Stochastic survival of the densest can solve the enigma of the expansion of mitochondrial mutations in muscle ageing and neurodegeneration
The clonal expansion of mitochondrial DNA molecules carrying deletions is associated with ageing, particularly in skeletal muscle – where it is causally implicated in muscle loss – and in the brain, where it is associated with neurodegeneration. The mechanism driving this expansion remains unclear, despite more than 30 years of research. Previous accounts assumed a replicative advantage for deletion mutations, but there is also evidence that defective mitochondrial DNA is preferentially eliminated.
We introduce a spatial stochastic model predicting travelling waves of mutants in skeletal muscle fibres, with spatial features and speed consistent with experiments. The wave-like spread stems from the combined effect of noise, the widely reported higher copy-number density of mutants and the spatial structure of skeletal muscle fibres. Crucially, our model yields travelling waves of mutants without a replicative advantage and even if mutants are preferentially eliminated. We show that stochasticity, density differences and spatial structure produce selection in a general setting.
We provide a formula predicting that wave speed drops with copy number, consonant with observations. We reproduce observed mutant loads with realistic de novo mutation rates, unlike previous neutral models. The same mechanism extends to directed graph topologies that model neurons and the directed trafficking of mitochondria. Finally, we characterise the genetic signatures of noise-induced selection and determine when it can be distinguished from a selective sweep driven by explicit replicative advantage.
This mechanistic understanding has therapeutic implications, since existing drugs can influence some of the factors modulating the clonal expansion of mutants. Given how spatial structure, noise and density affect muscle and brain ageing, we introduce the evolutionary mechanism of stochastic survival of the densest, an alternative to replicative advantage with potential applications in a range of evolutionary models and counterintuitive phenomena.