Abstract
The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase (kb)-sized extrachromosomal circular DNA elements (eccDNAs). However, it must be expected that kb eccDNAs exist in normal cells as a result of mutations. Here, we purify and sequence eccDNAs from muscle and blood samples from 16 healthy men, detecting ~100,000 unique eccDNA types from 16 million nuclei. Half of these structures carry genes or gene fragments and the majority are smaller than 25 kb. Transcription from eccDNAs suggests that eccDNAs reside in nuclei and recurrence of certain eccDNAs in several individuals implies DNA circularization hotspots. Gene-rich chromosomes contribute to more eccDNAs per megabase and the most transcribed protein-coding gene in muscle, TTN (titin), provides the most eccDNAs per gene. Thus, somatic genomes are rich in chromosome-derived eccDNAs that may influence phenotypes through altered gene copy numbers and transcription of full-length or truncated genes.
Highlights
The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase-sized extrachromosomal circular DNA elements
5 S ribosomal DNA and repetitive DNA have been found on extrachromosomal circular DNA (eccDNA) in human cell lines[12,13,14], showing that a fraction of the genome can exist as eccDNA, at least under certain conditions
EccDNA has long been known to form from proto-oncogenes and repeats in the human genome[9,10,32,45,46]
Summary
The human genome is generally organized into stable chromosomes, and only tumor cells are known to accumulate kilobase (kb)-sized extrachromosomal circular DNA elements (eccDNAs). We hypothesize that the healthy tissue contains larger eccDNAs of sufficient size to include one or several full-length genes, because (1) eccDNAs larger than 100 kb are found in human tumors[9,10,24], most likely arising by random mutational processes that would be expected to form eccDNAs from all parts of the genome; (2) deletions are known to produce eccDNAs in yeast[25] and in cattle[26]; and (3) deletions in somatic cells can be up to Mb in size[6]. EccDNAs derive from every human chromosome with sequences from all known types of genomic structures, including genes, intergenic, and repetitive regions, revealing that eccDNAs are common mutational elements in human soma. Our discovery suggests that products of deletions are maintained in somatic cells, leading to novel questions regarding their cellular influence and potential biological roles
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