“Unraveling the Longevity of Unrepaired DNA Damage: A Revolutionary Perspective on Mutations”

Researchers from the Wellcome Sanger Institute and their partners examined the family trees of hundreds of individual cells derived from several subjects. The group constructed these family trees using patterns of shared mutations among the cells, indicating shared ancestry.

Scientists discovered surprising patterns of mutation inheritance within these trees, exposing that some DNA damage remains unrepaired. For instance, in blood stem cells, this can persist for two to three years.

The findings, published today (15 January) in Nature, transform our understanding of mutations and have significance for comprehending the development of various cancers.

Throughout our lives, every cell in our body accumulates genetic mistakes in the genome, referred to as somatic mutations. Such mutations may arise from harmful environmental factors, like smoking, as well as the ordinary chemical processes occurring in our cells.

DNA damage is different from a mutation. While a mutation involves one of the standard four DNA bases (A, G, T, or C) misplaced, akin to a typographical error, DNA damage refers to a chemical change in the DNA, similar to a blurred, illegible letter. DNA damage can lead to the genetic sequence being read and replicated incorrectly during cell division — known as DNA replication — introducing enduring mutations that can contribute to cancer development. Nevertheless, the DNA damage itself is typically identified and repaired promptly by the cell’s repair systems.

If scientists can gain a deeper understanding of the origins and mechanisms behind mutations, they might be able to intervene and mitigate or eliminate them.

In a recent investigation, researchers from the Sanger Institute and their collaborators analyzed information in the form of family trees of hundreds of individual cells from various subjects. These family trees are formed from mutation patterns across the genome that are shared among cells — for instance, cells exhibiting numerous shared mutations have a recent common ancestor and are closely linked.

The team compiled seven published sets of these family trees known as somatic phylogenies. The dataset included 103 phylogenies from 89 individuals¹, covering blood stem cells, bronchial epithelial cells, and liver cells.

The researchers discovered unexpected patterns of mutation inheritance within the family trees, showing that some DNA damage can remain unrepaired through numerous rounds of cell division. This was particularly noticeable in blood stem cells, where approximately 15 to 20 percent of the mutations stemmed from a specific type of DNA damage that lasts an average of two to three years, and in some instances, even longer.

This means that during cell division, whenever the cell attempts to replicate the damaged DNA, it might make a different error, resulting in varied mutations from a single DNA damage source. This is significant as it creates multiple possibilities for hazardous mutations that could contribute to cancer. Researchers propose that while these types of DNA damage are infrequent, their long-lasting nature over the years means they can result in as many mutations as more prevalent DNA damage.

On the whole, these discoveries alter the perception of mutations among researchers and carry implications for cancer development.

Dr. Michael Spencer Chapman, the primary author from the Wellcome Sanger Institute and the Barts Cancer Institute, stated: “With these family trees, we can trace the relationships of hundreds of cells from a single individual back to conception, enabling us to track through the divisions each cell has undergone. It’s these large-scale, novel datasets that have led us to this unforeseen discovery that some forms of DNA damage can persist for an extended time without repair. This study exemplifies exploratory science — one cannot always predict what will be found until exploration occurs; it requires curiosity.”

Emily Mitchell, an author from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute, and the University of Cambridge, remarked: “When examining the family trees of blood stem cells specifically, we identified a unique form of DNA damage that accounts for about 15 to 20 percent of the mutations in these cells, lasting for several years. It remains unclear why this process occurs solely in blood stem cells rather than other healthy tissues. Understanding the long-lasting DNA damage opens new pathways to investigate what the damage actually entails. As we continue to enhance our understanding of mutation causes, there may come a time when we can intervene and eliminate them.”

Dr. Peter Campbell, the lead author previously from the Wellcome Sanger Institute and now Chief Scientific Officer at Quotient Therapeutics, stated: “We have pinpointed types of DNA damage that successfully evade our DNA repair systems and persist in the genome for days, months, or even years. These findings contradict what scientists have previously believed about the fundamental mechanisms of mutation acquisition. This shift in perspective adds a new layer to how we regard mutations and is vital for the research community when planning future investigations.”