Replicative aging is associated with loss of genetic heterogeneity from extrachromosomal circular DNA in Saccharomyces cerevisiae

Abstract

Circular DNA of chromosomal origin form from all parts of eukaryotic genomes. In yeast, circular rDNA accumulates as cells divide, contributing to replicative aging. However, little is known about how other chromosome-deri ved circles segregate and contribute to geneticvariation as cells age. We identified circular DNA across the genome of young S. cerevisiae populations and their aged descendants. Young cells had highly diverse circular DNA populations, but lost 94% of the different circular DNA after 20 divisions. Circles present in both young and old cells were characterized by replication origins and included circles from unique regions of the genome, rDNA circles and telomeric Y’ circles. The loss in genetic heterogeneity in aged cells was accompanied by massive accumulation of rDNA circles >95% of all circular DNA. We discovered circles had flexible inherence patterns. Glucose limited conditions selected for cells with glucose-transporter gene circles, [HXT6/7circle], and up to 50% of cells in a population carried them. [HXT6/7circle] cells were eventually substituted by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNA were intermediates in chromosomal amplifications. In conclusion, DNA circles can offer a flexible adaptive solution but cells lose genetic heterogeneity from circular DNA as they undergo replicative aging.