Atlas of eccDNA in Mus musculus reveals intron and isoform gene-density dependent protection of transcription-induced eccDNA formation

EccDNA is a driver of many cancers and a potential intermediate in other age-related disorders. However, little is known about the mechanisms underlying eccDNA formation in healthy tissue and how age affects these processes. We generated an Atlas of eccDNA across seven tissues of mice spanning four ages. EccDNA was overrepresented from open chromatin characterized by signatures of H3K27ac and H3K4me1 in 3 and 12-month-old mice but not in 22-month-old mice. The mutational load of eccDNA on genes increased logarithmically as a function of transcription and this phenomenon was enhanced as mitotically active tissue aged. Still, a population of intron-dense genes with many splice forms was sheltered from eccDNA formation. We also found that the number of eccDNA did not increase as mice aged, unlike other types of mutations. Our data reveal a link between eccDNA formation, transcript level and aging that might have driven gene architecture in mammals.