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Clonal Hematopoiesis Drivers Detected in Selection-Focused Study

NEW YORK – Investigators at the Wellcome Sanger Institute, the University of Cambridge, Calico Life Sciences, and elsewhere have uncovered new driver genes behind a condition called clonal hematopoiesis, marked by the age-related accumulation of somatic mutation-containing blood cell clones.

"In the past decade, genomic sequencing of blood samples has revealed that clonal hematopoiesis (CH) is common in elderly individuals with apparently normal hematopoiesis, with large-scale retrospective studies identifying associations of CH with hematological malignancies, cardiovascular disease, and all-cause mortality," the authors wrote in Nature Genetics on Tuesday, noting that "there are ongoing efforts to comprehensively map the drivers of CH to better understand clonal selection and aging phenotypes of blood."

Together the results expand on the list of genes implicated in clonal hematopoiesis, co-senior and co-corresponding author Jyoti Nangalia, a researcher affiliated with the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute, said in an email, noting that dozens of driver genes reported in the past only appeared to explain roughly one-third of the cases of clonal expansions in blood cells that are identified.

Using exome sequencing data for 200,618 UK Biobank (UKBB) participants between the ages of 40 and 70, Nangalia and her colleagues highlighted somatic mutations in participant blood samples. From there, they incorporated gene-level positive selection clues to focus in on 17 suspected driver genes for CH, providing insights to better understand and uncover CH and related conditions.

"While existing genetic tests have been valuable for early disease detection, our findings suggest there are opportunities to improve them further," co-first author Michael Spencer Chapman, with the Wellcome Sanger Institute and the University of Cambridge Wellcome-MRC Cambridge Stem Cell Institute, said in a statement. "By incorporating these 17 additional genes linked to clonal hematopoiesis, we can enhance genetic testing methods to better identify risks of associated blood cancers and cardiovascular diseases."

To confirm, and further dig into the signs of positive selection that they found in the exome sequence data, the researchers performed whole-genome sequencing on more than 10,800 hematopoietic cell colonies that were each established from an individual cell.

"Overall, across [more than] 10,000 single cell-derived clonal hematopoietic cell colonies derived from 50 individuals, we identified 150 somatic mutations in 16 of the 17 new fitness-inferred drivers, with a strikingly similar pattern of non-synonymous mutations to bulk whole-exome sequencing data from the UKBB," the authors reported.

By incorporating information on CH clone sizes in relation to participants' health outcomes, genetic profiles, and available RNA sequencing-based gene expression data on preleukemia or leukemic cells of hematopoietic origin, the researchers saw signs that the suspected new driver genes had ties to blood clonal expansion, infection, and disease that resembled those previously described for established CH driver genes.

Together, such results hint at opportunities for identifying individuals at risk of age-related diseases linked to CH, though Nangalia cautioned that additional research will be needed to explore this possibility and to dig into mechanistic explanations for the way driver genes influence the development of CH and related conditions.

"Our study reveals a much broader set of genes fueling mutant blood cell clone accumulation with age, but this is only the beginning," Nangalia said in a statement. "Larger studies across diverse populations are needed to identify remaining driver genes and provide further insights into this process and disease links."