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Abstract
BackgroundInteractions between the epigenome and structural genomic variation are potentially bi-directional. In one direction, structural variants may cause epigenomic changes in cis. In the other direction, specific local epigenomic states such as DNA hypomethylation associate with local genomic instability.MethodsTo study these interactions, we have developed several tools and exposed them to the scientific community using the Software-as-a-Service model via the Genboree Workbench. One key tool is Breakout, an algorithm for fast and accurate detection of structural variants from mate pair sequencing data.ResultsBy applying Breakout and other Genboree Workbench tools we map breakpoints in breast and prostate cancer cell lines and tumors, discriminate between polymorphic breakpoints of germline origin and those of somatic origin, and analyze both types of breakpoints in the context of the Human Epigenome Atlas, ENCODE databases, and other sources of epigenomic profiles. We confirm previous findings that genomic instability in human germline associates with hypomethylation of DNA, binding sites of Suz12, a key member of the PRC2 Polycomb complex, and with PRC2-associated histone marks H3K27me3 and H3K9me3. Breakpoints in germline and in breast cancer associate with distal regulatory of active gene transcription. Breast cancer cell lines and tumors show distinct patterns of structural mutability depending on their ER, PR, or HER2 status.ConclusionsThe patterns of association that we detected suggest that cell-type specific epigenomes may determine cell-type specific patterns of selective structural mutability of the genome.
Highlights
Interactions between the epigenome and structural genomic variation are potentially bi-directional
Breakout exhibits superior performance on low-coverage breakpoint detection To compare Breakout with other structural variation analysis tools, we used as a benchmark structural variants in the HCC1954 breast cancer cell line
An HCC1954 dataset was sequenced using the SOLiD, yielding 72 million mate pairs; the reads were mapped onto the human genome, NCBI Build 36/UCSC hg18 using bfast [10]
Summary
Interactions between the epigenome and structural genomic variation are potentially bi-directional. Structural variants may cause epigenomic changes in cis. The first link ever discovered between chromatin structure and epigenetics was due to a structural genomic variant - a breakpoint induced by a chromosomal inversion on the × chromosome in Drosophila [1]. This variant explained position-effect variegation of the Drosophila eye color by stochastic spreading of heterochromation. Structural genomic variants, including inversions, duplications, deletions, and translocations are being mapped on large scale in human germline and in cancer using mate-pair sequencing. One practical challenge is the deployment of multiple analysis tools and databases with reproducible and transparent records of analyses
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