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Positive Selection Influences Clonal Hematopoiesis That Occurs in Blood During Aging

NEW YORK – Positive selection contributes to the genetic diversity observed among blood cells, according to a new mathematical modeling analysis.

As people age, they accumulate mutations — including in cancer-linked genes — within healthy tissues like blood. While many of these mutations are benign, clonal hematopoiesis may herald an increased risk of developing blood cancer.

That risk, though, depends on the genes in which the alterations arise. Researchers from the University of Cambridge analyzed sequencing data from about 50,000 people to uncover the prevalence of these clonal mutations and gauge their fitness advantages. As they reported in Science today, the researchers found that positive selection, rather than drift, shapes clonal hematopoiesis and that alterations with high fitness are also associated with an increased risk of developing acute myeloid leukemia.

"These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age," Cambridge's Jamie Blundell and his colleagues wrote in their paper.

Using nine publicly available datasets, the researchers examined sequencing data generated from blood samples from about 50,000 people without cancer. They determined and catalogued the variant allele frequencies (VAFs) within these samples, noting that the distribution of variants skewed to low VAFs.

By building a simple stochastic branching model of hematopoietic stem cell dynamics, they examined how factors like genetic drift, differences in mutation rate, and cell-intrinsic fitness effects influence the variation they observed in VAFs. More complex scenarios, they noted, yielded a relatively similar model.

The model suggests neutral mutations either go extinct quickly or grow slowly and remain at low VAFs, while beneficial mutations eventually grow exponentially. It further predicts that variants with a high fitness effect or those acquired early in life reach high VAFs, while variants with a low fitness effect or acquired later in life remain at low VAFs.

They further estimated that, with a large hematopoietic stem cell population size, it would take 100,000 years for a variant to reach a VAF of 50 percent by drift alone and more than 2,000 years to reach a level at which it could be detected by standard sequencing approaches. Based on this, they concluded that most clonal hematopoiesis variants that reached a VAF of more than 0.1 percent during a human lifetime had to do so due to positive selection. 

Most highly fit variants, they noted, are found at low VAFs only because not enough time has passed for them to expand to reach higher numbers.

They then estimated the fitness of different variants. The DNMT3A R882H variant, which is the most common clonal hematopoiesis alteration, confers a large selective advantage, as over the course of about 55 years — the mean age of the participants in the cohort — it reaches a VAF of about 12 percent and, in some instances, up to 50 percent. Other variants like ones in the spliceosome genes SF3B1 and SRSF2 have even higher fitness effects.

By comparing pre-AML and control samples from three studies, the researchers found that individuals with one or more highly fit variants were about four-fold more likely to develop AML, as compared to those with less fit variants.

Future studies, they noted, will be needed to track participants over time to see how these initial mutations then led to the acquisition of other mutations. 

Still, they said this approach could be used to determine fitness estimates and stratify AML risk.

"The integration of clinical, demographic, and phenotypic information with detailed genomics will yield insights into clonal dynamics and mutation rates of healthy blood, as well as molecular features associated with prognosis and aging," Stanford University's Christina Curtis, wrote in an accompanying commentary in Science. "Such information should also provide clues as to how to better detect and intercept early malignancy, when therapeutic intervention should be most effective."