The review, by collaborators Professors Matthias Merkenschlager, Group Head at the LMS, and Philip Boone, clinician at Boston Children’s Hospital, explores how X-linked genetic variation combines with X-chromosome inactivation to drive competition between cell populations. Ultimately this competition may influence whether female individuals who carry disease-causing mutations on one of their X chromosomes will remain healthy or develop symptoms of disease.  

What is X-chromosome inactivation?  

Embryos receive two copies of each chromosome, one from each parent. Male and female humans differ in the number of their X chromosomes: females have two X chromosomes (XX), whereas males have one X and one Y chromosome (XY). In early XX embryos, a process called X-inactivation silences one of the two X chromosomes in the embryonic cells. The decision of which X chromosome to silence is stably inherited by daughter cells as the embryo develops.   

If the choice of which X chromosome to inactivate was truly random, the expectation would be that an organism would have a 50:50 split of cells in their body; half would have silenced the maternally-inherited ‘X’ and half would have silenced the paternally-inherited ‘X’, but this is not always the case. The Boone/Merkenschlager Perspective examines stochastic (random) and deterministic (rule-based) factors that bias X chromosome usage to affect health outcomes in X-linked genetic diseases, with the long-term aim of ultimately improving treatments.  

How the mystery began…  

In early 2023, the Lymphocyte Development Group were looking at a database of healthy volunteers’ genetic information. To their surprise, they found an individual who had a genetic variant – or mutation – in a gene called STAG2. This was unexpected as the STAG2 gene is essential for life, and the variant was known to affect the function of the protein made by STAG2. Surprisingly, the volunteer was healthy and even brought along her daughter, indicating that she was also fertile. How she remained healthy with this mutation was a mystery that could hold answers for improving the health of others with mutations on their X chromosomes.  

To untangle this, the team requested cells derived from the volunteer’s original blood sample. They found that the answer was related to X inactivation. STAG2 is on the X chromosome, and none of the blood-derived cells used the X chromosome harbouring the variant STAG2 gene. Instead, they expressed the X chromosome with the standard STAG2 sequence.  

Competition between cells expressing different X chromosomes  

To ensure this finding was not a chance occurrence, the team created mice with corresponding mutations in Stag2, the mouse version of the human STAG2 gene. In these mice, cells expressing the X chromosome with the Stag2 variant generated roughly half of the cells in most tissues. The exception was that cells expressing the Stag2 variant were absent from blood, just as in the human volunteer. When the team looked at mice where both X chromosomes carried the Stag2 variant, they found that cells expressing the Stag2 variant were perfectly capable of forming blood cells but did so only in the absence of cells that express the standard version of Stag2. This indicated that competition between cells, rather than the mutation alone, was responsible for the skewed outcome.  

This meant that in the mice with only one X chromosome carrying the Stag2 mutation, cells without the mutation outcompeted cells with the mutation, suggesting that a ‘fitness’ competition was taking place between cells expressing one or the other X chromosome within the same individual.  

Start of a new collaboration  

Matthias presented these findings at a conference and was approached by a paediatrician working on genetic illnesses, Philip Boone. Philip was interested in the work as he had observed that people with the same X-linked mutation often had different health outcomes, possibly linked to the extent to which cells in these patients used the healthy X chromosome or the X chromosome that harbours the mutation.  

New work will investigate how biases in X chromosome usage can impact the manifestation of X-linked disease, with the goal of improving treatments for people who carry X-linked disease mutations.   

The Perspective was released on 12th May 2025. 

 

Full publication here: Boone, P.M., Buenaventura, T., King, J.W.D. et al. X-linked competition — implications for human development and disease. Nat Rev Genet (2025). https://doi.org/10.1038/s41576-025-00840-3

Image credit: García-Nieto, A., Patel, A., Li, Y. et al. Structural basis of centromeric cohesion protection. Nat Struct Mol Biol 30, 853–859 (2023). https://doi.org/10.1038/s41594-023-00968-y