Shedding light on sex differences in human disease

Researchers at Linköping University in Sweden made an unexpected discovery while investigating genetically unique women. Their insights advance our understanding of our most enigmatic chromosome, the X chromosome.

Diseases in which the immune system attacks your own body, known as autoimmune diseases, are much more common in women than men. For example, rheumatoid arthritis, multiple sclerosis and SLE (systemic lupus erythematosus) are at least three times more common in women than men.

On the other hand, a woman’s immune system tends to be better at fighting off bacterial and viral infections, such as COVID19. But why? An obvious genetic difference between the biological sexes is that women have two X chromosomes (XX), whereas men have one X chromosome and one Y chromosome (XY). Indeed, a lot of evidence supports a role for the X chromosome in the sex bias of several diseases.

Escaping genes

Although women have two X chromosomes, each cell in a woman uses only one of their two X chromosomes. The other is switched off in a process called X-inactivation, so that the genes are not used. However, the process of X-inactivation is not complete. As many as 20 per cent of the genes on the inactivated X chromosome may still be used, meaning that cells in women have more of these genes than cells in men.

“Several of the genes that ‘escape’ X-inactivation play important roles in the function of the immune system, so women basically have higher activity in these important immune-related genes. This is a possible contributing factor to why women and men react differently to immune diseases and infection,” says Colm Nestor, senior associate professor at Linköping University, LiU.

A better understanding of the cellular mechanisms behind sex differences in various diseases could contribute to improved treatments.

Due to an unexpected finding made by the LiU researchers, we are much closer to unlocking the mysteries of the X chromosome.

A rare phenomenon

To understand what the researchers found, we first need to know a little more about the inactivation of X chromosomes in women. In most women, half of the cells use the X chromosome inherited from their father and the other half use their mother’s X chromosome – in other words, the woman is a 50/50 mixture of both parents’ X chromosomes. But in some women, the distribution has become very skewed. In these women, the same X chromosome is disabled in all cells in the body. This phenomenon was thought to be exceptionally rare, expected to occur in 1 in 1,000 healthy women.

The discovery that the LiU researchers made together with Professor Olov Ekwall at Gothenburg University now challenges this.

“We were shocked to discover that one of three females we were studying had 100 per cent skewed X chromosome inactivation. So, we proceeded to check in large databases and found more such females. Suddenly it was 1 out of 100, not 1 out of 1,000,” says PhD student, Björn Gylemo, who performed the analyses.

That skewed X-chromosome inactivation seems to be much more common than previously thought is important.

“This could have a major impact on the health of a woman with skewed X-chromosome inactivation. If the same X chromosome is used in all the cells of the body, she is more similar to men when it comes to certain diseases,” says Colm Nestor.

The discovery may be important for future research on sex differences in various diseases, as many researchers are interested in individual “escape” genes on the X chromosome. But such research has been difficult to do until now. As most women are a 50/50 mixture of both their X chromosomes, it has been very tricky to find out if certain genes really “escape” from the otherwise inactivated X chromosome.

But the LiU researchers’ discovery of several girls and women with skewed X chromosome inactivation has opened new doors in research. They have now created an atlas of how the X chromosome is inactivated in humans, which they have presented in the journals Nature Communications and eLife. In their studies, they were able to find out exactly which genes “escape” from the inactivated X chromosome in different tissues.

 “The map of genes on the X chromosome that escape inactivation may serve as the reference in the research field for the next 20 years and allow us to learn even more about the role of the X chromosome in human disease,” says Colm Nestor.

Articles mentioned in the text:

A landscape of X-inactivation during human T cell development, Gylemo et al, (2024), Nature Communications, published online 4 December 2024, doi: https://doi.org/10.1038/s41467-024-54110-7

A whole-organism landscape of X-inactivation in humans, Gylemo et al, (2025), eLife, published online 8 January 2025, doi: https://doi.org/10.7554/eLife.102701.1