Homology-associated nonhomologous recombination in mammalian gene targeting

Nonhomologous (illegitimate) recombination of DNA underlies many changes in the genome. It involves no or little homology between recombining DNAs and has been considered unrelated with homologous recombination, which requires long homology. In mouse cells, however, we found recombination products whose sequences suggest that homologous interaction between DNAs caused nonhomologous recombination with another DNA. The intermediates of homologous recombination were apparently trapped at various stages and shunted to nonhomologous recombination. In one product, the nonhomologous recombination disrupted gene conversion. In another, it took place exactly at the end of long homology shared between two DNAs. This finding explains why gene targeting needs long uninterrupted homology and why mammalian homologous recombination is often nonconservative. We discuss possible consequences and roles of this type of homology-driven gene destruction mechanism.