New research using data from the TwinsUK cohort has helped reveal how naturally occurring DNA mutations in healthy tissue may contribute to ageing and the early development of cancer.
The study, published in Nature, was led by researchers from the Wellcome Sanger Institute in collaboration with TwinsUK at King's College London. It introduces an improved version of nanorate sequencing (NanoSeq) - a highly accurate DNA sequencing technique that can detect rare genetic mutations with unprecedented precision.
Using targeted NanoSeq, researchers analysed cheek swabs from more than 1,000 TwinsUK participants, alongside 371 blood samples. This large dataset provided a unique opportunity to study how genetic mutations arise in normal tissues over time, and how lifestyle and environmental factors such as smoking and alcohol consumption can influence these changes.
The researchers discovered over 340,000 mutations in cheek cells, including more than 62,000 in genes known to drive cancer. They identified 49 genes under positive selection, which means they have mutations that give cells a growth advantage, including many well-known cancer genes such as TP53.
The research also identified clear genetic "signatures" (patterns of mutations in the genome) associated with ageing, smoking, and alcohol intake. For example, smoking was associated with more mutations in the NOTCH1 gene and more growth of mutant clones, while heavy drinking left a distinctive pattern of DNA changes. Importantly, most mutated clones in normal tissue were found to be very small and did not continuously grow over time. This suggests that while mutations are common, most mutated cells are prevented from expanding and progressing to cancer.
By combining NanoSeq's ultra-accurate sequencing with the depth and diversity of TwinsUK's long-term twin data, researchers were able to gain the most detailed picture yet of how normal tissues mutate and evolve over time. These insights could help scientists better understand the earliest biological changes that precede disease and how factors such as lifestyle, environment, and genetics contribute to cancer risk.
The combination of deep clinical and lifestyle data from the TwinsUK study and the new NanoSeq method allowed us to investigate how genetic mutations accumulate in human tissue at unprecedented scale and depth. This work has revealed links between environmental exposures, ageing and the development of mutational patterns, which improves our ability to identify the exposures and mutations that lead to cancer and other diseases.
Professor Kerrin Small, Professor in Genomics at King's and co-author of the paper
The improved version of NanoSeq is now being used in other studies at the Sanger Institute, including in another collaboration with TwinsUK published in Nature. The study examined how harmful DNA changes accumulate in sperm cells as men age, offering new opportunities to explore how environmental and lifestyle factors may affect genetic risks in future generations.
