Jamie Blundell

Hematopoietic Stem Cell Parameters and Clonal Dynamics Revealed by Applying Branching Process Models to Clonal Hematopoiesis Datasets

The large population sizes and rapid turnover rates of blood cells (>200 billion produced each day) make blood susceptible to the acquisition and expansion of pre-cancerous mutations ("clonal hematopoiesis"). Clonal hematopoiesis is observed in >95% of healthy individuals over the age of 60, with large mutant clones being associated with an order-of-magnitude increased risk of blood cancer. Here we present a novel quantitative analysis of clone size distributions (VAF spectra) from 7 large publicly available clonal hematopoiesis datasets. We show that the clone size distribution follows a universal scaling behaviour, consistent with a simple branching process model of stem cell dynamics. This scaling relationship, together with mutation rate estimates, enable us to infer the total number of hematopoietic stem cells (HSCs), stem cell division rates and the selective advantage conferred by mutations in key cancer associated genes. Most non-synonymous mutations in these genes are under strong positive selection. Estimates of HSC numbers can be independently validated using the clone size distribution of synonymous mutations, while the selective advantages can be independently validated using time-series data. The overall distribution of clone sizes is consistent with the increased prevalence of clonal hematopoiesis in older age being driven by clones growing exponentially in time and thus becoming increasingly detectable. These previously under-appreciated insights gained from existing clonal hematopoiesis datasets provide valuable estimates for parameters of hematopoietic stem cell dynamics that will likely be key for improving predictive models of blood cancer risk.