Phenotypic Analysis of Dominant Mutant Effects in Mice

Dominant effects of a mutation may show up at any time during a mutational analysis, including during the early stages of an embryonic stem (ES) cell gene targeting experiment. Here, we discuss the mechanisms of dominant and semidominant effects and how they might appear if they show up in heterozygous ES cells, in ES cell chimeras, or in heterozygous progeny of chimeras. Similarly, dominant effects may be seen in mice heterozygous for CRISPR–Cas-targeted, -induced, or spontaneous mutations. If the dominant effects prevent the germline transmission of ES cells or cause fertility problems in heterozygotes, they can severely limit further analysis of the mutation. Ways to circumvent such reproductive problems are presented. The special case of imprinted genes, which may be functionally hemizygous and present a different phenotype when inherited from the mother than when inherited from the father, is discussed.