A fascinating discovery reveals that as women age, a phenomenon known as mosaic loss of X (mLOX) occurs in their blood cells. This condition, where one copy of the X chromosome is lost in some cells, has implications for health, particularly in terms of cancer risk.
The groundbreaking study, published in Nature, maps out the frequency of mLOX across different ages and demographics, as well as the genetic and environmental factors that may contribute to it.
“It’s really important research because the X chromosome has often been sidelined in genetic studies,” said Amy Roberts, a molecular epidemiologist at King’s College London, who was not involved in the study. This large-scale research helps clarify the health impact of losing the X chromosome.
Understanding mLOX and Its Frequency
In women, one of the two X chromosomes is typically inactivated early in life to balance gene expression between sexes. While mLOX, a loss of one X chromosome copy, occurs more frequently later in life, its extent was previously unknown.
Led by Mitchell Machiela at the National Cancer Institute, researchers analysed genetic data from 900,000 individuals with two X chromosomes from eight biobanks worldwide. They found mLOX in 12% of women across all ages, with rates rising significantly with age. By 80 years, more than 35% experienced mLOX, compared to around 3% under 40. Interestingly, mLOX affected only about 2% of blood cells in most cases, though some individuals showed mLOX in 5% of cells—a rate linked to higher smoking levels.
Health Implications and Genetic Links
The study revealed that mLOX is more than a biological anomaly; it’s associated with cancer-related genes, notably TP53, a well-known tumour suppressor. Women with higher rates of mLOX had an increased risk of specific blood cancers. A recent study by the same group also found that mLOX correlates with a higher risk of atrial fibrillation, a heart condition.
Delving deeper, researchers identified 56 genetic variants linked to mLOX, many tied to genes involved in immunity, cancer susceptibility, and chromosome segregation. One variant in the FBXO10 gene was found to double the risk of mLOX. FBXO10 encodes a protein that regulates anti-apoptotic molecules, but researchers are still investigating how it might drive X chromosome loss.
“These are genetic age-related traits examined on an unprecedented scale,” commented Taru Tukiainen, a geneticist at the University of Helsinki and coauthor of the study.
Comparing X and Y Chromosome Loss
Men similarly experience loss of the Y chromosome with age, prompting researchers to compare the two. While both processes share some genetic risk factors, each has distinct genetic influences. For instance, immune-related genes are more prominently linked to mLOX, suggesting that X and Y chromosome loss may follow separate biological pathways.
A Path to Predictive Health Insights
The study highlights the potential to use genetic data to predict mLOX and associated cancer risks in women. Future longitudinal studies could deepen our understanding of how mLOX progresses and whether it can be mitigated. The findings also prompt further inquiry into the connection between early-life X chromosome inactivation and later X loss, a relationship that could shed light on mLOX’s unique role in female health.
“The X chromosome has a lot of unexplored biology,” Tukiainen noted. “This research opens doors to understanding its broader health implications for women.”
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