Researchers at KU Leuven and Erasmus MC have discovered that cells can compensate for the loss of genes by increasing the activity of their remaining copy. Surprisingly, this balancing act does not occur across an entire chromosome, but gene by gene.

Every healthy human cell normally contains two copies of each chromosome, with the exception of the sex chromosomes. These chromosomes contain our DNA and the genes that provide instructions for producing proteins and regulating cellular functions.

The X chromosome presents scientists with a particularly interesting problem.

People born with two X chromosomes generally have one of those X chromosomes largely inactivated. At the same time, activity on the remaining active X chromosome is increased in cells. This mechanism, known as X-chromosome upregulation (XCU), helps maintain a balance with other chromosomes that are present in two copies.

Scientists have known about XCU for some time. What remained unclear was exactly how cells achieve this compensation.

New research led by Professor Vincent Pasque of KU Leuven and Professor Joost Gribnau of Erasmus MC now provides an answer — and it is considerably more precise than expected.

No central control system

The researchers initially suspected that a particular DNA segment on the X chromosome might act as a kind of central control mechanism.

Such a “compensation centre” could detect that genetic material was missing and subsequently increase activity across the chromosome.

But that is not what they found.

Instead, individual genes or regions appear capable of detecting the loss of their counterpart and responding independently.

In other words, the cell does not simply turn up the volume of the entire X chromosome. It adjusts genetic activity gene by gene.

That reveals a remarkably precise internal regulatory system.

Removing pieces of a chromosome

To uncover this mechanism, the researchers worked with mouse stem cells containing two X chromosomes.

They selectively removed parts of one X chromosome and then observed what happened to corresponding genes on the other chromosome.

If compensation were controlled centrally, deleting one section should have produced a broader response across the chromosome.

Instead, the researchers found that compensation was highly localised.

When one copy of a gene disappeared, activity of the remaining copy could increase.

This showed that individual genes or regions are able to respond to genetic imbalance themselves.

An internal genetic balance

KU Leuven researcher Ryan Allsop describes the phenomenon as resembling an internal scale operating inside the cell.

When genetic material disappears, the cell can compensate by adjusting the activity of what remains.

This ability makes cells more resilient to genetic changes.

But the researchers discovered something else.

The phenomenon is not restricted to the X chromosome.

Similar compensatory responses were observed on other chromosomes as well. That could become particularly important when a mutation causes a gene to become partly or completely inactive.

Why the X chromosome is special

There is, however, an important difference.

The X chromosome appears to be particularly effective at compensating for gene loss.

On other chromosomes, the response seems to be much weaker.

According to the researchers, compensation elsewhere may sometimes be sufficient to keep a cell alive but insufficient to prevent disease.

Understanding why the X chromosome performs this balancing act so effectively could therefore have wider implications for genetics and medicine.

From Turner syndrome to cancer

The discovery could help researchers better understand conditions in which genes or entire sections of chromosomes are missing.

One example is Turner syndrome, in which a person has only one complete X chromosome instead of the usual two sex chromosomes.

Chromosomal and genetic losses are also important in cancer research, while chromosome behaviour is relevant to fertility research and treatments.

The new findings therefore provide scientists with another piece of the puzzle of how cells remain functional despite changes to their genetic material.

Could the mechanism eventually be used medically?

The researchers are particularly interested in understanding why compensation works so efficiently on the X chromosome.

If scientists can determine the molecular mechanisms responsible, it raises the possibility that similar processes might eventually be influenced on other chromosomes.

That remains a future prospect rather than a current treatment.

KU Leuven explicitly emphasises that this is fundamental research. Translating such findings into diagnostic or therapeutic applications requires considerably more research and can take many years.

For now, the discovery provides something equally valuable: a clearer picture of the extraordinary precision with which cells monitor and regulate their own genetic information.

Rather than being passive containers of DNA, cells appear capable of continuously adjusting gene activity to preserve a delicate genetic balance.

And remarkably, they can do so one gene at a time.

Source: Based on “Nieuw inzicht in hoe cellen genetisch evenwicht bewaren”, published by KU Leuven on 30 September 2025. The research was led by Professor Vincent Pasque (KU Leuven) and Professor Joost Gribnau (Erasmus MC). The underlying study, “X-chromosome upregulation operates on a gene-by-gene basis at RNA and protein levels”, by Allsop et al., was published in Nature Communications.