Evolutionary dynamics of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low (~10-8). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.Author summary: The mechanisms leading to expansion of HSC with mutations in the PIG-A gene that leads to the PNH phenotype remains unclear. Data so far suggests there is no intrinsic fitness advantage of the mutant cells compared to normal cells. Assuming neutral drift within the HSC compartment, we determined from first principles the incidence of the disease in a population, the average clone size in patients, the probability of clonal extinction, the likelihood of several separate clones coexisting in the HSC pool, and the expected expansion rate of a mutant clone. Our results are similar to what is observed in clinical practice. We also find that in such a model the probability of multiple PNH clones arising independently in the HSC pool is exceptionally small. This suggests that in clinical cases where more than one distinct clone is observed, all but one of the clones are likely to have emerged in cells that are downstream of the HSC population. We propose that PNH is perhaps the first disease where neutral drift alone may be responsible for clonal expansion leading to a clinical problem.