Individuals are assumed to reproduce asexually, which involves two separate processes: (1) selecting individuals for reproduction based on their fitness and (2) creating offspring, which includes mutation of evolving parameters U (update factor) and T (giving-up threshold).
As shown in Fig. 4D, under such combinations of mutation parameters, mutation accumulation is impeded or even reversed at later portions of life.
Since we were unable to define a common set of mutation parameters that would recapitulate the experimentally observed mutation accumulation rates, somatic evolution/leukemia incidence, and HSC fitness decline with age, we tested an alternative, evolutionary model.
For this reason, estimates of mutation parameters for this fitness component are likely biased downward for both mutation rate and effect size.
This overlap (the common set of mutation parameters needed to replicate both reference phenomena) only occurs in the middle range of mutation DFE variance (Y axis in plots in Fig. 5B) and requires a ≥4-fold mutation rate increase over lifetime (X axis in plots in Fig. 5B).
To access this information, we described the trajectory of each observed sterile mutation by a set of parameters.
For priors of mutation parameters, only the Uniform and the Gamma distributions are considered, but hierarchical schemes are possible, with a mean mutation rate or coefficient P (of the geometric distribution in the GSM) drawn from a given prior and individual loci parameter values drawn from a gamma distribution around the mean.
We took Carlin and Chib's suggestion and obtained preliminary posterior distributions of mutation model parameters by running a short MCMC (of 40,000,000 steps) with each microsatellite model.
Therefore, the plausible range of mutation parameters is not permissive for significant exponential age-dependent increases in the rates of somatic evolution (clonal expansions).
Other competition indices also were tested, but no difference in estimates of mutation parameters was found among them (data not shown).
