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Wellcome Sanger Institute’s NanoSeq sequencing breakthrough enables study of DNA mutations from any human tissue

An extraordinary breakthrough that follows four years of work at the Wellcome Sanger Institute means scientists are now able to study changes in the DNA of any human tissue.

The new technique, called nanorate sequencing, or NanoSeq, promises to drive forward research into cancer and ageing significantly.

A stock image of DNA sequencing
A stock image of DNA sequencing

And the first findings using NanoSeq have already challenged the long-standing assumption that the main mechanism behind genetic changes is cell division.

Researchers now look forward to using the technology to study the effect of carcinogens like tobacco or sun exposure on healthy cells much more easily and on a far greater scale than ever possible before.

Through painstaking work, they have improved the accuracy of a type of genome sequencing technology so that it makes fewer than five errors per billion letters of DNA.

Until now, genome sequencing has not been accurate enough to study new mutations in non-dividing cells.

While tissues in our body are composed of both dividing and non-dividing cells, the vast majority do not divide or do so only rarely. Instead, stems cells - which renew themselves throughout our lifetimes - are responsible for resupplying non-dividing cells in order to keep the body running.

Among these cell types are granulocytes in our blood, which are produced in the billions every day but live for a very short time, and neurons in our brain, which live for much longer.

As we age, genetic changes known as somatic mutations naturally occur in our cells. This happens at a rate of about 15 to 40 mutations of year. While most of these changes are harmless, some can start a cell on a path towards cancer.

Studying somatic mutations in tumour DNA has enable researchers to better understand the formation of cancers, and how to treat them, since the advent of genome sequencing in the late twentieth century.

New technologies have more recently enabled scientists to study mutations in stem cells taken from healthy tissue too.

But since genome sequencing has not had the accuracy required to study new mutations in non-dividing cells, somatic mutation in the vast majority of human cells has been impossible to observe accurately - until now.

Dr Robert Osborne, formerly of the Wellcome Sanger Institute and now COO of Biofidelity
Dr Robert Osborne, formerly of the Wellcome Sanger Institute and now COO of Biofidelity

Dr Robert Osborne, an alumnus of the Wellcome Sanger Institute who led the development of the method, said: “Detecting somatic mutations that are only present in one or a few cells is incredibly technically challenging. You have to find a single letter change among tens of millions of DNA letters and previous sequencing methods were simply not accurate enough. Because NanoSeq makes only a few errors per billion DNA letters, we are now able to accurately study somatic mutations in any tissue.”

In a study published last week in Nature, researchers described how they refined an advanced sequencing method called duplex sequencing, a method that greatly improved the accuracy of genome sequencing when first used in 2012. It reads DNA multiple times to sift out errors, leading to one error in every million DNA letters.

The team searched for these errors in duplex sequence data and discovered they were concentrated at the ends of DNA fragments. They also found other features suggesting flaws in the process used to prepare DNA for sequencing.

Implementing improvements to the DNA preparation process, such as using specific enzymes to cut DNA more cleanly, as well as improved bioinformatics methods, led to the dramatic improvement in accuracy.

They then used NanoSeq to study samples of blood, colon, brain and muscle.

They compared the rates and patterns of mutation in both stem cells and non-dividing cells in several human tissue types.

In blood cells, they were surprised to find similar number of mutations in slowly dividing stem cells as in more rapidly dividing progenitor cells, suggesting cell division is not the dominant process causing mutations here.

Similarly, analysis of non-dividing neurons and rarely dividing cells from muscle showed that mutations accumulate throughout life in cells without cell division and at a similar pace to cells in the blood.

First author Dr Federico Abascal, from the Wellcome Sanger Institute, said: “It is often assumed that cell division is the main factor in the occurrence of somatic mutations, with a greater number of divisions creating a greater number of mutations. But our analysis found that blood cells that had divided many times more than others featured the same rates and patterns of mutation. This changes how we think about mutagenesis and suggests that other biological mechanisms besides cell division are key.”

Observing mutation in all cells opens up fresh avenues for research and is expected to help us better understand the impact of known carcinogens, or discover new ones.

It could help greatly improve our understanding of how lifestyles choices and exposures to carcinogens lead to cancer.

The technology also means it will be much easier to collect samples for study, as rather than taking biopsies of tissue, cells can be collected non-invasively by, for example, scraping the skin or swabbing the throat.

Dr Inigo Martincorena, a senior author of the paper from the Wellcome Sanger Institute, said: “The application of NanoSeq on a small scale in this study has already led us to reconsider what we thought we knew about mutagenesis, which is exciting.

“NanoSeq will also make it easier, cheaper and less invasive to study somatic mutation on a much larger scale. Rather than analysing biopsies from small numbers of patients and only being able to look at stem cells or tumour tissue, now we can study samples from hundreds of patients and observe somatic mutations in any tissue.”

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