Circular DNAs from chromosomes are common copy number variations in Saccharomyces cerevisiae

Common mutations in all organisms are small nucleotide polymorphisms, insertions and deletions. We have shown that another common genetic alternation exists, extrachromosomal circular DNA (eccDNA). Though eccDNA is previously reported from tumor cells (also known as double minutes) and a few other cell types, eccDNA has so far been given little attention. Even though eccDNA are capable of replicating and integrating into the genome, their contribution to genetic variation and evolution of the eukaryotic genomes have largely been deemed irrelevant.

To explore the existence of circular DNA in eukaryotes we have developed a highly-sensitive eccDNA purification method, Circle-Seq. We reveal that CNVs, in the form of eccDNAs, are common in the budding yeast Saccharomyces cerevisiae. More than a thousand different eccDNAs larger than 1 kb were recorded, increasing the known number of eccDNA more than a hundred fold. A number of eccDNAs were found repeatedly in different genetic backgrounds, suggesting conserved hotspots for DNA circularization, e.g. at ribosomal RNA genes, glucose transporter genes HXT6, HXT7, metallothionein genes CUP1-1, CUP1-2, Ty-retrotranposons and Y’-telomeric genes. Recording of HXT6-HXT7 geneotypes in prolonged nutrient-limited yeast cultures suggested selection for  [HXT6/7circles] in glucose-limited conditions and [HXT6/7circle] also appeared to serve as intermediate of chromosomal HXT6-HXT7/6HXT7 amplifications.

Our results support that eccDNA can lead to deletions and transient gene amplifications and suggest S. cerevisie as model for studying the molecular basis and evolutionary consequences of for this phenomenon.

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Dr Jon Houseley
The Brian Heap Seminar Room