Reprogramming of global methylation in normal and cloned preimplantation embryos. (a) The mouse paternal genome (blue) (in the mouse distinguishable as the larger pronucleus at the 1-cell stage) undergoes active demethylation while the maternal genome (red) is passively demethylated. Differential demethylation and topological separation of the maternal and paternal genomes continues through to at least the 4-cell stage, after which the two parental genomes attain roughly the same levels of global hypomethylation (green). (b) Bovine embryos exhibit the same active and passive demethylation as the mouse up to the 8- to 16-cell stage, after which de novo methylation is observed (black line on the graph; the parental genomes cannot be distinguished to determine whether methylation is acquired at the same rate in the maternal and paternal chromosomes). (c) Cloned bovine embryos (with somatic nuclei in orange) have active but not passive demethylation activity. Precocious de novo methylation is observed in all nuclei beginning at the 4-cell stage. MII, meiotic metaphase II.