Epigenetic instability in ES cells and cloned mice

Cloning by nuclear transfer (NT) is an inefficient process in which most cl ones die before birth and survivors often display growth abnormalities. In an effort to correlate gene expression with survival and fetal overgrowth, we have examined imprinted gene expression in both mice cloned by nuclear t ransfer and in the embryonic stem (ES) cell donor populations from which th ey were derived. The epigenetic state of the ES cell genome was found to be extremely unstable. Similarly, variation in imprinted gene expression was observed in most cloned mice, even in those derived from ES cells of the sa me subclone. Many of the animals survived to adulthood despite widespread g ene dysregulation, indicating that mammalian development may be rather tole rant to epigenetic aberrations of the genome. These data imply that even ap parently normal cloned animals may have subtle abnormalities in gene expres sion.