RESEARCH HIGHLIGHTS GENETICS Hitting the mark Genome-editing technologies gener- Researchers led by Linzhao Cheng Suzuki et al. did observe evidence that exist- ally stay on target, but researchers should and Zhaohui Ye of the Johns Hopkins ing predictive strategies may overlook a sub- remain vigilant for variants acquired dur- University Medical School used both set of TALEN-associated off-target events. ing experimental manipulation. TALENs and CRISPR-Cas9 to introduce Instead, the majority of SNVs and indels Even the most devastating genetic disor- the gene encoding GFP into four differ- appear to accumulate randomly during stem ders are often traceable to relatively small ent induced pluripotent stem cell (iPSC) cell cultivation and expansion. These results defects in the genome. Fortunately, scientists lines (Smith et al., 2014), whereas Kiran indicate that existing genome-editing strate- now have a plethora of options for attempting Musunuru’s team at the Harvard Stem gies achieve sufficient specificity for the use the precise editing of DNA typos, including Cell Institute used the same two edit- of edited lines in disease modeling. synthetic transcription activator–like effec- ing strategies to target the SORT1 gene Michael Eisenstein tor nucleases (TALENs) or the bacterially in human embryonic stem cells (Veres et derived clustered, regularly interspaced, short al., 2014). Finally, Guang-Hui Liu of the RESEARCH PAPERS palindromic repeat (CRISPR)-Cas9 system. Chinese Academy of Sciences, Yingrui Smith, C. et al. Whole-genome sequencing analysis No biological process is 100% precise, how- Li of the Beijing Genomics Institute and reveals high specificity of CRISPR/Cas9 and TALEN- ever—and the consequences of an editing Juan Carlos Izpisua Belmonte of the Salk based genome editing in human iPSCs. Cell Stem Cell 15, 12–13 (2014). error could be just as dire as the initial muta- Institute for Biological Studies used four Suzuki, K. et al. Targeted gene correction minimally tion. A trio of recent reports largely lay these different editing approaches to correct impacts whole-genome mutational load in human- concerns to rest; their authors used whole- disease-related alterations in iPSC lines disease-specific induced pluripotent stem cell clones. genome sequencing to profile single-nucle- derived from patients with a variety of Cell Stem Cell 15, 31–36 (2014). Veres, A. et al. Low incidence of off-target mutations otide variants (SNVs) along with insertions genetic disorders (Suzuki et al., 2014). in individual CRISPR-Cas9 and TALEN targeted and deletions (indels) in cell lines subjected True or likely off-target editing events human stem cell clones detected by whole-genome to genomic editing via various techniques. proved rare in all three studies, although sequencing. Cell Stem Cell 15, 27–30 (2014). Nature America, Inc. All rights reserved. America, Inc. Nature 4 © 201 npg 894 | VOL.11 NO.9 | SEPTEMBER 2014 | NATURE METHODS.