Enhanced DNA sequencing finds somatic mutations in twins

An advanced DNA sequencing tool can identify previously undetectable genetic mutations in human tissue with high accuracy.

Using samples from over 1000 pairs of twins, a large-scale analysis aimed to uncover how the mutational landscape of the human genome changes in response to age, lifestyle and environmental exposure. Researchers at the Wellcome Sanger Institute, near Cambridge, refined an existing genome sequencing technology called NanoSeq to analyse either the whole genome or specific gene regions, while maintaining its low error rate. This updated 'targeted NanoSeq' approach allowed the team to accurately find rare mutations in healthy tissue.

Dr Federico Abascal, co-first author of this study published in Nature and a staff scientist at the Wellcome Sanger Institute, said, 'This is the largest study to date on how somatic mutations accumulate in a human tissue, as a result of ageing, smoking, alcohol, biological sex and other risk factors. Mutational landscapes could one day be used as measurable indicators of cancer risk, allowing earlier and more precise interventions.'

In collaboration with scientists at King's College London, the team applied targeted NanoSeq to samples from over 1000 identical and non-identical twins. Participants ranged in age from 21 to 91 and had varied lifestyles, including differences in alcohol consumption, smoking and cancer exposures. The study used targeted NanoSeq on blood and cheek swabs to track how rare DNA mutations accumulate in normal cells. It also examined whether these mutations gave cells a 'growth advantage', allowing them to multiply more quickly, thereby increasing the risk of cancer.

The team identified over 340,000 DNA mutations in cheek tissue, including over 62,000 within cancer-related genes. Mutations in 46 genes, including TP53, gave cells a growth advantage. Distinct mutation patterns were linked to lifestyle factors. For example, smoking increased NOTCH1 mutations and was also associated with this growth advantage. However, most mutated cells remained few in number, suggesting natural mechanisms may limit their spread and reduce cancer risk.

Nanorate sequencing (NanoSeq) is a precise DNA sequencing method developed in 2021. Unlike standard sequencing, which can mistake technical errors for real mutations, NanoSeq detects true genetic mutations (particularly rare somatic mutations) with a near-zero error rate.

Dr Andrew Lawson, co-first author of this study at the Wellcome Sanger Institute, said, 'We're proud to present targeted NanoSeq, a new method that has completely transformed our ability to study somatic mutations in normal and diseased tissues. We've used NanoSeq to begin to understand the earliest steps in cancer development and uncover the role of somatic mutations in ageing and different diseases.'

It has been proposed that somatic mutations contribute to ageing and cancer development, and this refined NanoSeq technology provides a systematic way to study these somatic mutations across multiple tissues. This approach has also recently been used to examine how mutations accumulate in sperm as men age (see BioNews 1310).