New method analyses DNA changes with ‘unprecedented accuracy’

In collaboration with the Press Association

Scientists have developed a new sequencing method to study changes in the DNA of any human tissue – in a major breakthrough for cancer and ageing research.

Genetic changes (mutations) occur naturally in our cells as we age, in most cases causing no harm. But certain mutations can set a cell on the path to cancer. While genome sequencing has been used for many years to understand how cancer develops, it’s never been accurate enough to detect new mutations in non-dividing cells – the large majority – until now. 

A new study by the Wellcome Sanger Institute, funded in part by Cancer Research UK and published in Nature, showcases a new approach called nanorate sequencing (NanoSeq), that can uncover changes in the DNA of all human tissues with unprecedented accuracy. 

“Until recently, detecting mutations reliably in single cells has been an intractable task.”Professor Charles Swanton, cancer evolution expert and Cancer Research UK’s chief clinican

The research has also opened eyes to the possibility that cell division isn’t the main driving force behind genetic changes, as previously assumed.

A lengthy and technical process

The team originally set out to improve an advanced sequencing method called duplex sequencing, through which DNA is read multiple times to locate errors in the data. 

When searching for mistakes in the data it became clear they were gathered at the ends of DNA fragments, and had other features that suggested flaws in how the DNA was being prepared  for sequencing. Spanning 4 years, the research focused on enhancements and improving accuracy, until fewer than 5 errors per billion letters of DNA was achieved. 

Dr Robert Osborne, an alumnus of Wellcome Sanger Institute who led the work, said detecting mutations that are only present in one or a few cells is “incredibly technically challenging”. But because of Nano Seq’s vastly limited errors, they are “now able to accurately study somatic mutations in any tissue”.

An unexpected find

Taking advantage of the techniques improved sensitivity, researchers were able to compare the rate and pattern of mutation in both stem cells and non-diving cells in multiple human tissue types, which led to an unexpected discovery.

Analysis of blood cells revealed a similar number of mutations in slowly dividing stem cells and a more rapidly dividing population called progenitor cells. 

The same pattern was confirmed in analyses of non-dividing neurons and rarely-dividing cells from muscle, which revealed that changes accumulate throughout life in cells without cell division, and at a similar pace to cells in the blood.

Swanton commented that mutations in normal cells have always been thought to occur as a result of normal cell division, meaning the greater the cell turnover, the greater the number of mutations in that cell. But the latest results reveal “that the old dogma of the accumulation of mutations with cell divisions may not be entirely correct” and open up a whole new area of study.  

Unraveling cancer's secrets 

It’s hoped the NanoSeq method will enable scientists to study the effects of carcinogens like tobacco or sun exposure on healthy cells, as well as discover and understand new harmful substances that may cause cancer. 

NanoSeq will also make it easier to take and test samples from people. Instead of taking intrusive biopsies of tissue, cells can be collected simply by scraping the skin or swabbing the throat. 

“Understanding how normal cells accumulate mutations outside of the cell division process may help us unravel the biological secrets behind ageing and human diseases, including cancer,” said Swanton. 

References

Federico Abascal, Luke M. R. Harvey and Emily Mitchell et al. (2021). Somatic mutation landscapes at single-molecule resolution. Nature. DOI: https://doi.org/10.1038/s41586-021-03477-4