DNA damage can last unrepaired for years, changing our view of mutations

Scientists from the Wellcome Sanger Institute and their collaborators analysed family trees of hundreds of single cells from several individuals. The team pieced together these family trees from patterns of shared mutations between the cells, indicating common ancestors.

Researchers uncovered unexpected patterns of mutation inheritance in the trees, revealing that some DNA damage persists unrepaired. In the case of blood stem cells, this can be for two to three years.

The research, published today (15 January) in Nature, changes the way we think about mutations, and has implications for understanding the development of various cancers.

Throughout our life, all of the cells in our body accumulate genetic errors in the genome, known as somatic mutations. These can be caused by damaging environmental exposures, such as smoking, as well as the everyday chemistry occurring in our cells.

DNA damage is distinct from a mutation. While a mutation is one of the standard four DNA bases (A, G, T or C) in the wrong place, similar to a spelling mistake, DNA damage is chemical alteration of the DNA, like a smudged unrecognisable letter. DNA damage can result in the genetic sequence being misread and copied during cell division -- known as DNA replication -- and this introduces permanent mutations that can contribute to the development of cancers. However, the DNA damage itself is usually recognised and mended quickly by repair mechanisms in our cells.

If researchers can better understand the causes and mechanisms of mutations, they may be able to intervene and slow or remove them.

In a new study, Sanger Institute scientists and their collaborators analysed data in the form of family trees of hundreds of single cells from individuals. The family trees are constructed from patterns of mutations across the genome that are shared between cells -- for example, cells with many shared mutations have a recent common ancestor cell and are closely related.

The researchers collated seven published sets of these family trees, known as somatic phylogenies. The data set included 103 phylogenies from 89 individuals¹, spanning blood stem cells, bronchial epithelial cells and liver cells.

The team found unexpected patterns of mutation inheritance in the family trees, revealing that some DNA damage can persist unrepaired through multiple rounds of cell division. This was particularly evident in blood stem cells, where between 15 to 20 per cent of the mutations resulted from a specific type of DNA damage that persists for two to three years on average, and in some cases longer.

This means that during cell division, each time the cell attempts to copy the damaged DNA it can make a different mistake, leading to multiple different mutations from a single source of DNA damage. Importantly, this creates multiple chances of harmful mutations that could contribute to cancer. Researchers suggest that although these types of DNA damage occur rarely, their persistence over years means they can cause as many mutations as more common DNA damage.

Overall, these findings change the way researchers think about mutations, and has implications for the development of cancer.

Dr Michael Spencer Chapman, first author from the Wellcome Sanger Institute and the Barts Cancer Institute, said: "With these family trees, we can link the relationships of hundreds of cells from one person right back to conception, meaning we can track back through the divisions each cell has gone through. It's these large-scale, novel datasets that have led us to this unexpected finding that some forms of DNA damage can last for a long time without being repaired. This study is a prime example of exploratory science -- you don't always know what you're going to find until you look; you have to stay curious."

Emily Mitchell, an author from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute and University of Cambridge, said: "When exploring family trees of blood stem cells in particular, we found a specific type of DNA damage that results in around 15 to 20 per cent of the mutations in these cells, and can last for several years. It is unclear why this process is only found in blood stem cells and not other healthy tissues. Knowing that the DNA damage is long-lasting gives new routes to investigate what the damage actually is. As we continue to better understand the causes of mutations, we may one day be able to intervene and remove them."

Dr Peter Campbell, lead author previously from the Wellcome Sanger Institute and now Chief Scientific Officer at Quotient Therapeutics, said: "We have identified forms of DNA damage that manage to escape our DNA repair mechanisms and persist in the genome for days, months, or sometimes years. These findings don't fit with what scientists have previously thought about the fundamentals of how mutations are acquired. This paradigm shift brings a new dimension to the way we think about mutations, and is important for the research community when designing future studies."