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New sequencing method for studying genetic changes in any human tissue

4 May 2021
Appeared in BioNews 1093

Scientists are able to study changes in single DNA molecules of any human tissue with unprecedented accuracy, for the first time. 

The research, led by scientists at the Wellcome Sanger Institute, Hinxton, Cambridgeshire, is marking a major scientific advancement. The new sequencing method, called nanorate sequencing (NanoSeq), resolves the long-standing technical challenges of genomic sequencing and has a significantly lower error rate than previous methods.

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.'

Genetic mutations occur in cells as the body ages. Most of these mutations are harmless, but some can lead to the development of cancer. Researchers have been able to study these mutations in tumours to understand how cancer develops and how to treat it. But until now, genome sequencing has not been precise enough to study new mutations in non-dividing or rarely dividing cells, which make up the majority of the body's tissues.

In this study, published in the journal Nature, the researchers improved an existing genomic sequencing technique by searching for errors in the sequence data. The scientists found that errors seemed to concentrate at the ends of DNA fragments, and they identified other features suggesting the errors might result from problems in DNA preparation.

Over the course of four years the scientists improved the DNA preparation process and tweaked bioinformatic methods until they achieved fewer than five errors per billion letters of DNA sequenced.

Using the newly developed NanoSeq method, the researchers found a similar number of mutations in slowly dividing blood stem cells and more rapidly dividing progenitor blood cells. In addition, they established that non-dividing neurons (brain cells) and rarely dividing muscle cells accumulated mutations throughout their life cycle. Their results suggest that the build-up of mutations that are not linked to cell division are an important contributor to the total number of mutations.

In addition to offering exciting possibilities for research into the development of cancer and ageing, NanoSeq has the advantage of being able to use non-invasively collected samples, including cells from skin or throat swabs.

Dr Inigo Martincorena, a senior author of the paper from the Wellcome Sanger Institute said: '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.'

SOURCES & REFERENCES
Major advance enables study of genetic mutations in any tissue
Wellcome Sanger Institute |  28 April 2021
Somatic mutation landscapes at single-molecule resolution
Nature |  28 April 2021
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