An Exact, Time-Independent Approach to Clone Size Distributions in Normal and Mutated Cells

Abstract: Biological tools such as genetic lineage tracing, three dimensional confocal microscopy and next generation DNA sequencing are providing new ways to quantify the distribution of clones of normal and mutated cells. Population-wide clone size distributions in vivo are complicated by multiple cell types, and overlapping birth and death processes. This has led to the increased need for mathematically informed models to understand their biological significance. Standard approaches usually require knowledge of clonal age. We show that modelling on clone size independent of time is an alternative method that offers certain analytical advantages; it can help parameterize these models, and obtain distributions for counts of mutated or proliferating cells, for example. When applied to a general birth-death process common in epithelial progenitors this takes the form of a gamblers ruin problem, the solution of which relates to counting Motzkin lattice paths. Applying this approach to mutational processes, an alternative, exact, formulation of the classic Luria Delbruck problem emerges. This approach can be extended beyond neutral models of mutant clonal evolution, and also describe some distributions relating to sub-clones within a tumour. The approaches above are generally applicable to any Markovian branching process where the dynamics of different "coloured" daughter branches are of interest.