Clonal expansion of single cells using human-induced pluripotent stem cell (hiPSC) technology or somatic cell nuclear transfer (SCNT) provides a biological alternative to WGA (80, 84). Any variant uniformly identified in the clonal line, but not in controls, represents a candidate somatic mutation that requires confirmation in the tissue of origin. In contrast, mutations introduced during cell culture will be present in a lower frequency of cells within a clonal cell line and can be discriminated from bona fide somatic mutations in downstream computational analysis. Although the clonal isolation and expansion of primary human neural stem and progenitor cells is possible, the analysis of human neuronal genomes using clonal reprogramming has several limitations. Foremost among these is the availability of live human neurons. Moreover, neither clonal reprogramming nor SCNT have been reported using human neurons; SCNT is further limited by the expense and availability of human oocytes. Finally, reprogramming approaches currently are only successful in ~10% of cells; thus, any neurons harboring highly aberrant genomes may be refractory to reprogramming. Despite these caveats, clonal reprogramming of human neurons is theoretically
