Appearances can be deceiving: phenotypes of knockout mice.

In the field of mammalian functional genomics, one of the main aims in the post-genomic era is to elucidate the function of all genes in the genome. The powerful technology of gene targeting in embryonic stem cells has enabled the simple generation of mice lacking a specific gene. However, it is evident that in a proportion of such knockout mice no deviation in phenotype could be detected. Advancements in the field of mouse phenotyping and use of extensive phenotyping tests on each knockout showed that abnormal phenotypes were sometimes detected in physiological areas where they were not initially anticipated, or only manifested under certain conditions, emphasizing the need for careful phenotypic investigation. Nevertheless, the effect of some genes became evident only upon inactivation of another gene, pointing to the phenomenon of biological robustness. Unlike in yeast, this phenomenon has not yet been analysed systematically in the mouse. In this review, we present examples of mouse knockouts that lend support to the concept of robustness, discuss the mechanisms by which it may have evolved, as well as speculate on the reasons for its evolution.