While lifestyle modifications may go some way to delay the signs of aging, research from two transatlantic biobanks has revealed the importance of genes in determining the rate at which DNA mutates as we grow older.
The Nature study revealed dozens of genes that regulate the expansion of DNA repeats—in which short genetic sequences become longer and more unstable with age.
It showed these expanded DNA repeats are present in most people’s genomes and are far more widespread than previously thought.
The findings suggest DNA repeat measurements could one day act as blood-based biomarkers to test the effectiveness of treatments that slow progression of genetic diseases such as Huntington’s.
“The strong genetic control of this expansion, with some individuals’ repeats expanding four times faster than others, points to opportunities for therapeutic intervention,” explained researcher Margaux Hujoel, PhD, from the University of California at Los Angeles.
“These naturally occurring genetic modifiers show us which molecular pathways could be targeted to slow repeat expansion in disease.”
Expanded DNA repeats are responsible for more than 60 inherited diseases, such as Huntington’s and myotonic dystrophy, the authors noted.
They studied whole-genome sequencing (WGS) data collected from 490,416 participants in the UK Biobank and 414,830 from the All of Us Research Program, an initiative from the U.S. National Institutes of Health.
Specifically, the team measured DNA repeat length and instability, examining 356,131 polymorphic repeat locations across the entire genome.
Results showed that common DNA repeats in blood cells grew in length as a person aged, and showed that most human genomes contained repeat elements that expanded with aging. Repeats at different loci showing widely different, tissue-specific propensities variable to mutate in the germline and blood.
The team pinpointed 29 loci at which inherited genetic variants increased the expansion of one or more DNA repeats in the blood, which had varying impacts and showed strong collective effects on repeat instability.
At one repeat, somatic expansion rates of unstable repeat alleles varied fourfold between individuals carrying the highest and lowest 5% of polygenic risk scores.
Of note, the same DNA repair genes could have opposing effects on different DNA repeats, with variants that stabilized some repeats destabilizing others.
Expanded DNA repeats in the GLS gene, which occur in around 0.03% of people, were identified as a new repeat expansion disorder. This was associated with a 14-fold increased risk of severe kidney disease and triple the risk of liver diseases.
The researchers said their findings “suggest the potential for repeats that are unstable in blood to be used as biomarkers of target engagement for future expansion-slowing therapies.”
They added: “The short-read WGS data that we analyzed provided only glimpses of somatic mutation, through observations of one or a few reads spanning shorter mutated alleles and through read-count-based evidence of expanded alleles of unknown lengths.
“Nonetheless, the analytical tools that we have developed here for biobank-scale WGS analysis provide a useful complement to studying repeat instability in families and in patient cohorts using targeted sequencing techniques and combining these approaches should provide opportunities for further discovery.”
