. The past decade of research suggests that LOY has important effects in shaping the activity of the immune system, and multiple studies have shown the effects of LOY on a range of diseases, including cancer, neurodegeneration, cardiovascular disease and acute infection. Epidemiological findings have been corroborated by functional analyses providing insights into the mechanisms by which LOY modulates the immune system; in particular, a causal role for LOY in cardiac fibrosis, bladder cancer and Alzheimer disease has been indicated. These insights show that LOY is a highly dynamic mutation (such that LOY clones expand and contract with time) and has pleiotropic, cell-type-specific effects. Here, we review the status of the field and highlight the potential of LOY as a biomarker and target of new therapeutics that aim to counteract its negative effects on the immune system.

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Fig. 1: Factors contributing to LOY, its underlying mechanisms, potential consequences and associated diseases.
Fig. 2: Proposed interactions between Treg cells and CD8+ T cells with LOY in different cellular compartments.
Fig. 3: Effects of LOY on expression of selected, well-characterized immune-checkpoint genes.

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Acknowledgements

The authors thank A. Riva, M. Essand, P. Kowalczyk and E. T. Janson for critical review of the manuscript. This work was sponsored, in part, by grants from the Swedish Research Council, the Swedish Cancer Society, and the National Science Center, Poland (Opus grant award no. 2023/49/B/NZ2/03680) to J.P.D.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Bozena Bruhn-Olszewska, Ellen Markljung, Daniil Sarkisyan & Jan P. Dumanski

  2. 3P-Medicine Laboratory, Medical University of Gdańsk, Gdańsk, Poland

    Edyta Rychlicka-Buniowska, Natalia Filipowicz & Jan P. Dumanski

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Glossary

Aneuploidy

The condition of a cell having an abnormal number of chromosomes owing to loss or duplication.

Clonal haematopoiesis

Describes the asymptomatic clonal expansion of blood cells descended from a single haematopoietic stem cell or haematopoietic progenitor cell.

Clonal haematopoiesis of indeterminate potential

(CHIP). The presence of a clonally expanded haematopoietic stem cell population caused by leukaemogenic mutations in individuals without evidence of haematological malignancy, dysplasia or cytopenia.

Emergency myelopoiesis

An essential component of the response to infection, characterized by inflammation-induced increased haematopoiesis skewed towards the myeloid lineage, that leads to increased myeloid cell production in the bone marrow and the rapid release of neutrophils into the circulation.

Low-density neutrophils

(LDNs). Also known as myeloid-derived suppressor cells of polymorphonuclear type. A subpopulation of neutrophils that co-segregate with peripheral blood mononuclear cells after density gradient centrifugation rather than with the normal-density neutrophils. They are thought to have an immunosuppressive phenotype.

Male-specific region of the Y chromosome

A large part of the Y chromosome that does not recombine with the X chromosome during meiosis.

Micronuclei

Small, extranuclear bodies formed by chromosomal fragments or whole chromosomes that are not incorporated into the daughter nuclei during cell division.

Mosaic chromosomal alterations

Genetic changes, including gains, losses or copy-neutral loss of heterozygosity, that occur in a subset of cells within the same individual.

Pseudoautosomal genes

Genes located on the two pseudoautosomal regions of the X and Y chromosomes that are inherited in an autosomal-like manner, enabling recombination between the sex chromosomes.

T cell exhaustion

A state of T cell dysfunction that arises from chronic antigen stimulation, typically during persistent infections or in the context of tumours, characterized by impaired effector functions and sustained expression of inhibitory, immune-checkpoint receptors.

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Bruhn-Olszewska, B., Markljung, E., Rychlicka-Buniowska, E. et al. The effects of loss of Y chromosome on male health. Nat Rev Genet (2025). https://doi.org/10.1038/s41576-024-00805-y

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