Abstract SY23-01: Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues

Abstract

Abstract DNA in normal mammalian somatic cells is either in long chromosomes or in mitochondria. Furthermore, other than in specialized tissues like B and T cells, the genomic DNA in normal tissues is usually considered to be an exact copy of germ-line DNA. We hypothesized that errors in DNA replication may lead to the production of extra-chromosomal DNA and/or changes in copy number of segments of the DNA in normal somatic tissue. We have identified tens of thousands of short double-stranded and single-stranded extrachromosomal circular DNA (microDNA) that are derived from unique, non-repetitive sequences of chromosomes in normal mouse brain, heart and liver as well as mouse and human cell lines. MicroDNAs are 200-400 bases long and high in GC content. Short direct repeats are often present at the start and end of the corresponding chromosomal sequence suggesting that microDNAs are produced by replication slippage, homologous recombination or microhomology mediated repair. Several of the microDNAs overlap with nucleosome-occupied DNA, explaining how such short double-stranded DNA can be bent into a circle. The genomic sources of the microDNAs are enriched in the 5′ region of genes, exons and CpG islands. Ultrahighthroughput sequencing of adult brain DNA targeted to chromosomal loci that are enriched sources of microDNA, reveals a small fraction of genomic DNA molecules with micro-deletions that may be generated by the excision of microDNAs. We have thus identified a new DNA entity in somatic cells and provide evidence that deletions may occur in different genomic loci in somatic tissues, leading to genetic variability between normal somatic cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY23-01. doi:1538-7445.AM2012-SY23-01