New insights into genetic triggers of X chromosome loss illuminate links to autoimmunity and cancer

An international team of researchers has uncovered genetic factors that predispose women to a genetic phenomenon where some cells lose one of their two X chromosomes.

The condition is not inherited but acquired by cells in the body during the lifetime of the woman. This phenomenon, called mosaic loss of the X chromosome (mLOX), results in a mix of cells with the normal two X chromosomes and cells with only one X chromosome within the body.

The study, recently published in the journal Nature, provides new insights into the underlying mechanisms driving susceptibility to mLOX, with profound implications for understanding ageing, blood cell formation, and cancer risk in females. 

The research was a collaborative effort between scientists at the University of Helsinki, Broad Institute, University of Cambridge, and NIH. With global effort, the researchers were able to utilize genetic data from more than 883,000 female participants from European, American and Asian biobank projects. The study included almost 170,000 women from the Finnish FinnGen study. 

”The reasons why some women lose an X chromosome have been understudied compared to loss of Y for men. This study shed light on this intriguing question and it does that thanks to the power of Finnish biobanks and international collaboration”, says one of the lead authors of the study, Associate Professor Andrea Ganna from the University of Helsinki.

The researchers detected mosaic loss of the X chromosome in 12% of the studied white blood cell samples. However, only a small fraction of these cells—2% on average—were affected.

“The prevalence of this finding could reflect shared evolutionary trajectories among white blood cells in aging women”, says the co-first author Dr. Giulio Genovese from the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard.

The study revealed more than 50 common genetic variants associated with an increased susceptibility to mLOX. Many of these genes play roles in cell division, cancer predisposition, and autoimmune diseases.

The results also demonstrated that participants with mLOX had an increased risk of myeloid and lymphoid leukemias. This is likely explained by the fact that the loss of an X chromosome in some blood cells can affect the process by which new cells are formed, potentially leading to changes in the blood cell population as women age.

“The mechanical insights gained by our study will largely change our understanding of aging and sex differences in general and also remind people to rethink the role of the underappreciated interplay between germline and somatic mutations in human health and diseases”, says the co-first author of the study, Dr. Aoxing Liu from the Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki.

Continued research in this area holds promise for advancing medical knowledge and improving health outcomes for women worldwide. The findings illuminate the complex biological processes that contribute to mLOX, offering a new perspective on how ageing influences blood cell development and the potential for haematologic malignancies.

"These findings are remarkable as they suggest inherited variation could predispose to the acquisition of age-related genomic alterations such as mosaic X chromosome loss and additionally influence which of the two X chromosome copies is lost", says one of the lead authors, Dr. Mitchell J. Machiela, from the U.S. National Cancer Institute.


Original publication

Liu, A., Genovese, G., Zhao, Y. et al. Genetic drivers and cellular selection of female mosaic X chromosome loss, Nature 2024, DOI: 10.1038/s41586-024-07533-7

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