The detection and quantification of low-abundance somatic DNA mutations by high throughput sequencing is challenging because of the difficulty in distinguishing errors from true mutations. While there are several approaches available for analyzing somatic point mutations and small indels, an accurate genome-wide assessment of somatic structural variants (somSVs) in bulk DNA is still not possible. Here we present Structural Variant Search (SVS), a method to accurately detect rare somSVs by low-coverage sequencing. We demonstrate direct quantitative assessment of elevated somSV frequencies induced by known clastogenic compounds in human primary cells.
Postzygotic somatic mutations have been found associated with human disease, including diseases other than cancer. Most information on somatic mutations has come from studying clonally amplified mutant cells, based on a growth advantage or genetic drift. However, almost all somatic mutations are unique for each cell, and the quantitative analysis of these low-abundance mutations in normal tissues remains a major challenge in biology. Here, we introduce single-molecule mutation sequencing (SMM-seq), a novel approach for quantitative identification of point mutations in normal cells and tissues.
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