Scientists at the Wellcome Sanger Institute have developed a new method – NanoSeq – that enables them to study genetic changes in human tissues with unprecedented accuracy. Their findings were published in Nature.
As we age, our cells accumulate somatic mutations. These somatic mutations can drive cancer development and can also contribute to ageing and other diseases. Despite the importance of these mutations, detecting them has been difficult as they are often only present in small groups of cells or even in single cells. Current technical limitations, such as high errors rates, has limited our understanding of somatic mutagenesis to a minority of tissues. As a result, our knowledge of the rates and patterns of somatic mutations across human cell types remains incomplete. This is particularly the case for non-dividing cells (vast majority of cells) and cells in post-mitotic tissues.
Detecting genetic changes in human tissues
To overcome these limitations, researchers developed nanorate sequencing (NanoSeq) – a duplex sequencing protocol that enables the study of somatic mutations in any tissue or cell population. The approach achieves this by reliably detecting somatic mutations in single DNA molecules. The error rates are less than five errors per billion base pairs in single DNA molecules from cell populations.
The team used this approach to compare the rates and patterns of somatic mutations within both stem cells and non-dividing cells across several tissues. They found that rapidly dividing progenitor cells in the blood had similar mutational loads and signatures to their corresponding stem cells. This suggests that cell division is not the dominant process that is causing mutations within blood cells. Furthermore, analysis of non-dividing neurons and rarely dividing muscle cells also revealed that mutations accumulate at a constant rate during the cells’ life independent of cell division, and at a similar pace to the cells in the blood.
Dr Federico Abascal, the first author of the paper from the Wellcome Sanger Institute, expressed:
“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.”
The ability to detect somatic mutations in all cells opens up the ability to study cancer and ageing, particularly the effects of how lifestyle choices and exposure to carcinogens can impact mutagenesis and cause disease.
Image by Darwin Laganzon from Pixabay