Scientists identified genes that drive age-related blood cell mutations

New research identifies a larger pool of genes involved in clonal haematopoiesis.

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Clonal expansions in dividing tissues appear as a tapestry with increasing age in humans; this is most visible in blood as clonal hematopoiesis (CH). CH, associated with aging-related phenotypes and cancer risk, is frequently caused by somatic mutations in a group of known genes. Most clones, though, don’t have identified drivers.

In a new study, scientists from the Wellcome Sanger Institute, Calico Life Sciences, California, and the University of Cambridge have discovered 17 additional genes that drive the abnormal overgrowth of mutated blood cells as we age. The research provides crucial new information on the genetics behind clonal hemopoiesis, a process linked to aging and a higher risk of blood malignancies.

Scientists examined sequencing data from the UK Biobank cohort, which included over 200,000 people. They looked for genes exhibiting “positive selection” signals, which occur when mutations cause mutant cell populations to grow significantly over time.

The clinical importance of the 17 recently identified genes in promoting the generation of mutant blood cell clones was highlighted by the discovery that they shared comparable illness correlations with previously identified clonal hematopoiesis mutations.

The discovery provides new pathways for investigating the molecular mechanisms underpinning clonal hemopoiesis and its role in disease development, leading to novel approaches for promoting healthier aging. The study has identified these hitherto unknown genetic factors. Better genetic tests that determine the risks of blood malignancies and cardiovascular illnesses may also result from it.

With aging, our cells develop haphazard genetic alterations. Specific mutations can provide mutant cells with a competitive growth advantage, enabling them to increase and surpass healthy cells in number, resulting in substantial “clones” or communities of identical mutant cells. Clonal hemopoiesis is the term used to describe this process of positive selection in blood stem cells. Blood malignancies, cardiovascular disease, and other age-related illnesses are linked to this process.

Although about 70 genes have been connected to clonal hemopoiesis, most instances reported recently do not have mutations in any of these driving genes. This implies the presence of extra genetic variables.

The study aimed to define distinctive positive selection patterns in the aging blood system using whole exome sequencing data from more than 200,000 members of the UK Biobank cohort. In addition to the known drivers, they discovered an additional 17 genes that are responsible for the build-up of mutant cell clones in human blood.

By incorporating mutations in these recently discovered genes, the prevalence of clonal hemopoiesis in the UK Biobank cohort increased by 18%, highlighting the influence of these genes on aging.

Dr Michael Spencer Chapman, co-first author of the study at the Wellcome Sanger Institute, said: “While existing genetic tests have been valuable for early disease detection, our findings suggest there are opportunities to improve them further. By incorporating these 17 additional genes linked to clonal haematopoiesis, we can enhance genetic testing methods to identify better risks of associated blood cancers and cardiovascular diseases.”

Nick Bernstein, the co-first author of the study, formerly at Calico Life Sciences, California, and now based at NewLimit, said: “With our newly identified genes, we now have a complete picture to explore strategies for delaying or reversing abnormal mutant cell overgrowths in blood to promote healthier aging. These genes seem to affect inflammation and immunity, important factors in conditions like heart disease and strokes. While interventions based on this research are still a long way off, it opens up possibilities for future treatments across a wide range of diseases.”

Dr Jyoti Nangalia, senior author of the study from the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, said: “Our study reveals a much broader set of genes fuelling mutant blood cell clone accumulation with age, but this is only the beginning. Larger studies across diverse populations are needed to identify remaining driver genes and provide further insights into this process and disease links.”

Journal Reference:

  1. Bernstein, N., Spencer Chapman, M., Nyamondo, K. et al. Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis. Nat Genet (2024). DOI: 10.1038/s41588-024-01755-1

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