Modifier screens in the mouse: time to move forward with reverse genetics.

Abstract

Amajor preoccupation of biology in the last decade was the sequencing of the human and mouse genomes. Having identified their constituent genes, the imperative was to understand the physiological, cellular, and biochemical roles that these genes play and to determine how this knowledge can be harnessed to improve treatment for many diseases with limited therapeutic options. Although a great deal of knowledge about fundamental processes has been gained from genetic screens in lower organisms such as yeast, flies (1), and worms, it is the mouse that holds a special place because not only has it recently become possible to perform large-scale genetic screens (2, 3) but also its genome can be manipulated in a precise manner to model human diseases, so-called reverse genetics. In a landmark article published in a recent issue of PNAS, Carpinelli et al. (4) have shown that it is possible to take a mouse model of a human disease (congenital thrombocytopenia) and to identify mutations that result in an amelioration or cure. In doing so, they have demonstrated that genetic modifier screens, which have proven so powerful in lower organisms (5, 6), are also feasible in the mouse, and they have shown that this technology might be applied to the discovery and validation of targets for the treatment of human diseases. When one throws into the mix the questions their study raises about the regulation of blood cell formation, it is clear that this article will be of interest to a wide range of geneticists and cell biologists as well as to those in the biopharmaceutical industry. Platelet transfusions are an effective therapy for thrombocytopenia, although limited supplies, transfusion-related toxicities, and the development of platelet alloantibodies make alternate treatments urgently required. Unfortunately, the use of thrombopoietin (TPO), the lineage-specific regulator of platelet production, has …