New paper co-authored by Downing PhD student published in academic journal
A paper co-authored by Downing PhD student Lily Wu (2022), which shows how DNA mutations acquired throughout life can protect liver cells from damage caused by an inherited genetic condition, has been published in the academic journal Nature Genetics.
The new research, published 10 March 2025, shows how acquired mutations in the SERPINA1 gene can protect liver cells from damage in patients with alpha-1 antitrypsin deficiency (A1AD), an inherited genetic condition that can cause lung and liver disease.
Cells slowly accumulate mutations in their DNA over time, many of which are harmless. Lily and the other researchers from the University of Cambridge and the Wellcome Sanger Institute explored whether mutations in the liver are disease-specific. They looked at acquired mutations in those with haemochromatosis and in patients with A1AD to understand if the mutations offer protection against cell stress in these conditions.
The team collected liver samples from five patients with haemochromatosis and five with A1AD undergoing transplantation. The researchers used laser capture microdissection on the tissue, using a laser to cut out smaller fractions of roughly 400 cells, which were sequenced to identify somatic mutations.
Patients with A1AD are born with faults in the gene SERPINA1. These faults cause changes to a type of protein called alpha-1 antitrypsin. The changes make alpha-1 antitrypsin proteins stick together and form clumps inside liver cells.
The scientists found that frequent mutations in SERPINA1 shorten one end of the alpha-1 antitrypsin – the C-terminus, eliminating the area responsible for the protein sticking together in A1AD. These mutations rescue the liver cell as the shortened protein cannot stick together, which alleviates cell stress and protects liver cells from damage. This provides significant advantage to liver cells, so cells carrying these mutations end up expanding in the liver.
For those with A1AD associated liver disease, liver transplantation remains the only treatment option. The new findings provide further understanding about how acquired protective mutations may help inspire therapies in patients with chronic liver disease.
“This is a great example of how natural selection helps cells adapt to cell stress and escape from the deleterious mutation they inherited. It’s incredibly exciting to publish this finding,” said Lily.
“My ongoing PhD research focuses on the underlying biology of this disease. Together it will give us more insights into potential therapeutic targets in A1AD.”
Published 11 March 2025