Unraveling the Paradox: Healthy Cells Harbor Hidden DNA Damage That Defies Mutation Norms

Though the majority of known types of DNA damage are rectified by the DNA repair systems within our cells, certain types of DNA damage can evade repair and endure for several years, as demonstrated by recent studies. Consequently, this damage has multiple opportunities to produce detrimental mutations, which may culminate in cancer.

Researchers from the Wellcome Sanger Institute, along with their partners, scrutinized family trees of hundreds of single cells obtained from various individuals. The team reconstructed these family trees using patterns of shared mutations among the cells, indicating common progenitors.

Investigators discovered surprising mutation inheritance patterns within the trees, displaying that some DNA damage remains unrepaired. Particularly in blood stem cells, this can last between two to three years.

The study, released on 15 January in Nature, transforms our understanding of mutations and carries implications for comprehending the onset of diverse cancers.

Throughout our lifetime, every cell in our body accumulates genetic errors within the genome, referred to as somatic mutations. These mutations can arise from damaging environmental factors, such as smoking, as well as the routine biochemical processes occurring within our cells.

DNA damage differs from a mutation. While a mutation involves one of the four standard DNA bases (A, G, T, or C) being misplaced—akin to a typographical error—DNA damage refers to a chemical modification of the DNA, similar to a smudged, unreadable character.

DNA damage may result in misreading and copying of the genetic sequence during cell division—known as DNA replication—and this can introduce irreversible mutations that may foster the development of cancers. Nevertheless, the DNA damage itself is generally identified and swiftly repaired by our cells’ repair mechanisms.

If scientists can enhance their comprehension of the origins and mechanisms behind mutations, they could potentially take action to impede or eliminate them.

In a recent study, scientists from the Sanger Institute and their collaborators examined data formatted as family trees of hundreds of single cells from individuals. The family trees are constructed from patterns of mutations distributed across the genome that are shared among cells—for instance, cells sharing numerous mutations have a recent common ancestor cell and are closely related.

The researchers consolidated seven previously published sets of these family trees, identified as somatic phylogenies. The dataset encompassed 103 phylogenies from 89 individuals, covering blood stem cells, bronchial epithelial cells, and liver cells.

The team observed unexpected patterns regarding mutation inheritance within the family trees, revealing that certain DNA damage can remain unrepaired through numerous cell division cycles. This was notably seen in blood stem cells, where between 15 to 20% of the mutations stemmed from a specific kind of DNA damage that persists on average for two to three years, and in some instances, even longer.

This signifies that during cell division, each time the cell tries to replicate the damaged DNA, it may create a different error, resulting in a myriad of mutations arising from a singular source of DNA damage.

Crucially, this escalates the chances of harmful mutations that could lead to cancer. Researchers propose that while such DNA damage occurs infrequently, their long-lasting nature allows for them to generate as many mutations as more prevalent forms of DNA damage.

Overall, these revelations alter the perspective of researchers regarding mutations and have 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 retrace the divisions each cell has undergone.”

“These extensive, novel datasets have brought to light this surprising discovery that certain forms of DNA damage can persist for long durations without being repaired. This research exemplifies exploratory science—sometimes you do not know what to expect until you delve in; it’s vital to remain inquisitive.”

Emily Mitchell, a co-author from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute, and University of Cambridge, remarked, “When investigating family trees of blood stem cells specifically, we identified a particular form of DNA damage responsible for around 15 to 20 percent of the mutations in these cells, which can endure for several years.”

“It remains uncertain why this process is observed solely in blood stem cells and not in other healthy tissues. Understanding that the DNA damage is long-lasting opens new avenues to examine what the damage actually is. As we progress in comprehending the origins of mutations, we may eventually have the ability to intervene and eliminate them.”

Dr. Peter Campbell, the lead author who previously worked at the Wellcome Sanger Institute and is currently Chief Scientific Officer at Quotient Therapeutics, noted, “We have identified types of DNA damage that manage to elude our DNA repair mechanisms, persisting in the genome for days, months, or even years.”

“These findings do not align with the previous scientific assumptions concerning the fundamental ways mutations are acquired. This paradigm shift adds a new dimension to our understanding of mutations and is significant for the research community in designing future studies.”