Lee, H.J. et al. Genome Res. advance online publication (19 December 2011).

Genomic structural variations are implicated in both normal phenotypic variation and in disease. Engineered nucleases, such as zinc-finger nucleases, can be designed to generate double-strand breaks at specific genomic locations and thus should be able to stimulate chromosomal rearrangements. Kim and colleagues report that zinc-finger nuclease pairs targeted to two endogenous locations in the genome of human cells can result in cells harboring not only deletions, as previously reported, but also genomic inversions and duplications, at an experimentally tractable frequency. The resulting cells can be screened for otherwise isogenic cells that differ only in the induced genomic change. The researchers use this approach to invert a 140-kilobase chromosomal segment carrying the gene encoding a blood coagulation factor that is implicated in severe hemophilia.