The impact of induced pluripotent stem cells on clinical and basic research depends on the extent to which they maintain the genomic background of the individual while avoiding changes to their DNA that can make them potentially dangerous or ineffective. The goal of this grant was to identify the extent to which different aspects of iPSC biology contribute to unwanted variation in these stem cell lines. To accomplish this goal, we adapted a method that we previously used to assess the role of mutations in mouse iPSC function, called the “sister line” approach. In this grant period we successfully adapted this approach to human iPSCs, generated a large number of “sister lines” and have applied sensitive whole genome sequencing to these lines to identify the source and scope of mutations that arise in the patient’s original cells compared to events that occur during reprogramming into iPSCs. In addition we have compared the effects of different commonly used reprogramming methods which should serve as a useful guide to researchers generating iPSCs for research and clinical use. These results are being translated to researchers involved in other CIRM funded stem cell genomics and translational studies as well as to those funded by the NIH and other institutes.