Genes driving age-related blood cell mutations uncovered

New research identifies a larger pool of genes involved in clonal haematopoiesis than previously thought, and their implications for disease and diagnostic tests. 

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Scientists have discovered 17 additional genes that drive the abnormal overgrowth of mutated blood cells as we age. The findings, published today (14 May) in Nature Genetics, provide a more complete view of the genetic factors behind clonal haematopoiesis – process associated with ageing and linked to increased risks of blood cancers1.

Researchers from the Wellcome Sanger Institute, Calico Life Sciences, California, and the University of Cambridge analysed sequencing data from over 200,000 individuals in the UK Biobank cohort. They searched for genes showing signals of “positive selection” – where mutations allow mutant cell populations to greatly expand over time.

The 17 newly discovered genes were found to have similar disease associations as previously known clonal haematopoiesis mutations, highlighting their clinical significance in driving the accumulation of mutant blood cell clones.

By uncovering these previously unrecognised genetic drivers, the research opens new avenues for studying the molecular mechanisms underlying clonal haematopoiesis and its role in disease development. Additionally, it could lead to better genetic tests that help identify the risks of blood cancers and cardiovascular diseases.

As we age, our cells accumulate random genetic mutations. Some of these mutations can provide a competitive growth advantage, allowing mutant cells to multiply and outnumber the healthy cells, forming large ‘clones’ or populations of identical mutant cells. When this positive selection happens in blood stem cells, it is called clonal haematopoiesis. This process is associated with blood cancers, cardiovascular disease and other age-related diseases.

While previous studies have identified around 70 genes linked to clonal haematopoiesis2, most cases observed recently have not involved mutations in any of these known driver genes. This suggests the involvement of additional genetic factors.

Researchers from the Wellcome Sanger Institute, Calico Life Sciences, California, and the University of Cambridge set out to map characteristic patterns of positive selection in the ageing blood system, leveraging whole exome sequencing data from over 200,000 individuals in the UK Biobank cohort. They identified 17 genes driving the accumulation of mutant cell clones in our blood, beyond the known set of drivers.

Incorporating mutations in these newly identified genes increased the prevalence of clonal haematopoiesis by 18 per cent in the UK Biobank cohort, underscoring their impact on ageing3.

“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 better identify risks of associated blood cancers and cardiovascular diseases.”

Dr Michael Spencer Chapman, co-first author of the study at the Wellcome Sanger Institute

“With our newly identified genes, we now have a more complete picture to explore strategies for delaying or reversing abnormal mutant cell overgrowths in blood to promote healthier ageing. 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.”

Nick Bernstein, co-first author of the study, formerly at Calico Life Sciences, California and now based at NewLimit

“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.”

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

More information

Notes to Editors:

  1. Clonal haematopoiesis is the development of mutations in genes involved in blood cell production. It is diagnosed when a test on a person’s blood or bone marrow sample shows that blood cells are carrying one of the genetic mutations associated with the condition. Clonal haematopoiesis becomes increasingly common with age, affecting more than one in every ten individuals older than 60 years.
  3. The team also validated the positive selection signals in an additional 10,837 single blood cell colony genome sequences.


M. S. Chapman et al. (2024) ‘Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis.’ Nature Genetics. DOI: 10.1038/s41588-024-01755-1


This research was supported by Wellcome, Cancer Research UK, Calico and the Alborada Trust. For full funding acknowledgements, please refer to the publication.