PNH in mice and humans. The two upper panels represent in cartoon form the mouse models constructed in refs 19 and 20, respectively. Although all cells have the same genotype, their phenotype differs depending on which X chromosome has been inactivated: white circles indicate cells in which the X chromosome with the normal pig-a gene is active; gray circles indicate cells in which the X chromosome with the inactivated pig-a gene (pig-a°) is active. As a result, in the peripheral blood there is a mixture of normal (white) and PNH (gray) blood cells. The lower proportion of PNH cells in the model by Tremml et al is caused by the fact that cre, driven by Ella, does not knock out pig-ain every cell (Tremml et al have produced also male mice with PNH [see text].) In both models the proportion of PNH cells in the peripheral blood depends on the proportion of cells in which cre-mediated recombination has taken place: there is no evidence of selection thereafter. The bottom panel represents in cartoon form what happens in the human disease, PNH. Here, unlike in the mice, the entire PNH population arises usually from a single stem cell in which a somatic mutation has taken place: therefore, selection must take place at the level of stem cells in order for a large proportion of the blood cells to have the PNH phenotype. Here only one allele of the PIG-Agene is shown because the entire process takes place after X-inactivation, when somatic cells are functionally haploid for most X-linked genes in both males and females.