Structural Mutations Set an Equilibrium Noncoding Genome Fraction

The evolution of noncoding genome size remains poorly understood. While part of noncoding DNA arguably plays a regulatory role, a significant portion does not appear to have a detectable phenotypic effect. The abundance of nonfunctional DNA in genomes, observed across the Tree of Life, challenges purely adaptationist explanations. Several nonadaptive theories have been proposed to explain its presence and identify its determinants, emphasizing either the mutational processes or the mutational hazard entailed by noncoding and nonfunctional DNA. However, those theories have not yet been integrated into a common framework, and the exact nature of the mutational hazard is not yet fully understood. In this work, we introduce a simple mathematical model of genome size evolution. Our model shows that the noncoding fraction of the genome is shaped by two fundamental forces: (i) inherent biases in mutational neutrality-adding base pairs being more likely to be neutral than removing some and (ii) robustness selection arising from the mere existence of structural mutations-larger genomes being more prone to double-strand breaks that generate such mutations, thereby imposing a second-order selection on robustness. Together, these forces establish an equilibrium noncoding fraction that depends solely on mutation biases and the product of population size and mutation rate.