Title: Evolutionary models of clonal expansion and niche construction
Abstract: Heart disease and cancer, the two leading causes of death in the industrialized world, are linked to expansions of clonal cell populations in the body, driven by the evolutionary processes of mutation, selection, drift, and niche construction. This dissertation develops a series of stochastic and deterministic mathematical frameworks to model the role of evolution in atherosclerosis and cancer metastasis and to highlight associated evolutionary principles that connect genotype, phenotype, and environment. In chapter one, a stochastic framework is introduced to study mutation accumulation and clonal expansion in hematopoietic cell populations during aging. Through simulation and in vivo experiments, it is demonstrated that clonal expansion is accelerated in individuals with atherosclerosis, reversing a dominant causal paradigm. In chapter two, a branching process framework is analyzed in mathematical detail and applied to growing metastatic tumor populations. Scaling laws for metastatic timing and diversity are derived, and inverse estimates for metastatic seeding rates are inferred from patient data. In chapter three, a minimal model is presented to describe the two-way interaction between an evolving population and its local environment. These coupled dynamics are shown to result in self-propelled evolution across a fitness landscape, even in the absence of or against selection gradients, and optimal transport of an evolving population towards a target phenotype is considered. In chapter four, an extended model of population-environment interaction is applied to niche construction in the context of termite nest morphogenesis. The model predicts the emergence of floors and ramps with statistics consistent with digitized, naturally occurring nest structures.
Committee: L. Mahadevan and Martin Nowak (advisors), Ben de Bivort, Kamila Naxerova, John Wakeley (chair)