Genetic Signals Linked to X Chromosome Loss Later in Life

A strange phenomenon sometimes happens to women’s blood cells as they age: They lose one copy of their X chromosomes. The process, called mosaic loss of X (mLOX), causes blood cells to abnormally divide and can contribute to health conditions such as cancer. Now, in a study published in Nature, a global team of scientists revealed the frequency of mLOX in the population and environmental and genetic forces linked to the process.¹

“This work is really important because the X chromosome has largely been excluded from genetic studies in the past,” said Amy Roberts, a molecular epidemiologist at King’s College London who was not involved with the study. “It's really great to see such a large-scale study of this magnitude.”

During early female development, one of the two X chromosomes is transcriptionally silenced through X inactivation. This ensures that females produce a similar number of X chromosome gene products to XY males. However, mLOX is a detrimental process. Although scientists know that mLOX largely occurs later in life, it was unclear how common this phenomenon is.

To explore the frequency of mLOX, Mitchell Machiela, a genetic epidemiologist at the National Cancer Institute and his team analyzed genotyping array data from approximately 900,000 participants born with two XX chromosomes, sourced from eight biobanks across diverse regions, including the UK, Estonia, and Japan.

When they analyzed allelic imbalances and copy number variations in the X chromosome, they found that 12 percent of females across the study had detectable levels of mLOX. “We didn't appreciate how common it was,” said Machiela.

More than 35 percent of individuals over 80 years old experienced mLOX compared to around three percent of individuals under 40 years old. The researchers found that, across all ages, the proportion of an individual’s blood cells that exhibited mLOX was small: around two percent. However, a subset of individuals exhibited mLOX in five percent of their cells, which the researchers linked to higher levels of smoking.

The team also studied whether mLOX was associated with an increased risk of certain medical conditions. They found that the phenomenon was associated with genes linked to cancer predisposition, including the TP53 gene that encodes the tumor suppressor protein p53. They also linked higher rates of mLOX with a greater risk for certain blood cancers. In a recent preprint, Machiela’s group also found a link between mLOX frequency and the risk of developing the heart condition atrial fibrillation.²

They also wanted to identify the genetic and cellular factors associated with mLOX that might be driving this process. When Machiela and his team took a closer look at the data, they identified 56 genetic variants associated with mLOX, many of which occurred in genes involved in cancer, immunity, and chromosome segregation. One rare variant in the gene FBXO10, which is short for encoding F-box protein 10, increased the risk of acquiring mLOX by two-fold. The protein encoded by this gene regulates levels of an antiapoptotic molecule, but researchers still don’t know how it influences the development of mLOX.

“These are genetic age-related traits in huge numbers at a scale that we haven't been able to do previously,” said Taru Tukiainen, a geneticist at the University of Helsinki and coauthor of the study.

Males similarly experience Y chromosome loss, so researchers were curious how the two phenomena differed. Although the researchers identified some overlap in genetic variants, particularly those associated with genes important for cancer susceptibility and blood cell traits, each process exhibited a unique set of genes. For example, variants in immune-related genes were more associated with mLOX than with the loss of the Y chromosome, indicating that the X and Y chromosome loss likely occurs through independent mechanisms.

The researcher’s findings suggest that genetic variants could help predict mLOX in women and assess their susceptibility to cancer. But first, Machiela said they need to run longitudinal studies. “This was just a snapshot in time,” he noted. “We don't really know much about the trajectory of how these events rose up.”

There is a lot of interesting biology to unpack with regards to the X chromosome, said Roberts. For example, she would like to see more studies examining the link between X inactivation during development and the pathological loss of X that occurs later in life. The present study also supports previous research that suggests that the chromosome lost through mLOX is the one that underwent X inactivation earlier in life.³

“The X chromosome is very curious,” said Tukiainen. “It has a lot of interesting biology with the potential to contribute to female health.”