Classical transgenic models are useful for quickly gauging the impact of transgene overexpression, but they are limited by the absence of the innate, subtle regulatory elements encoded in introns and other untranslated regions. Moreover, the widespread, high-level expression of oncogenes often leads to tumors that lack the histopathological and acquired genetic features of human cancers. Targeted mutation of endogenous loci, or knock-in (KI) alleles, facilitates more accurate modeling of human tumors by allowing for the expression of mutant alleles under normal physiological regulation. Advanced strategies enable the stochastic activation of such alleles in somatic cells, such that genotypically wild-type cells surround individual mutant cells. More recent technologies, such as site-specific engineered nucleases, have also accelerated the design and implementation of KI strategies. Together, these tools aid in the development of advanced mouse models that better recapitulate the features of human disease.
© 2014 Cold Spring Harbor Laboratory Press.