Your Genes Determine How Fast Your DNA Mutates With Age, Large Genetic Study Reveals
A massive new genetic study has found that your inherited genes play a major role in how quickly your DNA changes as you age. By analyzing genetic data from more than 900,000 people, researchers discovered that certain repetitive sections of DNA gradually become longer and more unstable over time—and that common genetic differences between people can speed up or slow down this process by as much as four-fold.
The research, led by scientists from the University of California, Los Angeles (UCLA) along with collaborators at the Broad Institute and Harvard Medical School, provides one of the most comprehensive looks yet at how DNA repeat instability behaves across the human lifespan. Importantly, the findings also connect specific DNA repeat expansions to serious diseases, including kidney failure and liver disease, revealing a previously unrecognized genetic disorder.
What Are DNA Repeats and Why Do They Matter?
The human genome is not just a long string of unique genetic instructions. Large portions of it contain short DNA sequences repeated over and over, known as short tandem repeats or DNA repeat elements. These repeats are normal and widespread, and most people carry thousands of them across their genome.
However, DNA repeats are inherently unstable. As cells divide over time, these sequences can expand, meaning the repeated pattern becomes longer. When expansion reaches extreme levels, it can interfere with how genes function.
More than 60 inherited disorders are already known to be caused by expanded DNA repeats. These include devastating neurological and muscular conditions such as Huntington’s disease, myotonic dystrophy, and certain forms of amyotrophic lateral sclerosis (ALS). Until now, most research focused on a small number of rare disease-causing repeats, leaving the broader picture largely unexplored.
A Study on an Unprecedented Scale
To address this gap, the research team analyzed whole-genome sequencing data from 490,416 participants in the UK Biobank and 414,830 participants in the All of Us Research Program in the United States. Together, this provided genetic data from over 900,000 individuals, making it one of the largest studies of its kind.
The researchers developed new computational methods capable of detecting and measuring DNA repeat lengths using standard genome sequencing data—something that had previously been very difficult to do at scale. Using these tools, they examined 356,131 polymorphic repeat locations across the genome.
They focused on how repeat lengths changed with age, particularly in blood cells, and searched for inherited genetic variants that influenced how fast or slow these repeats expanded. They also looked for links between repeat expansions and thousands of disease outcomes recorded in the biobank data.
DNA Repeats Expand as We Age
One of the clearest findings was that most common DNA repeats in blood cells gradually expand as people get older. This means DNA repeat instability is not limited to rare disorders—it is a widespread feature of normal aging.
What surprised researchers was just how common this process is. The study shows that repeat expansion affects a large portion of the genome in most individuals, making it far more widespread than previously recognized.
Genetics Can Speed Up or Slow Down DNA Changes
The study identified 29 specific genetic locations where inherited variants influence the rate at which DNA repeats expand. When combined into genetic risk scores, these variants could explain dramatic differences between individuals.
People with the highest genetic risk scores experienced repeat expansion rates up to four times faster than those with the lowest scores. This finding strongly suggests that DNA repeat instability is under tight genetic control, rather than being driven purely by random cellular errors or environmental factors.
Interestingly, many of the genetic variants involved are found in DNA repair genes—genes responsible for fixing damage that occurs when DNA is copied. Even more intriguing, the same DNA repair genes sometimes had opposite effects on different repeats, stabilizing some sequences while destabilizing others. This highlights the complex and context-dependent nature of DNA repair processes.
Discovery of a New Repeat Expansion Disorder
One of the most striking discoveries involved repeats in the GLS gene. Expansions in this gene were found in about 0.03% of the population, making them rare but not exceptionally so.
These expansions were associated with a 14-fold higher risk of severe (stage 5) chronic kidney disease and a three-fold higher risk of liver diseases. Until now, this connection had not been recognized as a repeat expansion disorder.
This finding suggests that additional repeat-related diseases may still be hidden within large genetic datasets, waiting to be uncovered as analytical tools improve.
Implications for Disease Monitoring and Treatment
Beyond identifying disease risks, the study opens the door to new clinical applications. Because repeat expansions can be measured in blood samples, they could serve as biomarkers for tracking disease progression or testing treatments designed to slow repeat growth.
This is particularly relevant for conditions like Huntington’s disease, where repeat length is known to influence when symptoms begin and how quickly the disease progresses. Having a reliable, blood-based measure of repeat expansion could significantly improve clinical trials and patient monitoring.
The naturally occurring genetic variants identified in the study also point to molecular pathways that could be targeted therapeutically. By understanding which DNA repair mechanisms slow repeat expansion, researchers may be able to design drugs that mimic these protective effects.
Why Repeat Expansions Are So Hard to Control
Despite these advances, many questions remain unanswered. The fact that the same genetic modifiers can stabilize one repeat while destabilizing another suggests that repeat expansion depends heavily on genomic context, cell type, and local DNA structure.
Understanding these differences will require detailed mechanistic studies of how DNA repair systems operate in different regions of the genome. This complexity may explain why repeat expansion disorders vary so widely in symptoms and severity.
A Broader View of Genetic Aging
This research adds an important new layer to our understanding of genetic aging. While much attention has focused on telomeres and epigenetic clocks, DNA repeat instability represents another fundamental way in which our genomes change over time.
The study shows that aging-related DNA changes are not uniform and that individual genetic makeup strongly shapes how our genomes evolve throughout life. This insight could eventually help explain why people age at different rates and why some individuals are more vulnerable to age-related diseases than others.
Research Publication
Nature: Insights into DNA repeat expansions among 900,000 biobank participants
https://www.nature.com/articles/s41586-025-09886-z
