Characterization of breakpoint regions of large structural autosomal mosaic events

摘要

Recent studies have reported a higher than anticipated frequency of large clonal autosomal mosaic events >2?Mb in size in the aging population. Mosaic events are detected from analyses of intensity parameters of linear stretches with deviations in heterozygous probes of single nucleotide polymorphism microarrays. The non-random distribution of detected mosaic events throughout the genome suggests common mechanisms could influence the formation of mosaic events. Here we use publicly available data tracks from the University of California Santa Cruz Genome Browser to investigate the genomic characteristics of the regions at the terminal ends of two frequent types of large structural mosaic events: telomeric neutral events and interstitial losses. We observed breakpoints are more likely to occur in regions enriched for open chromatin, increased gene density, elevated meiotic recombination rates and in the proximity of repetitive elements. These observations suggest that detected mosaic event breakpoints are preferentially recovered in genomic regions that are observed to be active and thus more accessible to environmental exposures and events related to gene transcription. We propose that errors in DNA repair pathways, such as non-homologous end joining and homologous recombination, may be important cellular mechanisms that lead to the formation of large structural mosaic events such as interstitial losses and copy neutral events that include telomeres. Further studies using next generation sequencing technologies should be instrumental in mapping the specific junctions of mosaic events to the nucleotide and provide insights into the molecular mechanisms responsible for clonal somatic structural events.