Next-generation DNA sequencing (NGS) defines the modern genomic era. This powerful technology has revolutionized traditional genetics and has made feasible the emerging field of personalized medicine. It is now routine to sequence billions of nucleotides and to identify inherited clonal mutations. However, all NGS approaches have a relatively high error rate: on the order of one erroneous base call per 100–1,000 sequenced nucleotides (Table 1; ref. 1). Although this error rate is acceptable for studying inherited mutations, it greatly limits the analysis of subclonal mutations, which are defined as mutations that are present in only a fraction of cells within a population.
