Efficient non-meiotic allele introgression in livestock

A method of replacing an endogenous allele in the genome of a bovine cell with an exogenous allele, the method comprising a step of introducing into the bovine cell

• a) a transcription activator-like effector nuclease (TALEN) comprising (i) a DNA binding sequence comprising a Repeat Variable Diresidue (RVD) sequence that binds to a target sequence in the endogenous allele;
• and
• b) a homology directed repair (HDR) template comprising (i) at least one nucleotide mismatch in the sequence to which the RVD binds and (ii) a nucleic acid sequence encoding the exogenous allele flanked by sequences that are homologous to DNA adjacent to the endogenous allele,
• wherein the exogenous allele is an isoform of the endogenous allele,
• wherein the TALEN causes a cleavage of a target site,
• wherein the at least one nucleotide mismatch and the exogenous allele is introduced in the target sequence, and
• wherein the introduced mismatch eliminates binding of the RVD to the target sequence and eliminates re-cleavage events by the TALEN.