In a recent study published in the journal Nature Genetics, a team of researchers from the United Kingdom (U.K.) and the United States (U.S.) analyzed whole blood samples from a large cohort of U.K. Biobank participants to discover 17 genes that are being positively selected at the population level and driving clonal hematopoiesis.

Study: Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis. Image Credit: BioFoto / Shutterstock

Background

Clonal hematopoiesis is the clonal expansion of dividing cells in the blood, carrying accumulated somatic mutations, leading to an assortment of clones that evolve with age. The emergence of clonal hematopoiesis and similar clonal expansions in other dividing tissues is often considered a hallmark of human aging. Given that some of these somatic mutations provide a fitness benefit, these clones often come under positive selection. However, some of the mutations in these clones can not only drive cancer but also contribute directly and indirectly to other diseases, such as chronic liver disease.

Genomic sequencing studies on blood samples have identified that the occurrence of clonal hematopoiesis is higher among elderly individuals. Furthermore, retrospective studies among large cohorts have also identified an association between clonal hematopoiesis and cardiovascular disease, hematological cancers, and mortality. However, most approaches to detect clonal expansion either fall short, such as bulk approaches that can detect only a few small clones, or detect a large number of clones, with most of them lacking the specific driver mutations, as in the case of single-cell sequencing.

About the study

In the present study, the researchers attempted to find better methods to map clonal hematopoiesis drivers, understand how these clones undergo selection, and determine the phenotypes of aging in blood. They obtained whole blood samples from a large cohort (200,618) of U.K. Biobank participants and studied the exomes from these samples to determine the drivers of clonal hematopoiesis.

The researchers worked on the principle that nonsynonymous mutations within a gene would be enriched compared to synonymous mutations if the gene was under positive selection. Therefore, the exomes from the buffy coats, which are the residual units enriched with leukocytes obtained when whole blood is centrifuged, were examined to determine the genes under positive selection.

The participants from the U.K. Biobank included in this study were between 40 and 70 years old. A method of somatic variant calling was used to filter out the germline variants and artifacts from the whole blood exomes. Subsequently, the non-synonymous to synonymous mutations ratio was used to identify specific mutations and genes under negative, positive, and neutral selection.

To verify that the genes identified to be under positive selection were not an unintended result of the somatic mutation calling method, the researchers used a method called Shearwater, which is used for calling subclonal variants, to call the somatic mutations in newly identified and classical clonal hematopoiesis genes.

Additionally, published whole-genome sequences from healthy individuals as well as patients with hematological cancers were examined for corresponding mutations to validate these fitness-inferred drivers of clonal hematopoiesis. Furthermore, the updated health records available through the U.K. Biobank were used to determine the clinical associations of these fitness-inferred clonal hematopoiesis drivers at the population level.

Results

The study identified 17 additional genes involved in clonal hematopoiesis that were positively selected at the population level. The 17 newly identified clonal hematopoiesis genes were ZNF318, ZNF234, ZBTB33, YLPM1, SRFS1, SRCAP, SPRED2, SIK3, SH2B3, MYD88, MTA2, MAGEC3, IGLL5, CHEK2, CCL22, CCDC115, and BAX.

This finding was further validated by comparing these genes with those in close to 11,000 whole genomes obtained from hematopoietic lymphoid and myeloid colonies derived from single cells. Furthermore, the prevalence of clonal hematopoiesis increased by 18% in the U.K. Biobank cohort when the mutations in these fitness-inferred clonal hematopoiesis genes were included in the analysis.

When the researchers examined the fitness effects specific to these mutations, they found that the fitness conferred by some of these mutations was substantial. Mutations in the MTA2, SPRED2, and SRFS1 genes were found to confer a clonal advantage to hematopoietic stem cells by providing an excess division rate of 15% to 20% per year. Surprisingly, the most common mutation found in the MYD88 gene was not found to be one of the sites under strong selection, and the researchers believe that recurrent mutations in this gene might be better explained by high mutation rates rather than selection.

Conclusions

Overall, the findings reported 17 additional clonal hematopoiesis genes under positive selection that conferred fitness and were being selected for at the population level. The study found that clonal populations carrying mutations in these genes increased in size and frequency with age and could be compared to the classical drivers of clonal hematopoiesis. These mutations also showed significant correlations with increased risks of hematological cancers, and infection.