Computational modelling human stem cell fitness of pre-leukaemic mutations

This interdisciplinary project will involve the student in a close collaboration between three research groups: Schumacher (computational modelling), Chandra (bioinformatics), and Kirschner (stem cell assays)

Age is the single biggest risk factor underlying the onset of many haematological (blood) malignancies. Clonal haematopoiesis of indeterminate potential (CHIP) affects more than 10% of individuals over the age of 60 years and is associated with increased risk for haematological cancers. Little is known about how individual mutations cause clonal outgrowth of blood stem cells and thus contribute to this risk. Knowing the fitness advantage conferred on stem cells by individual CHIP could enable us to predict the risk of progression to leukaemia.

The student will be working with data from the Lothian Birth Cohort, a longitudinal cohort of aged individuals, from which we have deeply sequence targeted chromosomal locations in late life over a 15 year span. The student will quantify variant allele frequency (VAF) for CHIP mutations and use mathematical modelling to infer stem cell fitness in vivo. This will allow us to measure how specific CHIP mutations increase stem cell fitness and reveal how they perturb homeostasis (blood production). The results will enable building of an age-dependent predictor of an individual's leukaemic risk based solely on their CHIP mutation frequencies. To test these predictions, we have gained access to Generation Scotland data (20,000 participants). The use of mathematical models will allow us to quantitatively combine both longitudinal data on clonal expansion in vivo over 15 years and in vitro data from the Kirschner lab for increased translational impact, improving our understanding of the effects of CHIP on normal haematopoiesis and how this contributes to leukaemia development.