Inherent instability of simple DNA repeats shapes an evolutionarily stable distribution of repeat lengths.

Using the Telomere-to-Telomere reference, we assembled the distribution of simple repeat lengths present in the human genome. Analyzing over two hundred mammalian genomes, we found remarkable consistency in the shape of the distribution across evolutionary epochs. All observed genomes harbor an excess of long repeats, which are prone to developing into repeat expansion disorders. We measured mutation rates for repeat length instability, quantitatively modeled the per-generation action of mutations, and observed the corresponding long-term behavior shaping the repeat length distribution. We found that short repetitive sequences appear to be a straightforward consequence of random substitution. Evolving largely independently, longer repeats (10+ nucleotides) emerge and persist in a rapidly mutating dynamic balance between expansion, contraction and interruption. These mutational processes, collectively, are sufficient to explain the abundance of long repeats, without invoking natural selection. Our analysis constrains properties of molecular mechanisms responsible for maintaining genome fidelity that underlie repeat instability.