New research has discovered how genetic mutations take over the production of blood cells at different life stages. The study, published in Nature, demonstrates how these changes relate to ageing and the development of age-related diseases, including blood cancer. This is the first time that the lifelong impact of ‘clones’ and genetic mutations on cell growth dynamics has been explored.
Clonal haematopoiesis
Human cells develop genetic changes in their DNA throughout life. These are known as somatic mutations and a specific subset of mutations drives cells to multiply. This is common in blood stem cells and results in the growth of ‘clones’ – populations of cells with identical mutations. This process, known as ‘clonal haematopoiesis’, becomes ubiquitous with age. It is a contributing risk factor for developing blood cancer and other age-related conditions.
“Understanding why some mutations prevail in youth and others in old age could help us find ways to maintain the health and diversity of our blood cells,” said Dr Margarete Fabre, lead researcher on the study from the Wellcome Sanger Institute and the University of Cambridge.
A Mediterranean longitudinal study
Researchers tracked nearly 700 blood cell clones from 385 individuals aged over 55. Participants donated regular blood samples for up to 16 years.
The participants were part of the SardiNIA longitudinal study, a ‘founder population’ project launched in 2001 focussing on the Mediterranean island of Sardinia. The Sardinian population is one of the most extreme in its relative lack of heterogeneity, making it an excellent case study to investigate genetic factors for a wide range of conditions. The longitudinal study, now in its 15th year, focuses on residents of the cluster of towns to collect longitudinal information on more than 400 age-related quantitative traits.
Past, present and future of mutant clones
Using the SardiNIA blood samples, DNA sequencing demonstrated that 92.4% of clones expanded at a stable exponential rate over the period studied. The growth rate was primarily influenced by the nature of the mutated gene in each clone.
After capturing the behaviour of clones in later life, the team used mathematical models to infer their growth patterns over the entire human lifespan. They found that clone behaviour varied markedly with age depending on the identity of the mutated gene.
First, clones driven by mutations in DNMT3A, expanded fast in young people and then decelerated in old age. Second, clones driven by mutations in TET2 appeared and grew uniformly throughout life, such that they became more common than DNMT3A-mutant clones after the age of 75. Finally, clones with mutations in splicing genes, U2AF1 and SRSF2, only expanded exclusively later in life and exhibited some of the fastest growth. This study has uncovered how genetic mutations hijack the production of blood cells in different periods of life.
“For the first time we have been able to use genomic analysis to understand the past, present and future of mutant clones in our blood. These data show that the dynamics of blood clones are surprisingly predictable over a period of years, but also highlight that they change over a lifetime in ways we don’t understand yet,” reported Dr Moritz Gerstung, co-senior author of the study, from EMBL’s European Bioinformatics Institute and the German Cancer Research Centre
Looking to the future
These age-dependent clonal behaviours mirror the emergence rate of different types of blood cancers and show that mutations associated with fast clonal growth are increasingly likely to lead to malignancy.
Professor George Vassiliou, co-senior author of the study and Professor of Haematological Medicine at the Wellcome-MRC Cambridge Stem Cell Institute said, “Remarkably, these changes lead to the emergence of different types of blood cancers at different ages, and with different risks of progression. With this new understanding, researchers can begin to develop approaches and treatments to stop the development of blood cancer in its tracks.”
Written by Poppy Jayne Morgan, Front Line Genomics
Image Credit: Canva
