Researcher
Dr Alkisti Manousaki
Supervisors
Dr Yolanda Markaki and Dr Rachel Evans
Institution
University of Leicester
Start date
August 2025
Funding
This project forms the basis of a Daphne Jackson Trust Fellowship jointly funded by ME Research UK and the Medical Research Council.
The Daphne Jackson Trust is dedicated to supporting research returners. Dr Manousaki has a wealth of experience in genetics and mitochondrial research, and is returning to research following maternity leave.
Background
One of the biggest mysteries of ME/CFS is why women are four times more likely to develop the disease than men.
This is a pattern also seen in other related diseases such as long COVID, where differences between the sexes have been linked to underlying genetic changes in females.
However, the situation is still unclear for ME/CFS. Why are women more affected than men, and how does their biology interact with the disease?
Another distinct feature of ME/CFS is severe, unexplained fatigue that does not improve with rest. This suggests a problem with how the energy powerhouses of cells (the mitochondria) produce and manage the energy needed for normal activity, but the exact cause of this is not known.
Dr Manousaki plans to investigate the genetic and cellular clues that might help explain why ME/CFS affects more women than men.
A closer look at the X chromosome
Chromosomes carry our genetic information and, typically, females have two X chromosomes while males have one X and one Y chromosome. In females, one of the X chromosomes is inactivated in each cell in order to avoid a double-dose of X-linked genes.
X chromosome inactivation (XCI) therefore needs to be maintained throughout life, and disruption of this can lead to developmental problems and diseases, including those affecting the immune system, such as systemic lupus erythematosus. There is also reason to suspect that dysregulation of XCI could affect the function of the mitochondria, the powerhouses of the cell.
Objectives
Dr Manousaki’s research will test the idea that, in ME/CFS, XCI is not being maintained correctly. This could lead to abnormal levels of certain X-linked genes, disrupting immune balance and energy production in cells.
This mechanism could therefore explain the higher prevalence of ME/CFS in females than in males. Dr Manousaki plans to investigate this using super-resolution microscopy and gene expression analysis.
She will first assess whether XCI is dysregulated in women with ME/CFS, specifically looking at genetic factors which regulate XCI and may therefore have value as a diagnostic biomarker.
She will also investigate whether cells from men and women with ME/CFS struggle to generate and use energy efficiently, analysing mitochondrial structure and its interactions with associated endoplasmic reticulum contact sites which have been implicated in other diseases such as Alzheimer’s and Parkinson’s diseases.
Finally, linking these two areas, Dr Manousaki will test whether XCI disruption can directly cause mitochondrial dysfunction, linking the genetic findings with cellular energy problems and exploring whether these effects differ between men and women.
Potential benefits
By revealing how genetics and cell biology interact in ME/CFS, this research will help explain why the illness is more common in women and better understand its biological cause.
Dr Manousaki hopes the findings of this study will “lead to improved diagnosis, guide new treatments and offer effective ways to better manage symptoms for those at risk. Understanding the root causes of ME/CFS is essential to moving towards a future where this illness is no longer life-limiting.”
“Understanding the molecular differences in how ME/CFS affects men and women could be key to unlocking its underlying biology. By combining advanced genetic analysis with cutting-edge imaging, I hope to identify the mechanisms driving symptoms and point the way towards earlier diagnosis and more targeted therapies.”
Dr Alkisti Manousaki
“It is such a privilege to work with funders like ME Research UK to help people return to their research careers. Our funders make these fellowships possible. When combined with the unique structure, retraining, and mentorship provided by the Daphne Jackson Trust, our funders truly do help transform lives and careers.”
Elaine Hunt, Fellowship Officer, The Daphne Jackson Trust
