Our ability to precisely and efficiently edit mammalian and plant genomes has 
been significantly improved in recent years, partially due to increasing use of 
designer nucleases that recognize a pre-determined DNA sequence, make a specific 
DNA double-strand break, and stimulate gene targeting. A pair of zinc finger 
nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs) 
that recognize two adjacent unique DNA sequences dimerize through the fused FokI 
nuclease domain and cut in the middle of target DNA sequences. We report here 
that increasing the length of recognition DNA sequences by TALENs or ZFNs does 
not necessarily translate to a higher efficiency or specificity. We also 
discover that one subunit of ZFNs and one subunit of TALENs can form a pair of 
hybrid nucleases with expanded specificity at two diverse targets, and stimulate 
gene targeting in multiple cell types including human induced pluripotent stem 
(iPS) cells with improved efficiency.