Whole-genome sequencing (WGS) or whole-exome sequencing (WES) of DNA derived from bulk brain tissue allows a straightforward approach to discovering somatic mosaicism (26). WGS and WES minimize sequencing artifacts that can confound downstream analyses and, in the case of WGS, provide an opportunity for identifying a wide range of structural rearrangements, including inversions and translocations. However, WGS and WES using standard sequencing depths have reduced statistical power to detect mutations that occur at low frequencies (i.e., <10% of cells in a population at 30 to 100x coverage). Although increasing sequence coverage allows detection of somatic variants at lower frequencies, it quickly becomes cost prohibitive. Moreover, WGS and WES do not provide information on how somatic variants are distributed across individual cell lineages within a bulk tissue sample.
