The dynamic fitness landscape of ageing haematopoiesis through clonal competition

Abstract

AbstractClonal haematopoiesis (CH) – the ubiquitous expansion of variants in blood with age – is a prime example of ongoing somatic evolution in otherwise normal human tissues. The details of the underlying evolutionary processes and how they drive clonal dynamics and intra-tissue genetic heterogeneity remain to be understood. Here we show that clonal competition can explain the complex dynamics of CH with age. According to the model numerous clones of differing fitness continually appear and compete. This clonal competition implies an emerging fitness landscape of haematopoietic stem cells (HSCs) that changes over time in a highly stochastic manner within and between individuals. It naturally explains the presence of decreasing variant trajectories and declining average fitness in the elderly, the varying fitness of identical variants across individuals, and characteristic transitions of site frequency spectra with age. Comparisons of stochastic simulations of clonal competition-driven CH to time resolved clone trajectories in 385 individuals, and to changes of the HSC site frequency spectrum from newborns to octogenarians allow us to estimate the shape of the innate CH fitness distribution and the arrival rate of advantageous clones. We find a non-exponential fitness distribution with mean 0.07 to 0.09 and standard deviation 0.025 per year. We estimate an arrival rate of 2 to 20 advantageous clones per year, but the number of detectable clones above 1% frequency in the HSC population to remain between 3 to 20 by the age of 80.