Schumacher, Linus

Abstract Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual’s lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.

Abstract The prevalence of clonal hematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously reported gene specific fitness effects in two longitudinal cohorts of aging. We now set out to define fitness effects across three longitudinal cohorts of aging in a total of 713 participants. We found that fitness correlates with timing of mutations, which needs to be taken into account when predicting health outcomes. We show that fitness and the time of mutations are superior predictors of outcomes such as all-cause mortality compared to the commonly used clone size (variant allele frequency). Our new predictor even outperforms age, the most important predictor for the onset of age-related disease thus far. In conclusion, the fitness landscape of mutations and their context in terms of clonal composition and timing of mutation acquisition are important parameters to bring CH predictors into the clinic.