The 4x rule: Why some people’s DNA is more unstable than others
A large genetic study shows that many people carry DNA sequences that slowly expand as they get older. Common genetic variants can dramatically alter how fast this expansion happens, sometimes multiplying the pace by four. Researchers also identified specific DNA expansions linked to severe kidney and liver disease. The findings suggest that age-related DNA instability is far more common than previously realized.
A large scale genetic analysis of more than 900,000 people has revealed that specific regions of DNA become increasingly unstable over time. These regions are made up of very short sequences that repeat again and again, and the study shows that they tend to grow longer as people age. Researchers also found that common inherited genetic differences can strongly influence how quickly this expansion occurs, speeding it up or slowing it down by as much as fourfold. In some cases, expanded DNA repeats were linked to serious health conditions, including kidney failure and liver disease.
Expanded DNA repeats are responsible for more than 60 inherited disorders. These conditions develop when repeating genetic sequences lengthen beyond normal limits and interfere with healthy cell function. Examples include Huntington's disease, myotonic dystrophy, and certain forms of ALS.
Although most people carry DNA repeats that slowly expand throughout life, scientists had not previously examined how widespread this instability is or which genes control it using large biobank datasets. This research shows that repeat expansion is far more common than previously recognized. It also identifies dozens of genes involved in regulating the process, creating new opportunities to develop treatments that could slow disease progression.
How Researchers Studied Nearly a Million Genomes
The research team, which included scientists from UCLA, the Broad Institute, and Harvard Medical School, analyzed whole genome sequencing data from 490,416 participants in the UK Biobank and 414,830 participants in the All of Us Research Program. To carry out the analysis, they developed new computational approaches capable of measuring DNA repeat length and instability using standard sequencing data.
Using these tools, the team examined 356,131 variable repeat sites across the human genome. They tracked how repeat lengths changed with age in blood cells and identified inherited genetic variants that affected the speed of expansion. The researchers also searched for associations between repeat expansion and thousands of disease outcomes in order to uncover previously unknown links to human illness.
Key Findings on DNA Repeat Instability
The study found that common DNA repeats in blood cells consistently expand as people get older. Researchers identified 29 regions of the genome where inherited genetic variants altered repeat expansion rates, with differences of up to fourfold between individuals with the highest and lowest genetic risk scores.
One surprising result was that the same DNA repair genes did not behave uniformly. Genetic variants that helped stabilize some repeats made other repeats more unstable. The researchers also identified a newly recognized repeat expansion disorder involving the GLS gene. Expansions in this gene, which occur in about 0.03% of people, were linked to a 14-fold increase in the risk of severe kidney disease and a 3-fold increase in the risk of liver diseases.