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When is a mutation a true genetic variant?
Large-scale sequencing studies have set out to determine the low-frequency pathogenic genetic variants in individuals and populations. However, Chen et al. demonstrate that many so-called low-frequency genetic variants in large public databases may be due to DNA damage. They scored libraries sequenced with and without a DNA damage–repairing enzymatic mix to assess the proportion of true rare variants. It remains to be seen how best to repair DNA before sequencing to provide more accurate assessments of mutation.
Science, this issue p. 752
Mutations in somatic cells generate a heterogeneous genomic population and may result in serious medical conditions. Although cancer is typically associated with somatic variations, advances in DNA sequencing indicate that cell-specific variants affect a number of phenotypes and pathologies. Here, we show that mutagenic damage accounts for the majority of the erroneous identification of variants with low to moderate (1 to 5%) frequency. More important, we found signatures of damage in most sequencing data sets in widely used resources, including the 1000 Genomes Project and The Cancer Genome Atlas, establishing damage as a pervasive cause of sequencing errors. The extent of this damage directly confounds the determination of somatic variants in these data sets.